Medical Milestones Celebrating Key Advances Since 1840

Medical Milestones Celebrating key advances since 1840

Publication of this online supplement is made possible by an educational grant from AstraZeneca

medical milestones CONTENTS

The Editor BMJ 2 Milestones on the long road to knowledge BMA House, Fiona Godlee Tavistock Square London WC1H 9JR [email protected] Timeline T + 44 (0)20 7387 4499 F + 44 (0)20 7383 6418 4 Let’s pension off the major breakthrough Geoff Watts BMA members inquiries [email protected] 5 anaesthesia Symbol of humanitarianism 020 7383 6955 Stephanie J Snow Reprints 6 antibiotics The epitome of a wonder drug [email protected] Robert Bud 020 8346 1339 For “Who is Who” at the BMJ chlorpromazine see bmj.com/contacts 7 Unlocking psychosis Trevor Turner ©BMJ Publishing Group Ltd 2007 All Rights Reserved. 8 computers Transcending our limits No part of this publication may be reproduced, stored in a Alejandro R Jadad, Murray W Enkin retrieval system, or transmitted in any form or by any other 9 discovery of dna structure The best is yet to come means,electronic, mechanical, photocopying, recording, John Burn or otherwise, without prior permission, in writing, of the BMJ. 10 evidence based medicine Increasing, not dictating, choice Printed by Precision Colour Printing Limited. Kay Dickersin, Sharon E Straus, Lisa A Bero 11 germ theory Invisible killers revealed ISSN 0959-8138 Harry Burns BMJ January 2007; 334 (suppl):s1-22 12 imaging Revealing the world within This commemorative supplement Adrian M K Thomas, John Pickstone was edited by Mabel Chew and Karl Sharrock and designed by Jane Walker. The 13 immunology Making magic bullets pictures editor was Jan Croot. D Michael Kemeny, Paul A MacAry

14 oral rehydration therapy The simple solution for saving lives Olivier Fontaine, Paul Garner, M K Bhan 15 the pill Emblem of liberation Carl Djerassi

16 risks of smoking All done and dusted Simon Chapman 17 sanitation Pragmatism works Johan P Mackenbach Longer versions of articles, including 18 tissue culture Solving the mysteries of viruses references, are available Yvonne Cossart on the new look BMJ website, which now has 19 vaccines Conquering untreatable diseases better navigation and Michael Worboys more opportunities for interaction. Find it all at 20 I’ve got a little list bmj.com Jeffrey P Koplan

MEDICAL MILESTONES | BMJ | jANUARY 2007 | volume 334 s1 medical milestones foreword

Some of the 15 may surprise you. Does it make sense to give milestone status to evidence Milestones on the long based medicine? Perhaps it says something about the culture of medicine that an effort to systematise our relation with science should have proved so controversial. As Kay Dickersin road to knowledge and colleagues say (p s10), how can something so intuitively obvious to lay people—the need to Fiona Godlee make decisions on the best available evidence— not be similarly viewed by clinicians? You’ll also no doubt find omissions. Jeffrey Koplan finds Seeking a way to mark the launch of the new journey—and these 15 accounts are all good several when he compared our list with one he BMJ, we hit on the idea of looking back at the stories. They combine all the elements of good initiated for the US Centers for Disease Control most important medical milestones since the fiction: serendipity in the discovery of penicillin and Prevention eight years ago (p s20). I’ve forerunner of the BMJ was first published in (p s6) and x rays (p s12); sheer determination found some too. Where are aspirin, Helicobacter 1840. We asked readers to nominate milestones, in the development of tissue culture (p s18); pylori, and Medline? which you did in good numbers. A panel of raw personal ambition—the emergence of But which of these 15—all extraordinary editors and advisers narrowed the field down ether as an anaesthetic owed much to one medical advances—will come out top? By the from more than 70 to 15. We invited champions dentist’s desire to advance his position (p time this supplement is printed, a winner will to write on each one; their contributions make s5); competition in the publication race over have been chosen by BMJ readers in an online up this commemorative supplement. chlorpromazine (p s7); drama in turning off the poll (see bmj.com). In terms of number of lives Medicine is about stories—the patient’s Broad Street pump (p s17); and tragedy in the saved, vaccines (p s19) seem hard to beat; if account, the doctor’s interpretation, the death of a friend, which led Semmelweis to his it’s societal consequences, then the pill might detective work of diagnosis, the research discovery (p s11). be the winner. (As Carl Djerassi points out

Richard Doll and Edwin Chadwick Austin Bradford publishes his In the US census a punch card Hill and Ernst Report on the Wynder and Sanitary Condition tabulator is used, Francis Crick Ilya Ilyich Alexander Evarts Graham of the Labouring invented by and James Mechnikov and Fleming 4560 RP, later called publish first Population of Herman Hollerith, Watson publish Paul Ehrlich are discovers chlorpromazine, is reports linking Carl Djerassi and Great Britain, whose company Ross Harrison their paper awarded Nobel penicillin in a synthesised by the tobacco and lung colleagues (from affirming Louis Pasteur later becomes IBM publishes paper proposing the prize for mould chemist Paul cancer the Mexican Archie Cochrane importance of establishes his on new tissue double helix medicine for Daniel Darrow Charpentier of the drug company publishes environmental germ theory: culture technique, structure of their work on advocates oral Rhône-Poulenc Syntex) Effectiveness and conditions to infection is a method DNA immunity and intravenous company synthesise the Efficiency: Random health caused by living improved on that rehydration first oral Reflections on organisms not by 1890 year by Alexis solutions to treat progestogen, Health Services, on “spontaneous Carrel and 1929 Ether first Wilhelm infantile norethindrone the importance of generation” Montrose used as an Röntgen 1908 diarrhoea 1950 1953 using evidence to anaesthetic, Burrows, who provide equitable Louis Pasteur discovers by Crawford used mammalian health care 1842 develops a x rays Long cells rabies vaccine 1949 1950 1972 1842 1862 1885 1910 1951 1895

1837 1840 1853 1854 1901 1914 1939 1952 1999 King William IV First issue of the Crimean war John Snow closes Queen Victoria dies, First world war Second world war George VI dies, World population dies, succeeded by Provincial Medical begins (ends London’s Broad succeeded by begins (ends begins (ends 1945) succeeded by reaches six billion Victoria Shouldand Surgical we have1856) a picStreet water here? pump Edward VII 1918) Elizabeth II Journal, the BMJ's to prevent spread precursor of cholera A BRIEF TIMELINE

s2 MEDICAL MILESTONES | BMJ | jANUARY 2007 | volume 334 medical milestones timeline

We can’t rely on the chance as Simon Chapman confidently asserts, “all career structures in research, and encourages done and dusted” (p s16), but can we share commercial investment while protecting against arrival of genius in our midst to his confidence that the end game for smoking the erosive influence of vested interest. may be just 20 years away? And will we have Knowledge and its implementation also take us forward to the next era the wisdom that Jadad and Enkin believe is need effective channels for communication. of discovery necessary to ensure that computers help us The BMJ has played a direct part in at least one to transcend all our boundaries rather than of these advances and born witness to all of (p s15), there’s no need to ask which pill, so contributing to our extinction? them. Now the new BMJ provides an even better enough said, perhaps.) Alex Jadad and Murray Finally, what do these stories tell us about how (and better looking) communication channel—a Enkin sweep up the whole history of human medicine advances? The image of researcher as space in print and online where researchers intelligence in their enthusiasm for the role of hero is compelling and central to many of these and clinicians can meet, where they can share computers in medical advance (p s8). How can stories. But as Geoff Watts says (p s4), a fixation what they have experienced, thought, or found humble oral rehydration therapy (p s14), the with breakthroughs skews the picture of how and where others can confirm, refute, build on, simple addition of salt and sugar to clean water, science really progresses: “Knowledge doesn’t reject, or implement their findings. The new compete with that? At least on the grounds of suddenly appear in neat and tidy quanta. Like BMJ will save you time and effort by covering cost effectiveness it can. patches of lichen spreading over a rock face, the important developments in medicine. It What can these 15 milestones tell us of it accretes over decades.” It follows that we will present the evidence based certainties medicine’s future prospects? Will genetics can’t rely on the chance arrival of genius in where they exist and the controversies and deliver on its promise of real clinical benefit? our midst to take us forward to the next era of debate where these are needed. Our aim is to John Burn says that the best is yet to come (p discovery. Knowledge and its implementation create a journal that helps doctors make better s9). The same might be said of monoclonal need an infrastructure that supports applied decisions—whether in clinical practice, public antibody technology: will it deliver vaccines and as well as basic research, encourages the health, policy making, or research—to improve safer treatments for chronic illness (p s13)? Our systematic implementation of what we already the future care of patients. understanding of the risks of smoking may be, know, nurtures young talent by creating Fiona Godlee, editor, BMJ

1837 1840 1853 1854 1901 1914 1939 1952 1999 King William IV First issue of the Crimean war John Snow closes Queen Victoria dies, First world war Second world war George VI dies, World population dies, succeeded by Provincial Medical begins (ends London’s Broad succeeded by begins (ends begins (ends 1945) succeeded by reaches six billion Victoria and Surgical 1856) Street water pump Edward VII 1918) Elizabeth II Journal, the BMJ's to prevent spread precursor of cholera A BRIEF TIMELINE

MEDICAL MILESTONES | BMJ | jANUARY 2007 | volume 334 s3 medical milestones introduction olland. olland. h any mp o C

Let’s pension off the er h sc E

Look, I know we all love lists, competitions, Comroe and Dripps then showed that these prizes, and so on and that choosing the Knowledge doesn’t 10 advances were, between them, founded top 15 milestones in medicine is just a suddenly appear in neat on what they described as 137 “bodies bit of fun. But, like the artistic and literary of knowledge.” Over several years they types who get sniffy about the Turner prize and tidy quanta. Like tracked down 2500 scientific reports that for art and the Orange prize for fiction, I’m patches of lichen spreading had played a major part in the development going to be po-faced and argue that in one of these bodies of knowledge. respect this enterprise is not only daft but across a rock face, it One of the 137 is the development damaging. of electrocardiography. As Comroe and It plays to the “breakthrough” view accretes over decades Dripps say, “Some might consider that of science: a wholly misguided notion [Willem] Einthoven in 1903 invented the that seeks to portray science as a kind of ECG [electrocardiograph] in its 1976 form intellectual trawler. Under the guidance of without help from those who preceded its steersmen—the elite scientists high up or followed him.” Their survey paints a on the bridge—the vessel charts a steady research to be common in the future. If different picture. They discovered that well and calculated course across our sea of they should arise they can be accepted as over 40 published reports had played an ignorance. Triumphant figures call down bonuses, but need not be expected.” Isn’t essential part in permitting the creation periodically to report that they have fished this a bit wide of the mark? and refinement of electrocardiography. The out another drifting barrel of knowledge One man who did understand the first of these reports dated from 1660; the and have drunk of the wisdom discovered fitful and faltering progress of science last appeared in 1967. therein. When what’s found in the barrel is was Arthur Koestler. By charting the Their comment is as germane now as it deemed exceptionally valuable—a “major history of astronomy, with all its errors, was 30 years ago: “We believe that a major breakthrough”—the crew members win misapprehensions, blind alleys, and defect in education in science in high medals. perpetual shuffling between faith and school and colleges is the perpetuation In reality there is not one vessel but reason, he exposed its true nature. of the one person=one discovery myth . . . many; not one course but a thousand. He titled his magisterial account of Marconi=wireless; Edison=electric light.” And the information in the barrels often our changing view of the universe The While we’re waiting for action on that bears less resemblance to an illuminating Sleepwalkers. The evidence is clear: there front, how about a simple experiment? Try draught of fine wine than to a small and never has been a road map. entering the phrase “major breakthrough” bewildering cloud of fog. Which should be One of the most striking illustrations into the Google search engine along with no surprise because, in truth, knowledge of the piecemeal accumulation of the word “medicine.” On the day I tried doesn’t suddenly appear in neat and tidy knowledge in science is the byproduct it I got 309000 hits. With so many major quanta. Like patches of lichen spreading of a painstaking but largely forgotten breakthroughs it’s really rather difficult across a rock face, it accretes over decades. 1976 study by Julius Comroe and Robert to understand why there are any medical Even medical research’s brightest aren’t Dripps of the Universities of California and problems left to solve. always fully aware of the significance or Pennsylvania. Using as an example the So here’s a modest but constructive meaning of what they’re engaged in. A medical conditions most familiar to them— proposal for starting to bring a little sometime colleague at the BBC World cardiovascular and pulmonary disease— more realism to the discussion of new Service, a reporter, used to say that César they set out to show how clinical advances developments in medicine and medical Milstein didn’t twig the likely practical are often built on work that, at the time it research. Whether we’re doctors or impact of monoclonal antibodies until was done, had no clinical application in scientists, editors or reporters, let’s all questioned about it by that reporter. As both mind. take a vow: to be parsimonious in our use men are now dead the claim is difficult to Their intention was to make a case of the term “medical milestone”—and verify. for more spending on basic research. To to abandon entirely the words “major But we do know for a fact what the demonstrate the value of research they breakthrough.” Let this clichéd old soldier Nobel prize winning immunologist Frank systematically traced the sources of the be pensioned off for good. Macfarlane Burnet wrote 35 years ago about knowledge underpinning 10 key advances Right, got that off my chest. Now, back to research in cell and molecular biology: made over the previous 30 years: the drug that top 15. “I do not expect conventional benefits to treatment of hypertension, for example, medicine or technology from biological and the development of cardiac surgery. Geoff Watts, freelance medical journalist, London

