The Rise and Fall of Modern Medicine
Page 20
Stomach (or peptic) ulcers were yet another of these illnesses of middle life whose cause was unknown, though they seemed to be related to an excess of acid production in the stomach which had been variously attributed to genetic factors, faulty diet and, of course, ‘stress’. And then along comes Dr Marshall, who identifies a single type of bacterium as the ‘trigger’, which not only profoundly changes the nature of understanding of the disease but also the manner in which it should be treated. If this is the situation for peptic ulcers then, by analogy, perhaps there should be a similar singular explanation for the other diseases of middle life.
The discovery of H. pylori thus illuminates in a striking way the last great intellectual challenge in medicine: finding out the cause of these illnesses. If a bacterium can cause peptic ulcer then presumably other as-yet-unidentified infectious agents might also be responsible for multiple sclerosis or rheumatoid arthritis.
In the summer of 1984 a 32-year-old Australian doctor, Barry Marshall, swallowed a cocktail containing large numbers of the bacterium helicobacter, obtained from the stomach of a man suffering from dyspepsia.1 Self-experimentation of this type has a long and distinguished history. Many researchers have in the past exposed themselves to considerable personal danger and discomfort in the pursuit of science. In 1892, at the age of seventy-eight, the German scientist Max von Pettenkoffer, sceptical that the cholera bacillus recently discovered by Robert Koch really was the cause of cholera, swallowed a mixture laced with cholera bacilli taken from the stool of a recent victim. His scepticism, he soon realised, was misplaced when he became acutely ill with profuse diarrhoea and abdominal colic. In January 1930, Dr Gail Dack of Chicago, convinced that – contrary to prevailing opinion – food poisoning could be caused by the bacterium staphylococcus, deliberately swallowed a piece of contaminated sponge cake. ‘Later on, as he was about to sit down for supper, he suddenly ran from the table to spend an hour in the bathroom. His wife heard him say between bouts of vomiting and diarrhoea, “Oh, this is wonderful!” But Mrs Dack thought otherwise. Believing her husband was about to die, she summoned his partner who came but could offer little comfort other than staying by his bedside until he recovered.’2
Marshall conducted his self-experiment for precisely the same reasons as Pettenkoffer and Dack: to prove (or disprove) a theory that bacteria found in association with an illness were actually the cause of that illness. And sure enough, within a week of swallowing his infective cocktail, Marshall developed symptoms of dyspepsia, with vomiting and abdominal discomfort. His friends noted his breath smelled ‘putrid’. A colleague passed a gastroscope into his stomach, whose lining appeared red and inflamed, and a biopsy showed inflammatory cells and ‘bacilli adhering to the surface’. Marshall started a course of antibiotics and ‘his symptoms resolved completely within twenty-four hours’.
The results of Dr Marshall’s self-experiment might seem predictable. It is only natural to presume that ingesting a cocktail of infective organisms might have adverse consequences on the lining of the stomach, but that was not the way things were viewed in 1984. The prevailing wisdom maintained, and for good reason, that bacteria simply could not be implicated in diseases of the stomach for the simple reason that they could not survive its high concentration of hydrochloric acid, which can burn a hole in concrete, dissolve a lump of meat and destroy 99.99 per cent of all bacteria within half an hour.3 Marshall’s self-experiment showed this to be incorrect. The stomach was not entirely sterile. Some bacteria, like the helicobacter, had clearly adapted to living in this hostile environment.
So why had the connection never been made before? It was scarcely for lack of opportunity to observe the presence of these bacteria in the stomach as, since the development of the fibre-optic endoscope in the 1960s, the stomach had become one of the most scrutinised organs of the body. But even though these bacteria must clearly have been present, pathologists examining the specimens apparently did not see them, or if they did they ignored them. Rather, blinded by the dogma that bacteria could not survive in the stomach, the causes of gastritis and peptic ulcer had been attributed to a variety of fanciful explanations.
