The Rise and Fall of Modern Medicine

by James Le Fanu

  More than fifty years later this first description of the use of penicillin has lost none of its power to amaze. Reading it one has the impression of witnessing a miracle, whose origins, as is well known, lay in the chance observation made by Alexander Fleming in his laboratory at London’s St Mary’s Hospital over ten years earlier. As a microbiologist Fleming’s research work involved growing colonies of bacteria on special plates called petri dishes and observing their behaviour in different circumstances. He had, for example, recently shown that the chemical lysozyme, present in tears, could inhibit the growth of several types of harmless bacteria. But then in 1928, returning from his summer holidays, Fleming, picking up a petri dish standing in a pile waiting to be washed, noticed how a contaminating mould (later identified as Penicillium notatum) had inhibited the growth of a colony of staphylococcal bacteria that can cause many different types of infectious illness. He then extracted the juice from the mould (which he called penicillin) and showed it was capable of inhibiting the growth of a whole range of bacteria. Curiously, however, when other scientists tried to replicate the accidental method by which he had made his discovery, they were quite unable to do so.

  It was not until 1964, almost forty years later, when Fleming’s former assistant Ronald Hare investigated the matter in detail, that the reason emerged. Hare found that this failure to replicate Fleming’s original observation was because the growth of the penicillium mould occurred at a different temperature (20 degrees Celsius) from that of the staphylococcus, which grows best at a temperature of around 35 degrees Celsius. So what had happened?

  Firstly, the penicillium mould that had ‘floated through the window’ was not a commonly occurring strain but rather a rare one that had wafted up from the laboratory below, where a fellow scientist and fungus expert, C. J. LaTouche, was working. Fortuitously this rare strain just happened to produce large amounts of penicillin. Some spores, it must be presumed, contaminated a petri dish on which Fleming had been growing some colonies of staphylococci. Inexplicably, but essential for his subsequent discovery, Fleming did not, prior to going on holiday, place the dish in the incubator but left it out on the laboratory bench. Consulting the meteorological records for London at the end of July 1928, Ronald Hare discovered that while Fleming was away there had been an exceptionally cool nine-day period – which would have favoured the growth of the penicillium mould – after which the temperature rose, which would have stimulated the growth of the staphylococcus. The penicillium mould was by now producing sufficient quantities of penicillin, and on his return Fleming noted that the pinhead-sized yellow spots on the plate, each of which represented a colony of the staphylococcus, had an unusual appearance. ‘For some considerable distance around the mould growth the colonies were obviously undergoing lysis [dissolution].’ Thus, without the ‘nine cool days’ in London in the summer of 1928, Fleming would never have discovered penicillin.3

  Fleming was much luckier than he realised, but he was then remarkably indolent in exploring the therapeutic potential of his findings. He used juice extracted from the penicillium mould to cure a colleague suffering from the mild bacterial infection conjunctivitis, but by the following year he had abandoned any formal research into its further clinical use, because of the prevailing view that naturally occuring chemicals such as penicillin were likely to be too toxic to be used to treat infectious diseases.4 Fleming did not take the matter further because he did not think it worth pursuing, ‘a good example of how preconceived ideas in medicine can stifle the imagination and impede progress’.5