s4 MEDICAL MILESTONES | BMJ | jANUARY 2007 | volume 334 medical milestones anaesthesia BAL cotland/ S

ibrary, Symbol of humanitarianism L Stephanie J Snow niversity U h In the 19th century anaesthesia was heralded as a civilising factor of the

dinburg Western world. In the 21st century, anaesthetics continue to evolve and are E James Young Simpson’s chloroform bottle the most vivid examplar of medicine’s capacity to lessen suffering

n the anaesthesia room I stroke my 6 demonstrating its effects at the Massachu- It is hard to overstate the extent to which year old daughter’s hair and watch the setts General Hospital in October 1846 is anaesthesia revolutionised the experience of liquid enter her veins through the can- due partly to serendipity (the ether worked surgery for patients and surgeons, although nula. A large yawn, closed eyelids, and and did not cause asphyxia) and partly to it remained a selective practice until the a lolling head signal the shutdown of Morton’s great ambition to expand his den- 1860s. It also reconfigured surgical practice: Iher conscious self. After her fractured elbow tal business with a method of numbing the patients were far more willing to be operated has been repaired, she wakes, remembering pain of teeth extraction. Within six months on for small injuries, and thus operations nothing except the prick of the needle. To news of ether had spread worldwide. became more common. contemplate this happening without anaes- Anaesthesia became integrated into the The risk of haemorrhage and infection thesia is almost impossible. Today’s medical structures of 19th century science only continued to deter surgeons from operating interventions may produce discomfort, but when news of ether—the “Yankee dodge”— in the cavities of the body; nevertheless, it is rarely do they cause the intense pain that was reached doctors in London. Here John likely that anaesthesia was a strong stimulus once endured in operations before anaes- Snow, a young general practitioner (who for developing methods to diminish infec- thesia. The discovery of a method to allevi- later achieved fame with his theory of chol- tion. Pain in childbirth too was alleviated ate pain during operations is rightly regarded era transmission), was among the first to wit- by anaesthesia, and Snow’s administration of as a landmark in the history of medicine. ness the use of ether for a tooth extraction chloroform to Queen Victoria for the births By the early 1840s successive cultural and and was captivated by the gas’s power to of Prince Leopold in 1853 and Princess Bea- medical changes had resulted in a view of produce “quietude” in patients. But, unlike trice in 1857 effectively silenced the debate physical pain as purposeless. Doctors had others, Snow did not rush to treat patients. on its risks in labour. become the masters of pain relief, and the Instead he began chemical and physiological rapid growth in consumption of opiates in experiments to establish the parameters of A civilising factor Britain from the 1780s indicates that patients the new technique and developed an inhaler By the end of the 19th century anaesthesia welcomed use of the drugs to palliate the that took into account the relation between had become a symbol for the wider humani- pain of chronic disease, death, and child- temperature and “strength” of ether vapour. tarian movement. It was proclaimed as one birth. But the pain of operations remained, In just six months Snow had described the of the civilising factors of the Western world despite attempts to circumvent it. Alcohol different degrees of anaesthesia that marked and remains the most vivid example of med- and opiates were used during operations, ether’s sequential suspension of conscious- icine’s capacity to diminish human suffer- but too much of these depressed the body’s ness and volition. Snow’s continuing standing. In different circumstances anaesthesia systems and exacerbated the dangers of ing among 21st century anaesthetists shows may well have emerged in a different form. surgery. At the same time surgeons began how impressively he secured ether within Mesmeric anaesthesia, although rejected to approach surgery differently. Rather scientific bodies of knowledge. by the London medical elite as quackery than amputations, they excised diseased or Snow mastered the intricacies of ether, in the early 1840s, was successful in India. injured tissue and bone; new operations for but other doctors struggled. Ether’s irritant But a world entirely without anaesthesia is cataract, stammering, squinting, and club qualities made it difficult to breathe, and unimaginable. foot were recorded in the Lancet. But more ill designed inhalers that gave too little of Anaesthesia continued to develop in the complex operations increased the duration the vapour stimulated rather than subdued 20th century: muscle relaxants and tech- of surgery and thus the duration of suffering. patients. Victorian society prided itself on niques such as spinal anaesthesia brought Few patients consented to operations unless self control and fortitude, so the spectacle new benefits; anaesthetists extended their absolutely necessary. of wriggling and riotous bodies clashed practice to intensive care and the manage- with social mores. Anaesthesia might have ment of chronic pain; and new inhaled and The Yankee dodge remained on the margins of medicine had it intravenous anaesthetic agents facilitated the Some pioneers carried out experiments not been for the introduction of chloroform development of day case surgery. The detail with nitrous oxide and ether to suspend by the Scottish obstetrician James Young of anaesthesia will surely continue to evolve. consciousness—for example, the physician Simpson in 1847. Simpson discovered chlo- But nothing is likely to be as significant as Crawford Long and the dentist Horace Wells roform by chance when testing a number of the early demonstrations of ether’s potential in the United States. But these experiments volatile fluids in the hope of finding one that to alleviate the pain of surgery. gained little recognition, because breath- was easier to breathe than ether. Chloroform ing gas carried the danger of asphyxia and, was less irritating to the lungs and produced Stephanie J Snow, research associate ultimately, death. That William Morton suc- unconsciousness swiftly. It immediately Centre for the History of Science, Technology and ceeded in establishing the use of ether by replaced ether. Medicine, University of Manchester

MEDICAL MILESTONES | BMJ | jANUARY 2007 | volume 334 s5 medical milestones antibiotics BAL

The epitome of a wonder drug ibrary/ L Robert Bud niversity U

The discovery of antibiotics not only heralded a dramatically new approach h

to infection control and health care but also enabled nations to prosper and dinburg E overturned the concept of health as a moral duty A penicillin mould presented by Alexander Fleming

ntibiotics can truly be considered just from infected wounds but also from the the drugs was not great by later standards. the epitome of the 20th century’s effects of sexually transmitted diseases. Com- The broader category of antibiotics soon “wonder drugs.” This term was pared with the previous long and risky treat- developed. Their name had been claimed widely used in the 1950s, express- ment for syphilis, penicillin provided a swift as early as 1942, when—following quickly ing the enthusiasm of patients, and effective cure. This would prove a critical on the isolation of penicillin—other new Adoctors, and policy makers for drugs that benefit in Europe during the early postwar antibacterial drugs were derived from fungi transformed once mortally feared bacterial years, when a syphilis epidemic threatened and streptomyces. Selman Waksman, a soil infections into curable conditions. the occupying armies and the impoverished microbiologist at Rutgers University, chose Penicillin is the iconic antibiotic. Its intro- former Axis countries alike. Syphilis might the word to describe those substances “inhib- duction into clinical practice was widely then have proved the threat to Europe that iting the growth or the metabolic activities celebrated and was the culmination of indi- AIDS would later pose in Africa, but penicil- of bacteria and other micro-organisms by a vidual achievements, long running trends in lin stopped the epidemic decisively. chemical substance of microbial origin.” science, and a supportive environment. In However, antibiotics had wider conse- 1929 Alexander Fleming, at St Mary’s Hos- quences than strictly medical ones. The new Genomic advances pital Medical School in London, reported drugs underpinned a surge in the use of health Antibiotics developed rapidly after the sec- his observation that the culture medium services in the postwar years. Fast throughput ond world war, but since the early 1960s few on which a penicillium mould had grown in general practice was possible because anti- fundamentally new families of antibiotics attacked certain bacteria. However, chem- biotics could be swiftly administered or pre- have been introduced, and at the beginning ists and bacteriologists, then working largely scribed after a short consultation. Surgeons of the 21st century 14 million people a year separately, failed to isolate the active sub- undertook more complex operations on die of infectious disease. From the mid-1990s stance in the mould juice. Only in 1940 was patients now protected from infection. multiply resistant staphylococci and resistant the isolation achieved, at Oxford, where Even more profound were the moral pneumococci have caused widespread anxiety Howard Florey had created a multidisci- consequences of the use of the drugs. Until across a world that seemed at imminent risk plinary team. The team’s efforts were sus- the mid-1930s prevention rather than cure of the emergence of bacteria that were resist- tained by the interest and talent of, among had been the general means of control of ant to all known antibiotics. Resistance has others, Ernst Chain, a German refugee, and most infections. Injunctions to the healthy become a public health issue worldwide. Norman Heatley, who developed key tech- were complemented by a moral disdain for The contemporaneous emergence of niques for growing the mould and isolating those who lapsed and then succumbed to genomics gave rise, initially, to the prospect the drug. But the financial support of the disease. The introduction of antibiotics in of the selection of many completely new Rockefeller Foundation in the United States the 1940s converted illness into a strictly antibiotics through a series of new technolo- and the Medical Research Council in the technical problem. In richer countries the gies. The sequencing of bacterial genomes, United Kingdom was also crucial, as were avoidance of “germs” gradually ceased to understanding of the molecular basis of the need created by the outbreak of war be a duty. The immunologist Frank Mac- pathogenicity and protein expression, and and the remarkable properties of penicillin farlane Burnet expressed a then widespread combinatorial chemistry would, it was itself. This confluence of factors led rapidly (if eventually misplaced) hope in his Natu- hoped, generate huge libraries of potential to laboratory scale production and the dem- ral History of Infectious Disease (1953) that the agents for screening. Such advances have onstration of penicillin’s clinical potential. mid-20th century represented a revolution not yet yielded large numbers of new drugs, in human history—the “virtual elimination and the popularity of antibacterial vaccines Cheap production, mass protection of infectious disease as a significant factor to combat such diseases as pneumonia has When British industry, under the pressure of in social life.” once again emphasised prevention rather German bombing and with little experience in Undoubtedly, other factors also drove the than cure. Two generations after the intro- sterile fermentation, failed to take up penicillin transition in the health of richer nations. Bet- duction of antibiotics can we see—in the with enthusiasm, Florey and Heatley flew to ter nutrition and housing were among the renewed concern for cleanliness in hospitals the US to seek help. There they found exper- most important, but there were also techno- and greater reluctance to use antibiotics in tise in chemical production by fermentation logical innovations. The synthetic sulphona- the community—the revival of the hygienic and in growing organisms in deep tanks, even mides, developed in the 1930s, predated the and perhaps even the moral disciplines that aerobic ones. This expertise made cheap mass antibiotics derived from natural organisms, predated the antibiotic revolution? production possible. but bacteria quickly developed resistance From the time of the Allies’ invasion of to them. Also, many people suffered severe Robert Bud, principal curator of medicine Italy, soldiers were protected by penicillin not side effects, and the spectrum of action of Science Museum, London