The stomach lining is protected against the corrosive hydrochloric acid secretions by a layer of mucus on its surface. An ulcer or gastritis is best understood as arising from either an oversecretion of acid or a defect in this mucous protective layer. Certainly two important causes of peptic ulcer are readily explained within this model. The first is the very rare Zollinger-Ellison syndrome, where a tumour of the pancreas secretes a hormone (gastrin) that massively increases the amount of acid produced by the stomach, resulting in intractable ulcers of the upper intestinal tract. The second is drugs like aspirin, which disrupt the mucus layer, exposing the stomach cells underneath to the acidic secretions. The difficulty has always been trying to explain those ulcers – the vast majority – in which neither of these causes applies. Essentially two theories have been proposed – ‘personality’ and ‘stress’ – both of which are based on the supposition that chronic anxiety maintains levels of acid secretion ‘above the normal range’.
The role of personality in peptic ulcer can be traced back to the psychoanalytic theories of disease of the 1930s and 1940s. In 1935 an American analyst, Franz Alexander, asserted that patients with peptic ulcer were struggling against ‘feelings of dependence’ on parents and persons of authority. Freudian theory being based on the perverse proposition that everything is the reverse of what it seems, this ‘struggle against’ is actually a concealed ‘desire for’ dependence on parents. Thus, according to Alexander, ulcers occurred in those who had reverted to the ‘infantile’ state of wishing to be fed, ‘which serves as a permanent stimulus of the empty stomach and causes its dysfunction’. By the 1950s the psychoanalytic emphasis on the individual had shifted towards blaming the parents. Dr Elsa Goldberg from London’s Tavistock Institute found that the mothers of those with peptic ulcers were ‘striving, dominant and obsessional in the house’ while the fathers were ‘steady, unassertive and passive’.4
While the personality theory emphasised ‘internal conflict’ as the source of chronic anxiety leading to an increase in acidic secretions, the ‘stress’ theory focused on external factors and arose from a series of experiments conducted in the 1940s by Stewart Wolf and Howard Wolff of the New York Hospital on an unfortunate employee called ‘Tom’.5 Tom was a 56-year-old Irishman who, at the age of nine, had the misfortune of drinking some extremely hot clam chowder his father had left in a pail in the kitchen, which caused severe burns to the oesophagus. The strictures that resulted could not be dilated so, with Tom unable to swallow any food, the surgeons had no alternative other than to fashion an opening from the abdominal wall directly into the stomach – a gastrostomy – through which he learned to feed himself. Wolf and Wolff placed a thin plastic tube through the gastrostomy to assess the amount of acid secreted by the stomach, which appeared to be related to Tom’s moods and emotional states, increasing when he was fearful of losing his job, when depressed after being unable to move from his ‘unpleasant neighbourhood’ to a more desirable area, when anxious during his stepdaughter’s investigations for suspected cancer of the bladder, and so on. From these studies they concluded that excess secretion (of gastric acid) occurred in situations that posed a threat to the emotional security of the individual. Here, then, was an apparently scientific explanation that over the next two decades was deemed to be so self-evident that it was merely perverse to challenge it. Stress pushed up the levels of gastric acid in an empty stomach and the result was a peptic ulcer. Many other studies provided apparent independent confirmation, including some cruel and ingenious experiments on monkeys placed in the situation where one of the pair was obliged to assume ‘executive’ responsibility for avoiding electric shocks to itself and to the second member of the pair. In each pair the ‘executive monkeys’ developed peptic ulcers; and some even died from perforation of the stomach.6
These psychosomatic explanations for peptic u
lcer were never formally disproved, but gradually the emphasis shifted to constitutional or genetic factors that might increase the secretion of acid and other hormones. The belief that ‘excess acid’ was the culprit certainly seemed to be vindicated by the introduction in 1976 of the drug cimetidine which, by reducing the amount of acid in the stomach, allowed ulcers to heal. But the main difficulty with these diverse theories is that they failed to offer any explanation as to why any individual should develop a peptic ulcer in the first place. Indeed, there was simply no recognition that there might be some unknown ‘initiating factor’ to explain the whole process – despite the fact that the changing pattern of peptic ulcer disease over the previous 100 years strongly suggested that an infectious agent must be involved.