s6 MEDICAL MILESTONES | BMJ | jANUARY 2007 | volume 334 BAL medical milestones chlorpromazine taly/ I enice, V a’ Pesaro, a’ C Unlocking psychosis Trevor Turner rteModerna di A The discovery of chlorpromazine ushered in a radically changed biological and psychosocial psychiatry that saw an end to the neglect and desperate Museod’ The Madhouse (1865) by Telemaco Signorini remedies of the asylums

he sights, sounds, and smells of Within three weeks he had largely settled. But the demeaning nature of the tasks required. untreated psychosis linger down he had also been given ECT, an analgesic, The modern emphasis on users and their the ages, from Shakespeare’s Mad and a barbiturate, so was this a specific effect carers would have been impossible, given Tom in King Lear to the screaming of chlorpromazine? the inarticulacy of the patients, locked in inmates of the forbidding New York Several trials began, but it was Pierre their mutism and word salads, and the revul- Tmental hospital in Anatole Litvak’s The Snake Deniker and his assistant Jean Delay, at St sion and despair of the carers. Pit, 1948’s most shocking cinema event. In Anne Hospital in Paris, who won the pub- his Experiences of an Asylum Doctor of 1921, lication race. They treated 38 psychotic A psychic penicillin the retired general practitioner Montague patients with injections of between 75 mg The lifetime prevalence of psychoses (schizo- Lomax described the “lunatics in the refrac- and 150 mg a day of chlorpromazine, pub- phrenias and severe bipolar disorders) is about tory ward of our public asylums. Bestialised, lishing their findings in the Annales Médico- 2% to 3% worldwide. Their effects are pro- apathetic, mutinous, greedy, malevolent … Psychologiques in 1952. Describing the events longed, incapacitating (in terms of self neglect their habits quarrelsome and filthy, their per- in 1970, Deniker commented on the limited and social unacceptability), and even fatal, sons dirty and malodorous.” The carefully information about the drug and the “sudden, with 10% or more of patients committing sui- controlled therapeutic aridity of the ever great interest of the nursing personnel,” who cide. It is hard not to see chlor-promazine as enlarging lunatic asylum system was the were usually “reserved about innovation.” a kind of psychic penicillin, enabling patient institutional response: museums of madness The wards were transformed, “aggressive- and carer to communicate and transforming with their collections of certified inmates. ness and delusive conditions of schizo- our understanding of human function—neu- Yet by the 1940s university research phrenia improved,” and contact with the ropsychologically, interpersonally, and in departments and entrepreneurial drug patients re-established. evolutionary terms (as the gene mutation companies were busily synthesising new By 1954 chlorpromazine had been actively for big forebrains probably carries the risk compounds. By 1926 acetylcholine was used and researched in double blind trials of psychosis). Importantly, modern psychop- known to be a neurotransmitter; in 1937 in Canada, the United Kingdom, and the harmacology dynamically reflects brain func- the anti-histamines were discovered and in United States, although diehard US psycho- tion, enabling non-moralistic assessment of 1943 LSD. Psychiatry and its patients—stig- analysts continued to consider it no substitute emotions and judgments. matised, dangerous, some psychoanalysed, for “analytically orientated psychotherapy.” Every clinician longs for more effective, but mostly hopeless—were receiving new Because of the drug’s combination of effects ever safer treatment, whether it be anti-psy- physical treatments, such as insulin coma (and side effects), by 1955 its French research- chotic, antidepressant, anxiolytic, or antibi- therapy, electroconvulsive therapy (ECT), ers decided to call it a neuroleptic (“taking otic. But the holy grail of psychiatric research and leucotomy. Sedatives such as bromides, hold of the neuron”). From 1956 the num- probably remains the definitive test or scan barbiturates, and paraldehyde were avail- bers of inmates in UK asylums began to fall that will crack the diagnosis and link psy- able, the last overused for “the noisy and dramatically, and over the next few years chiatry to scientific medicine. However, troublesome patient.” From the phenothi- antidepressants and antipsychotics arrived en genetic markers such as those postulated azine group of the antihistamines, the drug masse. A new world of a truly biological as for schizophrenia tend to attract life insur- 4560 RP, later called chlorpromazine, was well as psychosocial psychiatry had begun. ance salesmen and notions of eugenics; synthesised in 1950 by Paul Charpentier, a Without the discovery of drugs such as patients prefer being talked to rather than chemist with Laboratoires Rhône-Poulenc. chlorpromazine we might still have the mis- scanned; and clinical skills can become lost in erable confinements witnessed by Montague technology. The rise of psychopharmacology Lomax—a world of desperate remedies. Yet if the progress initiated by the dis- A French surgeon, Henri Laborit, had begun Then the attendant’s role was akin to a zoo- covery of chlorpromazine means that we experimenting with antihistamines in 1949, keeper’s: feeding, scrubbing, and forcibly can replace baggy words like depression to aid anaesthesia when operating on soldiers treating hundreds of “demented” patients. with psychobiological descriptions like in shock, and he noted how some patients The psychiatric workforce was largely cut off monoamine deficiency syndrome, or para- became obviously calmer. On moving to from surgical and physician colleagues, was noid schizophrenia with temporal lobe Paris he asked for the new 4560 RP, hoping it of poor quality, and was readily mocked. hyperdopaminergia, we may yet eradicate would enhance autonomic blockade, and on Ernest Jones, Freud’s biographer, remem- the monsters of stigma and neglect that still 19 January 1952 a 24 year old man who had bered jokes about psychiatrists discussing beset mentally ill people. mania was injected with chlorpromazine. The “varieties of Chubb lock” at their meetings. report of the experiment described how he Our modern, multiskilled mental health Trevor Turner, consultant psychiatrist lay calm for several hours with his eyes shut. workforce might never have emerged from Homerton Hospital, London

MEDICAL MILESTONES | BMJ | jANUARY 2007 | volume 334 s7 medical milestones computers ages Im etty

Transcending our limits G ee/ m a

Alejandro R Jadad, Murray W Enkin N

oto by WinMcby oto

By transcending physical, geographical, and cultural barriers computer h P technology can help achieve optimal health for all Claudia Mitchell, recipient of a “bionic arm”

he capacity to compute is at least as improvement and its unparalleled parallel reinforced by the defeat of the best human old as life itself. It has been driven processing capacity it began building tools to at chess by a computer, the advent of pilot- for billions of years by organic enhance itself. We created external devices less aircraft and spaceships, the emergence software encoded in elaborate that exponentially increased our ability to of robots able to perform surgery without sequences of base pairings embed- calculate, analyse, and learn. human intervention, and the creation of pros- Tded in DNA. Thanks to this biological com- It took us two millennia to jump from thetic limbs that can be operated mentally. puting system, nature was able to explode the Babylonian abacus to the mechanical Apocalyptics believe that what we call into a diverse community of living things as eight digit calculator that Pascal built in the civilisation is nothing more than a dead end simple as prions and as complex as humans— Enlightenment. After only two centuries trap, leading to human extinction. Current creatures armed with deliberative computers, Charles Babbage envisaged a massive, steam trends in climate change and environmental their brains. powered mechanical calculator designed to degradation, the raised threat of nuclear con- The hominid brain continued to evolve print astronomical tables. Less than a cen- flict, the prospect of devastating pandemics, over hundreds of thousands of years, gain- tury later Alan Turing created Colossus, an and the unmanageable burden of poverty, ing increasing layers of interconnecting neu- electronic computer that helped end a war chronic diseases, and ageing are strong sig- rones. This complex interconnectivity gave plagued by our self destructive drive and nals that the arrival of the four horsemen of us the ability to recognise our limitations power. the Apocalypse may not be far off. and our mortality and set us on an inexora- Over only decades in the second half of ble quest to overcome them. the 20th century we developed powerful Humanodes in the global superorganism resources to communicate and exchange But extrapolation does not acknowledge the A perpetual overcoming unlimited amounts of knowledge, almost complexity of evolution. A more exciting sce- Since the Stone Age we have evaluated, anywhere and at any time. We created a nario may be unfolding, in which the future is interpreted, calculated, and computed. As global network of computers able to decode not predetermined by immutable forces but we observed the effects of our primitive the genome; machines capable of seeing our shaped by our values, our interactions, and interventions we tried, tried again, and mod- body and its functions in three dimensions; our will to survive as autonomously as pos- ified our technology. Our legs could take us tools to track and control diseases remotely. sible against all odds. only so far, until we extended their reach Computers started to change the way we The 21st century computer age gives us the through increasingly sophisticated means learn, live, communicate, and heal. opportunity to create a “noosphere,” a true of transportation–technology that took us Nevertheless, the effect of computers on planetary thinking network with individual across land and sea and through the air. the delivery of health services, even in rich but interdependent humans as its nodes. We overcame the limits of our visual acuity countries, was not obvious. By the end of the The exponential development of wireless with lenses, opening new vistas of the heav- century most people still lacked electronic networks, mobile computing tools, and the ens and the microcosm. Our clinical gaze health records, and few health profession- internet may already be giving us a glimpse of was augmented by new understandings of als used email or even the phone as part of a future in which we could work as “human- anatomy, physiology, and pathology. New their clinical communication. Most budgets odes” in a true global superorganism. tools, such as the stethoscope, radiography, targeted the control or treatment of diseases, Computer technology can help us achieve and anaesthesia, let us listen to and see into rather than prevention or health promo- optimal levels of health and wellbeing the human body and tinker with it. tion. Collaboration across institutional or regardless of who or where we are. It can Inevitably, we moved beyond augment- geographical boundaries was almost non- help us transcend our cognitive, physical, ing our limbs and our sense organs. Our existent. In deprived areas of the world com- institutional, geographical, cultural, linguis- powerful brain began to realise its own puters had little effect on perinatal mortality, tic, and historical boundaries. Or it can con- limitations. With its insatiable urge for self major infectious diseases, or access to clean tribute to our extinction. We believe that the water. choice is ours. We hope that we choose, not just with information, not just with knowl- Computer technology can Twenty first century visions edge, but with wisdom. help us achieve optimal Extrapolations of 20th century trends into 21st century visions are not optimistic. Trans- Alejandro R Jadad, chair, professor, and founder levels of health and wellbeing humanists believe that our role will be over Murray W Enkin, emeritus professor regardless of who or when our brains create intelligent machines Centre for Global eHealth Innovation, that will continue the exponential pace of University Health Network, and University of where we are evolution for ever. Their views have been Toronto, Toronto

s8 MEDICAL MILESTONES | BMJ | jANUARY 2007 | volume 334 medical milestones DISCOVERY OF dna structure

The best is yet to come INSTITUTE John Burn CANCER

Watson and Crick’s discovery of the structure of DNA has opened up a NATIONAL DNA analysis is nowimportant in many specialties world of possibilities in new treatments

f the competition to determine the 15 inheritance in 1866 and Archibald Garrod’s unconvinced: all these promising develop- greatest medical milestones was judged recognition in 1923 that alkaptonuria fol- ments sound like “jam tomorrow.” Yet it on the basis of international recognition, lowed the same principles of genetic trans- is too easy to miss the significance of such then DNA, the ultimate in three letter mission. Geneticists were able to make great developments in many fields. After severe acronyms, would easily win the prize. advances before the discovery of the double acute respiratory syndrome hit the head- IIndeed, as the greatest scientific discovery of helix, not least Karl Landsteiner’s recognition lines around the world, no one expressed the past millennium, the elucidation of the of blood groups in 1909; but as late as 1952 surprise when the nature of the infectious structure of DNA would rank very highly, leaders in research had no idea how genes agent was published in a matter of weeks, if not first. Surely, then, a competition that worked. It was Watson and Crick’s recogni- a critical step that depended completely on focuses on 166 years of medicine would be a tion, at a stroke, of the digital basis of genetic the ability to analyse DNA. Virology and pushover—or perhaps not. For the effects of information and the mechanism of inherit- bacteriology have now embraced analytical the discovery of the structure of DNA have ance that opened the floodgates to further techniques that are based on DNA testing yet to reach their peak. Once they have, the discoveries. The most dramatic evidence of with an enthusiasm equivalent to that seen case for DNA will be unanswerably strong. that flood of research is the human genome in forensic science. In most developed coun- It is appropriate that I declare an interest. project, humanity’s biggest research endeav- tries every newborn baby is screened for the My interest in becoming a clinical geneti- our, which has permitted ever more rapid genetic condition phenylketonuria, and all cist was sparked by the excitement of hav- progress in linking variants in the sequences surgical patients have their blood group ana- ing the code of DNA explained to my sixth of genes to thousands of genetic disorders. lysed—more examples of how genetic sci- form biology class by a visiting scientist. A ence can reach the whole population without similarly revelatory moment occurred much Gene testing for everyone being recognised as “genetics.” later when I took my daughter, who was kill- Genetic disorders are collectively a major ing time between her university interviews health problem in the developed world, but Leaping into the future at Cambridge in 1994, to see the tiny brass even in these countries many doctors are But the best is yet to come. Human factor plaque “celebrating” the 1953 discovery of liable to think DNA means “Did Not Attend.” VIII, used in the treatment of haemophilia, the double helix in what is now a bike shed Technology has not yet caught up with our and human insulin will be followed by any As we marvelled at this manifestation of aspirations, and sequencing is slow and expen- number of human gene products whose typical British understatement, our conver- sive. However, this is changing as “array” manufacture will have its origins in that first sation turned to the imminent impact of the technology and “lab on a chip” devices begin report of the double helix. From hepatitis human genome project and, the next day, to to allow low cost, high throughput genetic B vaccine to trastuzumab (Herceptin), an a proposal that led to the successful effort to testing. Meanwhile, large scale projects such understanding of DNA permeates all sorts create the millennium landmark Centre for as UK Biobank will permit prospective stud- of developments in treatment. When the Life in Newcastle, which brings the wonders ies that will link genetic predisposition to out- first patients are treated with a new stem cell of DNA to visitors as well as being a centre for come in common diseases. treatment, few will note that treatment’s criti- teaching, research, and genetic medicine. Already we are seeing breakthroughs in cal dependence on our ability to unravel the common diseases such as eczema and inflam- genetics of early human development and Our biggest research project matory bowel disease. Mutations in the gene to manipulate the genetic control of tissue It is easy, in retrospect, to regard that 1953 coding for filaggrin, a protein that binds to differentiation. discovery by our centre’s patrons, Jim Watson keratin in skin cells, and in the CARD15 Zhou Enlai, first premier of the People’s and the late Francis Crick, as but a minor gene sequence are responsible, respectively, Republic of China, is reported to have said, step along the road from Gregor Mendel’s for a significant proportion of predisposition when asked to give his opinion of the French discovery of the principles of single gene to these diseases and affect up to one in 10 revolution, that “it is too soon to say.” Some people in each case. More importantly, such might make a similar argument in the case discoveries expose the relevant pathogenic of DNA. Such scepticism will risk ridicule in The most dramatic evidence pathways. New interventions that focus on years to come. The evidence already before of that flood of research is epidermal permeability in eczema and on us is dramatic, but it is nothing compared recognition in the gut of bacterial cell walls with the tsunami to come. the human genome project, in inflammatory bowel disease are likely to be humanity’s biggest research more important than direct testing of patients John Burn, medical director and head of institute for DNA variation in the underlying genes. Institute of Human Genetics, Centre for Life, endeavour Practising clinicians will probably remain Newcastle upon Tyne

MEDICAL MILESTONES | BMJ | jANUARY 2007 | volume 334 s9 medical milestones evidence based medicine

Increasing, not dictating, choice Kay Dickersin, Sharon E Straus, Lisa A Bero

The systematic synthesis of evidence is the foundation of all medical discoveries and of good clinical practice Logo of the journal Evidence-Based Medicine

vidence based medicine is healthcare It is curious, even shocking, from 1982 to the present, the cost of treating practice that is based on integrating these patients would be 35% higher. knowledge gained from the best that the adjective “evidence available research evidence, clinical Making the evidence accessible expertise, and patients’ values and based” is needed What is the future for evidence based medi- Ecircumstances. It is curious, even shocking, cine? The biggest challenge will be getting all that the adjective “evidence based” is needed. to poor quality evidence instead of good clinicians, consumers, policy makers, and other The public must wonder on what basis medi- quality evidence stakeholders on board. We need to help the cal decisions are made otherwise. Is it intui- • Clinicians need information, and they naysayers to understand what evidence based tion? Magic? The public must also wonder don’t get enough from the sources they medicine is and what it isn’t. It seems obvi- what happens to the research evidence in typically use ous to say that we also need to seek evidence which they have invested—either directly • The medical literature is growing expo- that it is useful. The results of evidence based through taxes or indirectly through buying nentially, and there is not enough time medicine often clash with the agenda of spe- drugs and other medical products—if it is not in the day to read even the good stuff, cial interest groups. The challenges created by guiding clinical practice. and rich and powerful manufacturers of drugs and How could something so intuitively obvi- • Undesirable gaps and variation in prac- devices cannot be overemphasised. Not to be ous to lay people not be similarly viewed by tice exist. left behind, the industry is developing its own clinicians? And how could this medical mile- systematic reviews and making them public. stone be so misunderstood by some? Critics Imagine a world without evidence based We need to alert clinicians and patients to of evidence based medicine worry that it dic- medicine. Most women with early breast studies showing that reviews sponsored by the tates a single “right” way to practise, despite cancer would still be undergoing mastectomy industry almost always favour the sponsor’s differences among patients; that some self instead of lumpectomy and radiation. Now product, whereas those that aren’t sponsored appointed group of “experts” will declare they can choose. by such companies do not. We also need to only one type of study to be useful; or that Many babies born prematurely would still provide patients and the general public with healthcare decisions will be made solely on be dying from respiratory distress syndrome, the tools to enable them to understand and the basis of costs and cost savings. not having the advantage of a mother who evaluate systematic reviews. Finally, it is not Giving a name to evidence based medi- took corticosteroids or of being given sur- enough to create high quality, evidence based cine and, now, awarding it milestone sta- factant themselves. resources: we need to ensure global access to tus could help everyone to realise that it is Pregnant women in Boston might still be them. about making decisions that are based on taking diethylstilbestrol to prevent miscar- The question has moved beyond “Why the best available evidence, not dictating riage, on the enthusiastic recommendation of is evidence based medicine important?” to what clinicians do. well respected local experts, with the result “Why is it not already a reality?” and “How that many of their children would be develop- can we all work together to make it a reality, Establishing a modern milestone ing reproductive abnormalities and cancer. quickly?” Evidence based medicine is one The term “evidence based medicine” was A boy with asthma might have his treatment of our most important medical milestones coined in 1991 by a group at McMaster Uni- changed every six weeks as new drug samples because, without it, the other 14 of the BMJ’s versity, Ontario. It arose from a confluence are dropped off at his doctor’s surgery. The milestones would not have been imple- of events and changes in our culture. These choice of drug to help prevent a second frac- mented. included a growing recognition that: ture in an elderly woman might be made on • The systematic synthesis of all reliable the basis of television advertisements. Kay Dickersin, professor information on a topic has greater value Finally, without evidence based medicine, Department of Epidemiology, Johns Hopkins than traditional reviews precious health resources might have been University Bloomberg School of Public Health, • Bias can explain results in many indi- spent unnecessarily. In the United States, Baltimore vidual studies, and randomised clinical research into preventing and treating AIDS Sharon E Straus, associate professor trials are now recognised as the study has cost $30bn (£16bn; 23bn) since 1981. Department of Medicine, University of Calgary, design that is best suited to avoiding bias Had the research results not been applied to Calgary, Alberta in questions of intervention effectiveness, practice, more than 50% of hospital beds in Lisa A Bero, professor although other types of study may be the US would be filled with AIDS patients, Department of Clinical Pharmacy and Institute for better for other types of questions at a cost of $1.4 trillion. Similarly, without Health Policy Studies, University of California, • Tragedy can result from paying attention the application of cardiovascular research San Francisco

s10 MEDICAL MILESTONES | BMJ | jANUARY 2007 | volume 334 medical milestones germ theory

Invisible killers revealed LONDON , Harry Burns LIBRARY

ELLCO Pioneers in several countries shed light on germs, enabling important W Pasteur’s drawing of Mycoderma aceti in vineger insights in the prevention and treatment of infectious disease

n May 1847 Jakob Kolletschka, a Vien- compound fractures fell in his wards as a The germ theory was the only nese doctor, cut his finger while doing result of these measures. an autopsy on a woman who had died of Neither in Vienna nor in Glasgow did these medical advance to make it puerperal fever in the city’s lying-in hos- innovations meet with approval. Semmelweis pital. A few days later Kolletschka was left Vienna in 1850 to return to his native into Life magazine’s top 10 Idead. His autopsy showed features identi- Hungary, after the Viennese establishment cal to those found in puerperal sepsis. His refused to accept his approach as scientifically most important, followed by the discovery of friend Ignaz Semmelweis concluded that the valid. Similarly Lister failed to gain the sup- the New World. The germ theory, at number disease was being carried on the hands of port of the managers of the Glasgow Royal six, was the only medical advance to make it medical students to the women in labour and Infirmary for his antisepsis techniques. They into the top 10. insisted that medical students should wash argued, with some evidence to support their Had the germ theory not emerged as an their hands before attending deliveries. Mor- case, that surgical patients’ nutritional state explanation for the common causes of death tality from puerperal sepsis among patients was more important to the outcome of sur- in the 19th century, it is hard to imagine that who came into contact with the students fell gery than antisepsis and refused to implement these major killers would have been overcome from 12% to 2%. By general consent Sem- his recommendations. Lister left Glasgow for in any other way. Admittedly, Jenner had melweis had, through his action, turned the the chair of surgery in Edinburgh. described variolation independently of the germ theory of disease into clinical reality. The scientific basis for the germ theory work of Semmelweis and Lister. Had anti-biot- was eventually universally accepted after ics not emerged as a treatment for bacterial Overcoming initial scepticism Koch’s demonstration that infectious agents disease, we might have been forced to explore Although Semmelweis is credited with being transmitted disease, Pasteur’s studies of the enhancements of the immune system as a way the first to recognise the clinical implications metabolism of micro-organisms, and ulti- to defeat infection. However, it is unlikely that of the germ theory, the existence of particles mately Fleming and others’ work leading to such profound societal benefit brought about as the cause of disease had been suspected the production of antibiotics and new ways by our grasp of microbiological science would since Roman times, and germs had actually to treat infection. have been achieved in any other way. been seen by Antonie van Leeuwenhoek in These insights into the prevention and the 17th century. Indeed, when the lying-in treatment of infectious disease produced an Relearning old lessons hospital was opened in 1784 no autopsies epidemiological transition. They moved us So what remains to be done? The systematic were carried out because the director, Lucas from a society at the end of the 19th century application of existing knowledge will yield Boer, apparently foresaw the danger of infec- in which infection typically caused 30% of all many more advances. The developing world tion. In 1823 Boer’s successor introduced deaths to one at the end of the 20th in which needs access to the sanitation and public autopsies for the purpose of teaching. The less than 4% of deaths were due to infection. health advances that have been so successful hospital had two clinics: medical students In 1900 one death in every 120 in the United elsewhere. Research into infections such as worked in the first clinic, and the second States was due to infection—40% of them in HIV and malaria has to continue and expand. clinic was used for training midwives. Mid- children aged under 5 years. We need to improve our systems of surveil- wives did not participate in autopsies, and By 1980 mortality from infectious disease lance and our understanding and detection mortality from infection was much lower in had declined in the US to 36 deaths in every of microbiological genetic mutation. We also their clinic. Recognising the importance of 100 000, and life expectancy had increased need to continue research and to develop new this disease pattern, Semmelweis took action by around 30 years. The fall in childhood ways to control infection. Perhaps the most that seems obvious to modern eyes but was mortality had a profound effect on family depressing task that remains before us is to far from accepted in Vienna at the time. size and fertility. continually restate the lesson Semmelweis Semmelweis’s work influenced Joseph Advances in our understanding of hygiene, taught his medical students 160 years ago. Lister, working in Glasgow, who introduced sanitation, and pathology that followed the Doctors and other healthcare workers are fail- antisepsis to his surgical practice. Lister was development of germ theory have done ing to wash their hands before contact with aware that carbolic acid was used to treat more to extend life expectancy and change patients, and such failure is still costing lives. sewage, and he concluded that the same the nature of society than any other medical Resistance to the simple but lifesaving 19th microbes that caused wound putrefaction innovation. century innovations remains alive and well might be killed through use of carbolic acid In 2000 Life magazine published its list of in the 21st century. solutions to dress wounds. He also insisted the 100 most important advances of the pre- that instruments and surgeons’ hands should vious millennium. It concluded that Guten- Harry Burns, chief medical officer for Scotland be washed with the solution. Mortality from berg’s invention of the printing press was the Scottish Executive Health Department, Edinburgh