Peptic ulcer was rare before the turn of the century but over the next fifty years it had become ever more frequent, affecting approximately one in ten of adult males. Then, suddenly, the rate started to fall quite dramatically, declining by almost 50 per cent between 1960 and 1972.7 It is clearly impossible to correlate this ‘rise and fall’ with changes in personality or methods of parenting or stressful types of work; points rather, inescapably, to an infectious cause, belatedly identified by the young Barry Marshall. So how did Marshall stumble on the cause of this common disease that had eluded the medical profession for so long?
In 1983 Dr J. Robin Warren of the Royal Perth Hospital in Western Australia observed the presence of ‘small, curved bacilli’ in biopsy specimens taken from the stomachs of patients with acute gastritis. ‘The extraordinary feature of these bacteria is that they are almost unknown to clinicians and pathologists alike,’ he reported, ‘even though they are present in about half our gastric biopsy specimens in numbers large enough to be seen routinely.’8 Meanwhile, as a junior doctor at the same hospital, Marshall was looking around for some interesting research project, so Warren suggested he might take a closer look at the patients in whose stomach biopsies he had just noted these ‘small curved bacilli’. Warren, it would seem, did not fully appreciate the true significance of his observations and, as Marshall had had no experience in medical research, he could scarcely have anticipated his investigations would lead to some momentous discovery. Marshall’s moment of revelation came, quite by accident, when one of the patients whose stomach biopsy specimen had contained the ‘unidentified bacilli’ reported that, following a course of the antibiotic tetracycline for a chest infection, his symptoms of dyspepsia had improved. Marshall promptly performed a gastroscopy to inspect the appearance of the stomach wall and found the bacilli had vanished. The conclusion seemed obvious. As both the patient’s symptoms and the bacteria in the stomach wall had disappeared following a course of antibiotics, then the bacteria must have been the cause of those symptoms.9
There was no reason why anybody should share the youthful Dr Marshall’s excitement about his observations, but what he may have lacked in experience he certainly made up for in enthusiasm. In the following twelve weeks he performed gastroscopies on a further 184 patients – almost four a day – and, now that he knew what he was looking for, the staggeringly high prevalence of helicobacter infections began to become apparent not only in those with gastritis but also, he noted, in 100 per cent of patients with peptic ulcers.10
The next step in understanding the properties and behaviour of this unusual bacterium was to grow it – but this proved surprisingly difficult. It is standard practice, once bacteria have been inoculated on to a dish of culture medium, to incubate them for forty-eight hours and look for evidence of growth; but nothing happened. The thirty-fifth attempt was interrupted by a five-day Easter holiday, and unintentionally the culture dishes were incubated for a further three days. When the microbiologists returned from their break they found that the culture plates were studded with small colonies of helicobacter.11 Now, with abundant helicobacter available, Marshall could undertake the crucial self-experiment to show helicobacter were not just ‘associated’ with inflammatory changes in the stomach wall but were the actual cause of that inflammation. If they were the cause, then logically antibiotic treatment should be curative. There already was – as mentioned – an effective treatment for peptic ulcers in the acid-suppresant drug cimetidine – but within a year of stopping treatment, the ulcers tend to recur.12 By contrast antibiotics should, by eliminating the helicobacter, ensure that once the ulcer was healed it stayed healed. And so it turned out: in a study of fifty patients with ‘intractable’ peptic ulcer reported in The Lancet in 1990, those in whom helicobacter was eradicated with antibiotics had ‘no ulcer relapse’. By contrast, in those treated with standard anti-ulcer medication but without antibiotics, 89 per cent had a further ulcer within the year.13 Rather than taking acid-suppressant drugs for years, patients with peptic ulcers now only had to take a seven-day course of antibiotics. There could be no more powerful illustration of the importance of knowing ‘the cause’ of a disease.
Nor indeed was that the end of the story. It soon became clear that helicobacter was not only implicated in gastritis and peptic ulcer but also some cases of stomach cancer.14 Soon after, every gut specialist in the world was looking for and finding helicobacter in their patients’ stomachs and curing their ulcers with antibiotics. There was now no escaping the scale of their earlier collective self-deception, for not only had they failed to see these bacteria – even though they were present in virtually all their patients – they had systematically misinterpreted the many clues pointing to the fact that peptic ulcers must be caused by an infectious organism.