MEDICAL MILESTONES | BMJ | jANUARY 2007 | volume 334 s11 medical milestones imaging

Revealing the world within ondon Adrian M K Thomas, John Pickstone L ibrary, L e

A chance discovery in a physics laboratory opened the body to sight— m from bones to molecules—and where the eye has penetrated, the hand is Wellco now reaching Radiograph of a hand (and ring) by W K Röntgen (1895)

n 8 November 1895 a Ger- hands or lives of many radiological pioneers. The discovery of x rays led to man physicist, Wilhelm Con- But despite awareness of the dangers of radi- rad Röntgen of Würzburg, was ation, dedicated x ray machines were used an array of visualisation and investigating the effects of pass- in the mid-20th century as an aid in shoe ing electricity through rarefied fitting in many high street shops. interventional techniques that Ogases. He was surprised to find that a distant permeate modern practice fluorescent screen glowed in the dark. He was From shadows to slices amazed when his wife placed her hand in Modern digital radiology was introduced and continue to astonish front of the screen and a shadow image of the with computed tomography, which has trans- bones appeared. Röntgen communicated his formed investigative medicine. The British disease, are now used to guide interventions discovery in a short manuscript entitled “Über designer of computed tomography, Godfrey such as angioplasty and insertion of stents. eine neue Art von Strahlen” (“On a new kind Hounsfield, and the South African Allan Thus radiology has advanced from diagno- of rays”), which he submitted to the Würzburg Cormack were jointly awarded the Nobel sis into treatment; it has become a tool used Physical Medical Society on 28 December prize for physiology or medicine in 1979. directly by physicians and surgeons. In rich 1895. He called the rays “X,” because their In this type of scanning Röntgen’s shadows countries, all cancers are imaged before they nature was unknown. In 1901 he was awarded are replaced by detailed, three dimensional are treated. Modern medicine can hardly be the first Nobel prize for physics. images, usually viewed as “slices” through imagined without imaging. But is this due In the 19th century many researchers, the body. Magnetic resonance imaging and only to the success of x rays? stimulated in part by the work of Michael positron emission tomography followed, Some recent imaging techniques, notably Faraday, had studied the passage of electricity firstly rendering the body effectively trans- ultrasonography, arose from technologies through rarefied gases. In England in about parent and then revealing the sites of bio- outside medicine and might have developed 1880 William Crookes had developed an chemical activity. For example, functional independently of x ray techniques. Computed evacuated glass bulb with which he observed magnetic resonance images can now locate tomography drew on mathematical principles “rays” at the negative electrode or cathode. the areas of the brain associated with par- of interest to several academic disciplines, but Röntgen was working with a Crookes tube ticular activities, such as listening to music. it was effectively developed for use with x when he discovered his x rays. X rays also found many other uses in sci- rays. Magnetic resonance imaging originated ence and industry, one of which was to prove in methods used for chemical analysis; but its Opening new fields of discovery hugely important for biology and medicine. adaptation to imaging, and the huge invest- Röntgen’s news spread rapidly around the X ray crystallography was pioneered by Wil- ments needed for this, depended on the prior world. The phenomena were readily demon- liam and Lawrence Bragg in Britain; and in success of computed tomography and hence strable in scientific laboratories and also in Cambridge after the second world war it on that of x rays. public fairs. But classical physics could not proved the key to unpacking the structures At the root of sophisticated 21st century explain the rays, and the era of modern of nucleic acids and proteins. That was the medical imaging we find a chance discov- physics began—a physics that was based on basis of molecular biology, which by the end ery in a 19th century physics laboratory. In new understandings of atomic structure. of the century had redefined many areas of transforming physics and later revealing the In medicine, too, x rays broke old assump- biomedical research and practice. secrets of biological molecules x rays were tions. The new technology came into its own the common root of the two great branches as an aid to surgery; it was particularly useful From investigation to intervention of 20th century science. for locating needles and bullets and for visu- Shortly after the discovery of x rays their And for medicine the discovery led to an alising difficult fractures. X rays were used therapeutic potential was realised, and array of visualisation and interventional tech- in the Italo-Abyssinian war of 1896, and in alongside radium treatment they became a niques that permeate modern practice and the first world war all the major armies had mainstay of cancer treatment and palliation. continue to astonish. Without x rays, doctors, well organised radiological services. After Therapeutic applications continue to develop like Röntgen, would be working in the dark. that war x ray examinations became rou- today, most recently with intensity modulated tine in civilian hospitals, and radiologists radiotherapy, which uses a computer to match Adrian M K Thomas, consultant radiologist became established as medical specialists, the beam of x rays to the three dimensional Princess Royal University Hospital, now assisted by radiographers. shape of tumours, minimising exposure of the Orpington, Kent By this time, too, more robust tubes were surrounding normal tissue. John Pickstone, Wellcome research professor available, and practitioners took precautions Cardiac catheters, initially used to visual- Centre for the History of Science, Technology and against the radiation burns that had cost the ise the coronary arteries in coronary artery Medicine, University of Manchester

s12 MEDICAL MILESTONES | BMJ | jANUARY 2007 | volume 334 medical milestones immunology LIBRARY

OTO PH Making magic bullets SCIENCE / D Michael Kemeny, Paul A MacAry BURGESS

M Y ERE J Continuing developments in our understanding of antibodies are taking us DR Hybridoma cells producing a monoclonal antibody into a future of limitless and highly specific treatments

ince the discovery of vaccination tant area for therapeutics. Two early pioneers with rheumatoid arthritis, with a spectacular at the end of the 18th century our of antibodies were Emil von Behring (Nobel reduction of symptoms. An antibody that understanding of the immune sys- prize for medicine, 1901) and Paul Ehrlich depletes B cells shows remarkable efficacy in tem has advanced in leaps and (who won the prize in 1908), who described treating autoimmune diseases such as systemic bounds, and we now know how the development and standardisation of anti- lupus erythematosus. Monoclonal antibodies Svaccination endows us with the capacity to sera treatment against diphtheria toxin. Karl have helped reduce organ transplant rejection fight invading pathogens. We appreciate too Landsteiner (Nobel prize for medicine, 1930) by inactivating the T cells that drive the host’s that our immune system has been shaped by used von Behring and Ehrlich’s theories on response to the transplant. Passive vaccina- the challenges of dealing with diverse infec- antisera in 1909 to develop the A, B, AB, and tion with monoclonal antibodies may be used tious organisms and that similar immune O blood group antigen system, thus leading to to fight new infections such as bird flu. The mechanisms underlie conditions such as the widespread use of blood transfusion. applications appear endless and include use autoimmunity, allergy, transplant rejection, In 1978 two scientists based in the Labo- in cancer, where monoclonal antibodies can and tumour immunity, even though these ratory for Molecular Biology in Cambridge, target radioactive and other cytotoxic agents may not involve invading pathogens. Césare Milstein and Georges Köhler, showed precisely to the tumour, in the so called magic Understanding of how the immune sys- that single clones of cells that produce anti- bullet approach. tem distinguishes host cells from “foreign” bodies could be formed by fusing individual cells leapt in 1958, when the French medical plasma cells with immortalised B cell myel- Limitless possibilities researcher Jean Dausset described the first omas, thus producing millions of identical Where will all this end? It is not really clear of many human histocompatibility antigens progeny secreting a single type of antibody. yet. Because monoclonal antibodies are so (HLA antigens). Our immune system uses These monoclonal antibodies have revolu- incredibly diverse, new and remarkable the pattern of HLA antigens on the surface tionised the diagnosis of disease through their properties of antibodies continue to emerge. of cells as a biological signature—one that application in immunoassays. Harnessing the Some antibodies can mimic the action of is almost unique to each of us. Whenever sensitivity of radioisotopes and enzymes, mon- specific ligands such as hormones; others the immune system does not recognise the oclonal antibodies are used to diagnose and can block or inactivate receptors on cell sur- pattern of HLA antigens on a cell it creates monitor human disease, to ensure the quality faces. For example, a monoclonal antibody antibodies and other substances to attack and of food and other biological materials, and has been generated that binds to the human destroy it. This is the main mechanism for to test for trace amounts of drugs and toxins. IgE receptor and displaces the patient’s immune recognition of infectious organisms. They have enabled scientists to visualise the own IgE without triggering the hypersensi- It also explains why our immune system outside and inside of cells, stimulating new tive response of mast cells and basophils and attacks transplanted tissues and organs. imaging technologies such as flow cytometry thus blocks the allergic attack. The number (used to analyse fluorescently tagged blood of antibodies produced by mice is as many Transplantation to monoclonal antibodies and tissue cells) and confocal microscopy (for as 109, and a complete recombination of vari- In the 1950s a Boston based team of doctors investigating the interior of our cells). able genes performed ex vivo (when there is led by Joseph Murray transplanted a kidney Initial use of monoclonal antibodies to no elimination of self reactive clones) yields from a 23 year old man into his seriously ill treat disease in humans was limited, because as many as 1012 different combinations. Thus identical twin. In the following years Murray the molecules were produced in mice and the properties and specificities of antibodies (who won the 1990 Nobel prize for medicine) induced an anti-mouse response in the human that can be selected are effectively limitless. and international colleagues were able to host. Later, Gregory Winter and Michael Indeed, it is estimated that more than a third show that by matching as many HLA anti- Neuberger at the Laboratory for Molecular of all drugs currently being developed by gens as possible between organ donors and Biology discovered how to engineer the com- drug companies are monoclonal antibodies, recipients, and by adding therapies to reduce bining site of the mouse monoclonal antibody and hence antibody technology will enable the immune response, organ transplantation into the human immunoglobulin gene. The many more medical milestones to be reached was feasible. Since then bone marrow, kidney, resulting chimeric antibodies, called human- in the foreseeable future. liver, skin, heart, and lung transplants have ised antibodies, could now be given to patients saved more than 400000 lives. with little or no anti-mouse response. D Michael Kemeny, head of department Greater understanding of the biological The benefits of humanised monoclonal anti- Paul A MacAry, assistant professor weapons that make up our immune system has bodies in the treatment of otherwise intracta- Immunology Programme and Department of resulted in antisera and monoclonal antibody ble diseases have been dramatic. Monoclonal Microbiology, Centre for Life Sciences, technology. This has had a major effect on dis- antibodies to an inflammatory protein have The Yong Loo Lin School of Medicine, ease diagnosis and is emerging as an impor- been administered to over a million people National University of Singapore

MEDICAL MILESTONES | BMJ | jANUARY 2007 | volume 334 s13 medical milestones oral rehydration therapy

The simple solution for saving lives Olivier Fontaine, Paul Garner, M K Bhan

Pirozzi/Panoso m

A simple and cheap oral solution, tested in refugee camps in the 1970s, iaco G has prevented millions of deaths among children with diarrhoea Oral rehydration has saved millions of young lives

ach day at the height of the mon- His vision led to the creation in 1978 of “To save the life of a person soon season in the early 1970s WHO’s diarrhoeal disease control pro- 6000 starving refugees from the gramme, which has popularised this treat- with diarrhoea is probably the India-Pakistan war poured into ment throughout the world. It is simple and refugee camps: a cholera epidemic it works—and a systematic review in the cheapest health intervention Ewas inevitable. The sheer volume of patients Cochrane Library has shown that even in you can think of.” meant that the government of India, the developed countries there are no clinically state government of West Bengal, and non- important differences in effectiveness and child with an infection that has the potential governmental agencies simply could not safety between oral and intravenous fluid to kill. With the proper use of oral rehydra- provide enough intravenous saline solution replacement. In 1970 Mahalanabis had to tion therapy these risks become almost zero. or staff to administer it, and 30% of patients prepare his own packets; now close to 500 Because more than 50 million children’s lives died within a few days. drug companies produce oral rehydration have been saved over the last 25 years, thanks One witness to the tragedy was Dilip solutions, the formulation of which was to oral rehydration, a large chunk of the adult Mahalanabis, who, as a member of staff of the recently improved for greater effectiveness. population in developing countries is alive Johns Hopkins Center for Medical Research In the 1980s nearly five million children today. and Training in Calcutta, had helped develop under 5 years old died each year from diar- What does the future hold? Vaccines against a new oral rehydration solution to replace the rhoea. In 2000 this figure had dropped to 1.8 rotavirus could be important but are currently water and electrolytes lost through vomiting million. Oral rehydration is central to the expensive. Oral rehydration solutions have and diarrhoea. Oral rehydration therapy had package of measures that has helped ensure been improved since the early days: the for- been discovered a few years earlier simultane- this fall in mortality. At the beginning of an mula was adjusted after a Cochrane Library ously in Kolkata (Calcutta) by N F Pierce and episode of diarrhoea the child is given increas- systematic review in 2001 showed that a less in Dhaka by N Hirschhorn but had only ever ing amounts of fluid prepared at home, to concentrated solution had better outcomes. been used by paediatric specialists in tertiary prevent dehydration. If the child is already And the treatment strategy now includes giv- referral hospitals. Mahalanabis seized on the dehydrated, oral rehydration solution is given ing zinc for a couple of weeks, as this not only idea that the therapy might work in this dire at home or in healthcare centres, and if this reduces the severity and duration of the epi- catastrophic context too. His team weighed fails intravenous fluid replacement is given. sode but also protects the child from further out the ingredients in Kolkata, tipped them Feeding and breast feeding continue during episodes in the following 2-3 months. into plastic bags with simple instructions, the illness and are increased after the episode, These improvements will make manage- sealed them with a hot iron, and rushed them and antibiotics are used only when appropri- ment of diarrhoea even more successful. But to the camps. Relatives, parents, and health ate, such as when the child has bloody diar- the great challenge is how to reach all children staff urged patients to drink large volumes rhoea or shigellosis. who are still suffering and dying from diar- of solution in the early stages of their illness. Diarrhoea as a cause of death in young chil- rhoea and who belong to the poorest section Over eight weeks mortality fell to less than dren has fallen from 33% of deaths to 18% of the population. It is a tragedy that 1.8 mil- 1%. since the 1980s, and this decline is largely lion preventable deaths from diarrhoea occur responsible for the fall in total mortality in every year just because children do not have An amazing discovery young children over this period. David Sack, access to this cheap, easily prepared solution. However, the medical establishment was director of the International Centre for Diar- There is still a desperate need worldwide to sceptical about these dramatic results and rhoeal Disease Research in Bangladesh, said, promote and distribute this life saving inter- rejected Mahalanabis’s paper reporting them. “To save the life of a person with diarrhoea vention and help parents use it when their It took a visit from Dhiman Barua, a cholera is probably the cheapest health intervention child becomes sick with diarrhoea. specialist from the World Health Organiza- you can think of.” tion, for the enormity of the discovery to be Olivier Fontaine, medical officer, child and realised. He was amazed by what he saw: Fifty million children’s lives saved adolescent health and development basic health orderlies, parents, and relatives Without oral rehydration treatment, and with World Health Organization, Geneva all treating cholera successfully with just oral a roughly static incidence of three episodes of Paul Garner, professor of community health rehydration solution. Barua understood then diarrhoea every year, children in poor coun- Liverpool School of Tropical Medicine, that not only could the solution treat cholera tries are faced with a potentially life threat- Liverpool but it also had the potential to completely ening infection every four months; and in M K Bhan, secretary for biotechnology revolutionise the community management of families of four children, every month of the Ministry of Science and Technology, diarrhoea in children. year the parents would be likely to have a Government of India, New Delhi

s14 MEDICAL MILESTONES | BMJ | jANUARY 2007 | volume 334 medical milestones the pill

Emblem of liberation Carl Djerassi ANN M

RK ke The pill is one of the few drugs to have remained essentially unchanged GESA The pill gave women contraceptive autonomy decades after its synthesis—testament to its enduring value

hat sort of pill?” is primary reason is that no other milestone If these examples are not convincing, add- a question that very has had as many societal, “non-medical” ing more to the list—such as that the pill is the few readers seeing consequences; the pill is a stone thrown into preferred method of reversible contraception the topic of this article water that has produced ripples and waves in more than half the countries in the world, would ask themselves. way beyond any reasonable expectation, for that more than 80% of women in the US have “WSurely, that already tells us something about the following reasons. at one time used the pill, or that about 100 the popularity of an oral contraceptive that I, • The pill and intrauterine devices raised million women worldwide at any one time an organic chemist, would call 19-nor-17α- the expectations for contraceptive are on the pill—would probably be overkill. ethynyltestosterone (norethindrone, or some effectiveness to an extraordinarily other closely related progestogen) combined high level, with enormous favourable An enduring classic with 17α-ethynylestradiol. What single pro- consequences for millions of women. Considering this implied panegyric, you cedure or vaccine would be known by the • The pill offers women the ability to decide might think that current research into even equivalent labels of “the operation” or “the on their own, in private, whether or when better methods of birth control would be jab?” The answer is none. Yet does the per- to become pregnant, thus undermining flourishing. Nothing could be further from sistent popularity of “the pill” warrant add- the historical dominance of men in all the truth. Of the 20 largest drug firms in the ing the invention of the oral contraceptive matters relating to sex and reproduction. world, only three are active in modest efforts to the list of 15 greatest medical milestones The consequences range from cultural to to improve the pill. The very long develop- since 1840? To justify my affirmative answer, economic, professional, and educational ment time (about 12-15 years, because of the I first need to define what in my view does aspects, most of them positive. need to study the side effects from long term not qualify as a medical milestone. • The pill and intrauterine devices intro- use), the fear of litigation, and the current Clean drinking water and effective sewage duced reversible birth control that was emphasis on blockbuster multibillion dol- disposal are of enormous benefit to public independent of the sex act, completely lar drugs aimed primarily at elderly people health, but in my book they are not a medi- changing the nature of sexual intercourse, make research in this field highly unpopu- cal milestone because only the consequence, which now ranges from unworried lar. In fact, desired demographic changes, and not the originator, is medical in nature. pleasure to undisciplined promiscuity. whether in “paediatric” countries (those Lifestyle changes such as stopping smoking, • The pill was the first potent drug to where population growth is undesirable) with its fantastic health benefits, still would be consumed for years by millions of in Africa, Asia, and parts of Latin America not qualify for me. Also, basic research “healthy” people, thus raising questions or in the “geriatric” countries of Europe advances that are far from the actual medi- of defining safety and the risk-benefit and Japan (where the opposite holds), now cal application won’t qualify, because then balance in the long term that were quite depend much less on changes in contracep- we would also have to include important distinct from those for other drugs taken tive “hardware”—the actual means of birth chemical synthetic reactions and analytical over long periods (such as cholesterol control—than on “software” considerations, methods that make possible many chemi- lowering drugs), where the “benefit” was the legal, economic, cultural, educational, cal syntheses of substances that eventually the prevention of a medical condition. and public health conditions in each coun- become drugs. The more serious the disease, the higher try. As a result, the active ingredient of the the tolerance for side effects, cancer being pill, though seemingly sold under hundreds Making waves around the world a classic example. In the case of the pill of labels worldwide, is still limited to about Nevertheless, there is such a mass of truly the “disease” is an unwanted pregnancy, half a dozen slight chemical variants of the important, practical, and medically unam- for which the level of tolerance of first oral progestogen, norethindrone, which biguous milestones that have affected mil- side effects is very low. The discipline was synthesised in a small Mexican com- lions of people that selecting the 15 most of epidemiology has probably been pany in 1951. The fact that norethindrone is important seems to me patently impossible. improved in depth and sophistication still being consumed by millions of women For instance, how would I compare the erad- more through the thousands of studies of is one of the relatively rare examples (aspirin ication of a global scourge such as smallpox the pill than of virtually any other drug. being the most famous) where the original or polio with the importance of oral contra- • No other drug has had such an enormous chemical is still being used in unmodified ceptives? Such disease eradication should effect on religion. For instance, Catholic form decades after its original synthesis. win hands down, since other types of birth couples, faced with their church’s control always did and do exist. So why did I opposition to contraception, often make Carl Djerassi, professor of chemistry emeritus agree to make a case for the inclusion of the family planning a higher priority than Department of Chemistry, Stanford University, pill among the 15 exalted milestones? The avoiding “mortal” sin. Stanford, California

MEDICAL MILESTONES | BMJ | jANUARY 2007 | volume 334 s15 medical milestones risks of smoking

All done and dusted Simon Chapman Two landmark studies in the 1950s led to a growing body of evidence for m

the harmful effects of tobacco and a decline in the prevalence of smoking, otos.co ph despite the efforts of the tobacco industry to fight back Cigarettes: now a mark of social disadvantage?