So how did the helicobacter protect itself against the corrosive effect of hydrochloric acid in the stomach? It turned out to be a very unusual organism, with a streamlined spiral shape propelled by a tail moving it very rapidly through the acidic secretions to find sanctuary in the mucus layer of the stomach wall. Though it does not directly penetrate the cells of the stomach wall to cause an ulcer, it does produce a range of toxins that, by causing inflammation, generate the fluids and debris that are believed to be its main source of nutrition. Helicobacter is thus perfectly adapted to its unusual environment and, once installed, persists probably for life.15
The elucidation of helicobacter’s role in so many diseases of the stomach has provoked another of those ‘paradigm shifts’ in changing scientific understanding, not only of the diseases with which it is directly associated, but of all diseases. Prior to the discovery of helicobacter the three main stomach diseases – gastritis, peptic ulcer and stomach cancer – were believed to be separate entities, each with its own plausible explanations, so stress-induced excess acid led to peptic ulcers, or pickled foods or salt or nitrate fertilisers in some way damaged the lining of the stomach wall to cause cancer.16,17 But these theories were essentially a ‘façade of knowledge’, providing little insight as to how these illnesses might be prevented or cured. And then along comes Marshall, for whom the reverse of the standard cliché applies: chance favoured his unprepared mind. It was precisely because he was young and inexperienced that he was able to think the ‘unthinkable’, that peptic ulcer might be an infectious disease. And in the aftermath of his self-experiment everything fell into place. Helicobacter offered both a unifying biological explanation for all the important diseases of the stomach, while simultaneously making treatment and prevention a practical proposition. There could be no more striking instance of the contrast between a coherent biological explanation that opens up the possibility of genuinely effective treatment and pseudo-explanations – whether psychological or dietary – that blame patients for their disease and leave them impotent to do anything about it.
Nor indeed do the implications of helicobacter stop here. Its discovery necessarily raises the question how many of the other diseases of unknown causation, such as multiple sclerosis or rheumatoid arthritis or diabetes, might also have a biological cause that will make them amenable to curative treatment in a similar way. This issue will be returned to.
PART I
The Rise
1
MEDICINE’S BIG BANG
In an influential essay, ‘Science: the Endless Frontier’, published in 1946, the American physicist Vannevar Bush described science as ‘a largely unexplored hinterland’ that would provide the ‘essential key’ to the economic prosperity of the post-war years. He himself had participated in ‘the greatest mobilisation of scientific power in the history of the world’, the Manhattan Project, which at a cost of $2 billion had built from scratch in under five years the first atomic bombs, which had been dropped with such devastating effect on the Japanese cities of Hiroshima and Nagasaki. This awesome power unleashed by atomic fission would, predicted Bush, soon cease to be a ‘jealously guarded military secret’, becoming instead ‘a source limitless energy’ in the service of peace and industrial progress.
Vannevar Bush’s optimistic anticipation of science’s ‘endless frontier’ was to be repeatedly vindicated over the following twenty years. In 1948 the invention of the transistor increased the calculating power of computers a million-fold, to usher in the Electronic Age. Five years later in 1953 Francis Crick and James Watson’s identification of the structure of DNA unlocked the mysteries of the genetic code. In 1961 Yuri Gagarin’s orbit of Earth launched the Space Race that would culminate eight years later in the first Moon landing. Even when compared to such momentous events, the Big Bang of the post-war therapeutic revolution was the most momentous of all, a multitude of discoveries in diverse scientific disciplines stretching over a period of three decades. And its ‘definitive moments’, already described, were only the headlines. For a proper sense of the scientific ferment that underpinned these achievements, it is necessary to imagine the thousands of chemists in their laboratories synthesising and testing millions of chemical compounds, or to reflect on the time and energy expended by similar numbers of physiologists, endocrinologists and neurochemists in making sense of, for example, the subtle hormonal regulation of the pituitary gland, or the mode of action of neurotransmitters in the brain.