fter tobacco was introduced from to make their case: worldwide about five mil- suggests that, without reductions in smoking, America to Europe in the 16th lion people die each year from tobacco related there would have been virtually no reduction century and then to the rest of illness. Among risk factors for disease, only in overall cancer mortality in either men or the world, its detractors lost little hypertension and malnutrition kill more peo- women since the early 1990s. The payoff from time in condemning the practice, ple than does tobacco. past investments in tobacco control has only Awhich was popularly reputed to benefit In developed countries alone, between just begun.” health. Early medical reports, including the 1950 and 2000 smoking caused about 62 In the early 1980s, while the tobacco French physician Nicholas Andry de Boisre- million deaths or 13% of all deaths (20% of industry was still reeling from growing public gard’s 1701 warning that people taking too deaths in men and 4% in women). It has been awareness of the dangers of active smoking, much tobacco could suffer a withering of estimated that tobacco will cause about 150 the second horseman of the industry’s apoca- their “noble parts,” presaged later epidemi- million deaths worldwide in the first quarter lypse rode into view: the emerging epide- ology on smoking and erectile dysfunction. of this century and 300 million in the second miological evidence for the harmful effects In 1771 the Encyclopaedia Britannica recorded quarter. In the United States each smoker loses of secondhand smoke. This broadened the “a person who through excess of smoking on average 13 years of life. The World Health ethical foundations of tobacco control: harm- had dried his brain to that degree, that after Organization estimates that by 2020 “the bur- ing oneself invites paternalistic advice, but his death there was nothing found in his skull den of disease attributable to tobacco will out- harming others justifies laws to protect the but a little black lump, consisting of mere weigh that caused by any single disease.” community. A Rip van Winkle awaking from membranes.” These are numbers to die for. Yet too often a 20 year sleep would be astounded by the the hazards of smoking fail to create a sense cultural transformation of the status of smok- Serendipitous research of urgency among the media, policy making from a pleasant, mannered pastime to a Fumophobic tracts from luminaries such as ers, and the public. The statistics are so strat- badge of low education, social disadvantage, Robert Baden-Powell and Henry Ford were ospheric that they have become almost banal. and ostracism. Cigarette packets have meta- imbued with the language of moral turpitude. As Stalin said, “A single death is a tragedy; a morphosed from elegant boxes to pathology A generation grew up hearing that smoking million deaths are a statistic.” The number museum exhibits. might “stunt your growth.” But the real risks of deaths from cancer arising from the 1986 At the end of the 1990s the tobacco industry of smoking became clear only after a seren- Chernobyl nuclear reactor meltdown is pre- was further undermined by the release under dipity in 1950: two major case-control stud- dicted to rise to 16000 by 2065. The Interna- the US Master Settlement Agreement of more ies on smoking’s harms were published, one tional Agency for Research on Cancer stated than 60 million pages of its internal docu- by the Americans Ernst Wynder and Evarts that “tobacco smoking will cause several ments. This effectively halted the industry’s Graham in the Journal of the American Medical thousand times more cancers in the same longstanding public denials of the dangers to Association and the other by the United King- population.” Few news bulletins picked up health of smoking, designed to undermine dom’s Richard Doll and Austin Bradford Hill on that comparison. public awareness campaigns. in the British Medical Journal. Smoking may well continue to be a major These findings triggered an avalanche of Tobacco control and falling cancer mortality health problem in much of the world. How- research. Where results were publicised by For all the money poured into cancer research ever, the world’s first legally binding health the media and governments the prevalence of in recent decades, most of the progress in treaty, the World Health Organization’s smoking began to fall. Although in the 1950s reducing cancer mortality has been due to Framework Convention on Tobacco Con- most countries reported a prevalence of smok- deaths avoided through successful tobacco trol, entered into force in February 2005. ing among men of more than 60%, today control. Now ratified by 140 nations (but not, notably smokers are typically outnumbered by more The American Cancer Society recently and disgracefully, by the US), it will unleash than three to one in areas where tobacco con- examined how much the decline in smoking unprecedented worldwide controls on the trol is taken seriously. In California just 9.8% had contributed to the decline in deaths from vector for tobacco related disease: the tobacco of people smoke daily. all cancers in the US. It concluded: “Even industry. The force of these events, first set People smoking 20 cigarettes a day for 40 our most conservative estimate indicates loose by researchers in 1950, means that the years will baste their lungs with a toxic, carci- that reductions in lung cancer, resulting from end game for smoking may well be just 20 nogenic fog 2.9 million times. In compelling reductions in tobacco smoking over the last years away in the vanguard of nations where them to do this, nicotine has caused unparal- half century, account for about 40% of the smoking is currently in free fall. leled mortality. Unlike their forebears before decrease in overall male cancer death rates. 1950, advocates of tobacco control now have “A more realistic straight line projection of Simon Chapman, professor of public health the dismal luxury of “great” statistics on which what lung cancer rates might have become School of Public Health, University of Sydney

s16 MEDICAL MILESTONES | BMJ | jANUARY 2007 | volume 334 medical milestones sanitation

Pragmatism works ondon L , Johan P Mackenbach m Despite erroneous theories of disease causation and the lack of an

cienceMuseu evidence base, new sewage disposal and water supply systems in the S Demonstration model of sanitary fixtures (1895) 1800s revolutionised public health in Europe

t some time in the 1780s the Indus- although some ideas came from France. that retrospectively related mortality to better trial Revolution began—firstly in Edwin Chadwick was its champion, neither water supply and sanitation have produced Britain then in other European a medical doctor nor a sanitary engineer but conflicting results. Perhaps the strongest sup- countries. Technical and commer- a lawyer who had designed the 1834 Poor port comes now from poor countries, where cial advances enabled European Law Amendment Act and who wanted to evaluation studies, although still beset by Asocieties to break through their pre-indus- cut the costs of poor relief by preventing a methodological problems and inconsisten- trial production ceiling. Expanding indus- major cause of poverty: acute infectious dis- cies, support a substantial effect of improved try attracted labourers and their families eases that killed male breadwinners. water supply and sanitation. to towns and cities, which grew rapidly, at Chadwick believed that these diseases One review showed that morbidity and the expense of rural areas. In terms of eco- were caused by air contaminated as a result total mortality from diarrhoea among chil- nomic output these transformations were an of poor urban drainage. He developed a dren were reduced by about a fifth. Better immense success; in terms of human well- comprehensive solution: new technologies water quality seems to have had less effect being they were not. Unplanned urbanisa- (sewers rinsed by water, his main reason for than better water availability or disposal tion, appalling working conditions, and low bringing piped water to individual homes) of excreta. The global burden of disease wages led to a deterioration in the health of and the legal and administrative structures study ascribed 1.8 million deaths in 2001 in much of the population. needed to build these expensive works. low and middle income countries to diar- Infectious diseases exacted a huge toll Britain took decades to implement these rhoeal disease. Unsafe water, sanitation, and in morbidity and mortality, among them measures, and they spread only slowly to the hygiene accounted for 88% of these deaths, tuberculosis, diphtheria, measles, smallpox, rest of Europe, but in the end they had a indicating that substantial health gains can be typhoid, and typhus, as well as the “enteric major effect on mortality. In the Netherlands, achieved by extending the global coverage of fevers,” whose causes were hotly disputed. for example, the first large municipality with adequate water supply and sanitation. We now know that dysentery is caused by piped drinking water was Amsterdam (1854), ingesting food or water contaminated with followed by Rotterdam and The Hague in The causation paradox faecal micro-organisms in environments the 1870s. By the end of the century around Improved water supply and sanitation are where sanitation and access to clean water 40% of Dutch people had piped drinking often held up as exemplars of how best to are inadequate. But at the time popular water, and in the early 20th century sew- improve public health, not only in the past explanations included the “miasma” theory erage systems covered more than half the but also now and in the future. Of course, it is that fevers were caused by foul damps aris- population. Between 1870 and 1970 age easy to read too much into a single historical ing from decaying organic material. standardised mortality in the Netherlands event; and that Chadwick succeeded despite It was cholera, another consequence of fell by almost 75%. An important contribu- his defective theory of disease causation may economic progress, particularly the increase tion to this decline was a fall in the numbers have been good luck. Nevertheless, we can in international trade and transport, that of deaths from infectious diseases, including still draw three lessons from this tale. “concentrated people’s minds.” The second, deaths from respiratory tuberculosis (down Firstly, effective intervention does not third, and fourth pandemics reached West- 15%), acute respiratory diseases (11%), and always need accurate knowledge of disease ern Europe in the 1830s, 1850s, and 1860s. acute digestive diseases (8%). Between 1901 causation. Secondly, environmental measures Observations on the spread of cholera, as in and 1970, when a more accurate classifica- may be more effective than changing individ- John Snow’s studies around London’s Broad tion of causes of death was used, a fall in ual behaviour (piped drinking water and sew- Street pump, improved understanding of the mortality from “diarrhoea and dysentery” erage systems worked better than educating causes of enteric disease. His pragmatism accounted for 12% of the overall decline in the public to improve hygienic practices). (turning off the pump in the face of general mortality in the Netherlands. Similar figures And thirdly, universal measures may be disbelief among his peers that water was were reported for England and Wales. better than targeted measures in reduc- the source of cholera) has rightly become Paradoxically, what is probably one of the ing health inequalities. These lessons have famous. And the psychological effects major breakthroughs in public health lacks become part of the “collective conscious- of cholera epidemics, which threatened the empirical underpinning we now think is ness” of public health, and this tale can still poor and rich people, fostered a collective essential for evidence based health policy. inspire us to always search for pragmatic response. Not only were the theories incorrect, but solutions to population health problems. empirical evaluations have produced less The British sanitary revolution than convincing results. Contemporaneous Johan P Mackenbach, professor of public health, As with the Industrial Revolution, Britain studies were often too crude to produce reli- Erasmus Medical Centre, University Medical also led Europe in the “sanitary revolution,” able evidence. More sophisticated studies Center, Rotterdam

MEDICAL MILESTONES | BMJ | jANUARY 2007 | volume 334 s17 medical milestones tissue culture LIBRARY

OTO Solving the mysteries of viruses PH SCIENCE / Yvonne Cossart EISSNER HM

Tissue culture methods have played a major part in the work of more than a GSC

third of the winners of the Nobel prize for medicine since 1953, and without STEVE it gene therapy and stem cell research would be impossible A HeLa cell (scanning electron micrograph)

issue culture entered mainstream 1930s Alexis Carrel, a French surgeon work- in vitro. This ultimately produced skin cul- medicine in 1949 when the US sci- ing at the Rockefeller Institute in New York, tures that could be used for grafting, but its entists John Enders, Thomas Weller, collaborated with the aviator Charles Lind- more profound consequences resulted from and Frederick Robbins reported berg to overcome the technical challenges of elucidating the functions of T cells as they that they had grown poliovirus in organ perfusion. Their tissue survival studies proliferated in vitro after stimulation with Tcultured human embryonic skin and muscle attracted enormous public interest, fuelled antigens. cells. This achievement soon led to methods by newspaper reports such as “birthday” for measuring immunity to polio and to the notices for one culture of chick embryo car- Exquisitely specific antibodies award of the Nobel prize for medicine to diac muscle cells. Before the second world Fusing cultured benign and malignant cells the three scientists in 1953. Fifty years on war Thomas Strangeways and Honor Fell in provided important insight into the control we are on the brink of eradicating polio by Cambridge used cell culture as part of their of cell division, and the technique was spec- using vaccines derived from cell cultures, multidisciplinary approach to bone and joint tacularly exploited to generate “hybridomas” and cells are grown on an industrial scale to disease, paving the way for the recognition between myeloma cells and B cells to pro- yield vaccines, antibodies, and other biologi- of tissue specific markers, which are now so duce monoclonal antibodies. cal products such as recombinant factor VIII widely used in diagnostic pathology. Immortalised cell lines now provided a for haemophilia. After the second world war, the serial sub- potentially unlimited source of antibodies In his Nobel lecture Enders described the culture of cells was achieved through the use of exquisite specificity for enzyme linked technical difficulties encountered before the of trypsin to produce single cell suspensions, immunosorbent assay and radioimmuno- second world war in efforts to grow viruses antibiotics to control contamination, and bet- assay, and monoclonal antibodies are now in culture and how, after the war, antibiotics ter growth media, such as the famous “199” being used in the treatment of haematologi- were used to keep bacterial contamination at with its 64 ingredients. The finite number of cal malignancies. bay. The new accessibility of tissue culture divisions achievable in the culture of normal The ability to transfect cultured cells with methods ushered in the golden era of virus cells contrasted with the “immortality” of can- DNA gene sequences has allowed us to discovery. It also revived many previously cer cell lines. assign functions to different genes and under- unattainable ambitions in medical science, HeLa, the most famous of these, was stand the mechanisms that activate or redress having a crucial role in no fewer than 18 derived from the cervical cancer that killed their function. Gene therapy has yet to fulfil of the 52 subsequent Nobel prize winning Henrietta Lacks in 1951. Continuous lines its promise, but it may ultimately overtake discoveries, including RNA interference were used to develop convenient in vitro the many other medical applications of cell (the 2006 winner), the nature of oncogenes methods for testing the efficacy of potential culture. (1989), monoclonal antibodies (1984), tumour anticancer drugs and the carcinogenic effects Without cell culture we would lack vac- viruses (1975), and virus genetics (1965). of drugs and chemicals. The demonstration cines against measles, mumps, and rubella of integrated viral genes in many tumours and would still be dependent on much more An old dream is realised and of similar homologues in normal cells expensive and reactogenic vaccines for polio, Although short term survival outside the revolutionised concepts of growth regula- rabies, and yellow fever. We would be unable body of the beating heart and twitching tion. The discovery of mutations in these to karyotype patients with suspected genetic muscle was known to the ancients, serious homologues—the cellular “oncogenes”—in disorders or to perform in vitro fertilisation. attempts to achieve lengthy tissue survival cancer tissues and in the normal cells of Antibodies for diagnostic or therapeutic use in vitro were possible only in the second family members with an inherited risk of would be derived from immunisation of half of the 19th century. Among the pio- cancer had applications in cancer diagnosis whole animals—with much greater variation neers were embryologists, who studied the and screening. in titre and specificity than products derived early development of amphibian and avian By the 1960s, cell culture technology from cells. Our concepts of growth, differ- eggs and began to experiment on “organis- was well established in virology and cancer entiation, biological ageing, and malignant ers,” soluble messengers that directed organ research. The time was right for the inter- transformation would be simplistic; and gene development. With the advent of cell culture action between cell biology and genetics that therapy and the use of stem cells to repopu- the nature of these growth factors could be gave birth to molecular biology. Study of late damaged organs or to clone individuals elucidated. Modern stem cell research is the the chromosomes of dividing cultured cells would be beyond imagination. most exciting and controversial descendent spawned the new discipline of cytogenet- of this work. ics, while work on gene expression began Yvonne Cossart, Bosch professor of infectious Surgeons had dreamt of organ transplanta- to explain the mechanisms involved in dif- diseases, Department of Infectious Diseases and tion since the Middle Ages. In the 1920s and ferentiation, which could now be observed Immunology, University of Sydney

s18 MEDICAL MILESTONES | BMJ | jANUARY 2007 | volume 334 medical milestones vaccines BAL Conquering untreatable diseases nstitutPasteur,Paris/ I Michael Worboys Vaccines have saved hundreds of millions of lives. All modern

MuseePasteur, innovations can be traced back to Pasteur’s 1885 breakthrough with “Cowpox battling the medical profession” (plaque) rabies vaccine

ouis Pasteur’s introduction in July that Pasteur named his own methods after it. a year. In the 1950s as many as 7500 cases of 1885 of a rabies vaccine that con- However, Jenner’s innovation was a one-off, polio were reported in a year; in the whole of tained a laboratory attenuated live and subsequent attempts at emulation, such the 1980s there were only 25. The incidence virus deserves the title of the great- as inoculating material from syphilis sores to of tuberculosis—the principal cause of death est medical milestone for three rea- treat infection, failed. By comparison Pasteur’s in adults a century ago—was reduced by the Lsons. First and foremost, Pasteur’s innovation breakthrough was grounded in knowledge BCG vaccination, introduced in 1927. Many introduced the laboratory modification of and techniques that have been the basis for elderly people now receive flu shots every micro-organisms by attenuation, to render all the vaccines we have today. year, as do high risk workers, who also receive them less pathogenic but still immunogenic. Pasteur, who was not a doctor, shifted his hepatitis A and B vaccines. And would we Vaccines have saved hundreds of millions attention from vaccines for anthrax, sheep have the same confidence about travelling of lives and spared generations the suffering pox, and rabies in animals to those for human overseas if it weren’t for yellow fever jabs or and long term consequences of infections. disease, because of medical interest in the new modern versions of the vaccines introduced Although this reason alone would make Pas- microbiology and because of the possibility, in the 1890s? teur’s work the leading medical milestone, in the case of rabies, of building up immu- two other reasons make the case for vaccines nity during the long incubation period. Pas- New delivery systems and new targets unanswerable. teur announced his breakthrough in October There is no reason to suppose that the future Pasteur’s rabies treatment was the world’s 1885, giving graphic accounts of the cases of of vaccines will be any less remarkable than first medical breakthrough to be recognised two children, savagely bitten by rabid dogs, their past. The greatest benefit to humanity and celebrated in the public domain. Pasteur who faced certain death until treated in his would be for all current vaccines to be made was hailed in the press as a great benefac- clinic. Medically, an untreatable disease had available in all countries and to all groups tor of humanity and to have opened a new been conquered. Such was the excitement across the world. Greater diffusion should be era in medicine. Finally, his high profile this generated that some doctors and scien- aided by new delivery systems—aerosols and and the support he gained garnered funds tists immediately looked to the eradication of skin patches—and by the move away from to establish the Pasteur Institute in Paris, the major communicable diseases. vaccines that need cold storage. world’s first purpose built medical research At this moment all things seemed possible Molecular biology means that we can look institute and the model for others that were for medicine, and the next decade seemed to forward to preventive and therapeutic vac- established soon after, such as the Robert prove this. Frightening killer diseases could cines for common infections such as those Koch Institute in Berlin, which opened in be cured, as Pasteur’s coworkers contrib- from staphylococci and pneumococci, for 1891, and what became the Lister Institute, uted to the development of antitoxic sera for parasitic diseases such as malaria and schisto- opened in London in 1893. diphtheria and tetanus; but they could also somiasis, for recent infections such as HIV, be prevented, as protective vaccines using viral haemorrhagic fever, and severe acute Milkmaids and cows, children and dogs inactivated micro-organisms were devel- respiratory syndrome, for autoimmune dis- It can be argued that the breakthrough with oped against cholera, typhoid fever, and the eases, and even for infective cancers. Indeed, vaccines actually occurred a century earlier, plague. a vaccine against human papillomavirus and with Edward Jenner’s introduction of vaccina- In the 20th century vaccines for many thus against cervical cancer was approved tion against smallpox in 1796. Jenner was a more bacterial and viral infections were very recently and could be seen as a medical country doctor in Gloucestershire who had introduced. To imagine a world without vac- milestone in its own right. noticed that patients, especially milkmaids, cines is to imagine a world threatened with Although Pasteur brought the great ben- who had suffered from cowpox (also known smallpox, which was eradicated in the 1970s efits of medical innovation to the public’s as vaccinia) were subsequently immune to the largely through vaccination campaigns. In the attention and pioneered the institutionalisa- deadly smallpox. He first trialled and then United Kingdom today only older generations tion of medical research, it is because of the promoted inoculation with small doses of vac- will remember the predations of childhood present and future potential for vaccines to cinia pustules, which he assumed carried the diseases made rare by jabs now taken for save lives and prevent suffering that we can poison, as a preventive measure—terming the granted: diphtheria (1923), whooping cough consider his 1885 discovery to be the great- inoculation “vaccine.” Although it attracted (1926), measles (1963), rubella (1969), polio est medical milestone. much scepticism, news of Jenner’s innovation (1958 and 1961), and measles, mumps, and spread rapidly round the world. Smallpox was rubella (1969). For example, from 1920 to Michael Worboys, director greatly feared, and it seemed miraculous that 1940 between 40 000 and 70 000 cases of Centre for the History of Science, Technology and so many thousands of lives could be saved; diphtheria were notified each year in the UK, Medicine and Wellcome Unit for the History of indeed, such was the standing of “vaccine” but by the 1990s the number was around 10 Medicine, University of Manchester

MEDICAL MILESTONES | BMJ | jANUARY 2007 | volume 334 s19 medical milestones EPILOGUE

Rarely do these lists have the I’ve got a explicit quantitative criteria that would satisfy a Cochrane little list collaborator. But the fun— and frustration—is in the Jeffrey P Koplan subjectivity of the choices

We all enjoy top 10 lists or other numerical mortality from the disease. All these items have variants, be they selections of riverside pubs, had a major and direct effect on quality of life. For classic rock guitarists or neurosurgeons, the example, more and healthier teeth permit a more world’s best beaches, or the Mann-Booker varied and enjoyable diet and better nutrition; shortlist. Such lists allow us to focus our own healthier diets and fortified food have eliminated views and congratulate ourselves for our good micronutrient disorders such as rickets, taste or astute judgment: “The list seems valid, goitre, pellagra, and iron deficiency from large as they chose Mark Knopfler, Jeff Beck, and populations across the globe. And the items Eddie Van Halen.” They also permit us to scoff at have reduced the number of preventable deaths the ignorance or lack of taste of the compilers: and injuries: the number of injuries sustained by “Where are Joe Perry, Dickie Betts, and Stephen miners, railway workers, and factory workers fell Stills?” But I digress. by 90% in the US from 1933 to 1997; rigorous Rarely do these lists have the explicit governmental standards have reduced exposure quantitative criteria that would satisfy a to toxic substances in most industries; mortality

Cochrane collaborator. But the fun—and p from motor vehicle collisions has fallen, thanks frustration—is in the subjectivity of the choices. If to safety equipment, better highway design, readers find themselves in agreement with over education, and a reduction in associated risk half the list then some modicum of satisfaction roberson/a factors such as alcohol use; and millions of life ff e is achieved. Thus all BMJ readers will have j years have been saved through large reductions turned, with a sense of anticipation mixed with medicine), major disciplines of bioscience in the prevalence of smoking in many countries. scepticism, to the list in this supplement of the (immunology), and a laboratory technique (A new book by J W Ward and C Warren, Silent top 15 (egregious inflation of the more decimally (tissue culture). This is a most interesting and Victories (New York: Oxford University Press, traditional 10 or the more familiar dozen) varied group of milestones, certain to stir debate 2006), describes these achievements.) medical milestones of the past 166 years. The and elicit reflection. One common feature of These two lists encourage a discussion of list was developed by inviting nominations from all these milestones is that their existence and the relative contributions of biomedical science readers, and then a final selection was made significance were likely unforeseen when the and public health. Biomedical science has won by a panel of experts—a quasi-democratic cum BMJ was established in 1840, but they have all more Nobel prizes, while public health has oligarchic process that is highly likely to lead to had a major effect on the length and quality of had a greater role in reducing morbidity and an untidy outcome. Unlike pubs, guitarists, or life. mortality and improving our quality of life. Of novelists, a medical milestone may mean quite I’ll admit to some bias. In 1999-2000 I course, each approach contributes to the other. different things to different people. It certainly initiated, at the US Centers for Disease Control We need to develop safe and effective vaccines would include leaps forward in diagnosis and and Prevention (CDC), a top 10 list of public for serious illnesses; and we need to be able to treatment, but it also permits the inclusion of health achievements of the 20th century in deliver these vaccines to people at risk. Similarly, methodological or experimental advances that the United States. Although this exercise was even as we develop an understanding of the are far upstream from their bedside application. specific to the US, other high income countries human genome, we must make this knowledge The impact in numbers of lives saved or have had similar achievements. A considerable practically useful and economically feasible diseases averted or controlled could be a factor overlap exists between the CDC’s list and the and must ensure that benefits of research are in identifying a milestone but is not so clearly BMJ’s final 15 milestones: half the items on the distributed equitably and ethically. stated or universally accepted. CDC list (effective and reliable birth control, So, peruse the BMJ’s top 15 milestones, Let’s look at the BMJ’s top 15. In the diagnostic antibiotics, vaccines, recognition of the risks consider the pipeline of discovery and category we find imaging. Several therapeutic of tobacco and the institution of effective experience that led to them, and imagine their advances are listed: anaesthesia, antibiotics, tobacco control programmes, and water and future evolution. In another 166 years, which oral rehydration therapy, and chlorpromazine. sanitation) are also represented on the BMJ of the items in the list will still be considered Now we move across the menu to items that list. But the missing five items merit discussion milestones? The current list is interesting and can be lumped into preventive measures here: improving safety and reducing hazards in provocative but, of necessity in such lists, (the pill, vaccines, sanitation), theories (the the workplace; providing safe and nutritionally incomplete. So, where’s Eric Clapton? germ theory), technology (computers), basic enriched foods; preventing motor vehicle scientific discoveries (the structure of DNA), injuries and deaths; improving oral hygiene; and Jeffrey P Koplan,vice president for academic epidemiological discoveries (risks of smoking), recognising the risks for coronary heart disease health affairs, Woodruff Health Sciences Center, approaches to medical science (evidence based and instituting actions to reduce morbidity and Emory University, Atlanta s20 MEDICAL MILESTONES | BMJ | jANUARY 2007 | volume 334