  So the near miraculous properties of penicillin had to be rediscovered all over again ten years later by Howard Florey and Ernst Chain in Oxford, which was preceded, interestingly enough, by recapitulation of Fleming’s work on the antibacterial properties of lysozymes in tears. Howard Florey had arrived in Britain from his home country of Australia in 1922, and after graduating from Oxford rapidly ascended the academic ladder. He was prodigiously industrious, very good with his hands and had the knack of attracting others as, or more, talented than himself to work as his collaborators. In 1935 when still only thirty-seven he was appointed Professor of Pathology at Oxford and promptly recruited Ernst Chain, a young German Jewish chemist refugee from Nazi Germany. Florey’s scientific interests included the study of the chemistry of the body’s natural secretions, so he initially hoped that Chain’s talents would be able to elucidate their biochemical structure. ‘When Florey and I in our first meeting discussed the future research programme in the department, Florey drew my attention to a very startling phenomenon,’ Chain recalled. This was Fleming’s observation, made back in 1921, that lysozymes in tears and nasal secretions were capable of dissolving thick suspensions of bacteria, though how they attacked the cell walls of bacteria was unknown. It took only a year for Chain to show that lysozyme was a complex enzyme. While writing up this work for publication, he looked around for other instances of compounds that might destroy bacteria and inevitably came across Fleming’s original paper describing the effects of penicillin. By now it should be clear why Chain and Florey were to succeed where Fleming had failed. The skills of a microbiologist like Fleming lay in the observation and interpretation of experiments with bacteria; the skills of a biochemist like Chain lie at a deeper level, in identifying the biochemical mechanisms that underpin the microbiologist’s observations. And so just as Chain had so rapidly solved the question of the biochemistry of lysozyme, it was only a matter of time before he would unravel the mechanisms of the action of penicillin and appreciate its real significance.

  Nonetheless, at the outset neither Chain nor Florey believed penicillin would have any ‘clinical applications’ in the treatment of infectious diseases, so the precise sequence of events that persuaded them to change their minds is of some interest. Firstly it seems that Chain was intrigued to find that penicillin was ‘a very unusual substance’. It was not, as he had imagined it would be, an enzyme like lysozyme, but rather it turned out to be ‘a low molecular substance with great chemical instability’. In brief, he had no idea what it was, so ‘it was of obvious interest to continue the work’. Secondly, he had the biochemical skills to extract and purify (though not to a very great extent) penicillin, which when tested against bacteria grown in culture proved to be twenty times more potent than any other substance. Thirdly, when penicillin was injected into mice it was apparently ‘non-toxic’. This last point was vital, for, as already pointed out, probably the most important reason why Fleming had failed to pursue the possibilities of penicillin was the common belief that any compound capable of destroying bacteria would necessarily harm the person to whom it was given. Finally, in a classic experiment Chain and Florey demonstrated that penicillin could cure infections in mice: ten mice infected with the bacterium streptococcus were divided into two groups, with five to be given penicillin and five to receive a placebo. The ‘placebo’ mice died, the ‘penicillin’ mice survived.6

  Florey naturally hoped the publication of the compelling results of the mice experiment in The Lancet would prompt interest from major pharmaceutical companies for, a man being 3,000 times larger than a mouse, it would require prodigious quantities of penicillin to assess its effects in humans. But these were difficult times. The previous year Britain had declared war on Germany and the British Expeditionary Force of 350,000 men had just been driven on to the beaches of Dunkirk to be evacuated by an improvised armada of ships that somehow survived the repeated attacks of the German dive-bombers. This shattering defeat, in which Britain lost the equivalent of an entire army, made the prospect of a German invasion almost inevitable and heralded the Luftwaffe’s daily assaults on London in the Battle of Britain.

  At this desperate moment, when the future of Britain lay in the balance, Florey decided, astonishingly in retrospect, to commit the puny resources of his laboratory in Oxford to making enough penicillin to test in humans. ‘The decision to turn an academic university department into a factory was a courageous one for whic
h Florey took full responsibility . . . if his venture had failed it would have been seen as an outrageous misuse of property, staff, equipment and time, and Florey would have been severely censured.’7

  The hallmark of Florey’s university-laboratory-turned-penicillin factory was improvisation, the penicillium moulds being grown on hospital bedpans and the precious fluid extracted and stored in milk jugs:

  [In] the ‘practical’ classroom, the washed and sterilised bedpans were charged with medium and then inoculated with penicillin spores by spray guns. They were then wheeled on trolleys to what had been the students’ ‘preparation’ room, now converted into a huge incubator kept at 24° Centigrade. After several days of growth, the penicillin-containing fluid was drawn off from beneath its mould by suction . . . The air was full of a mixture of fumes: amyl acetate, chloroform, ether. These dangerous liquids were pumped through temporary piping along corridors and up and down stairwells. There was a real danger to the health of everyone involved and a risk of fire or explosion that no one cared to contemplate.8

  By the beginning of 1941 there was just enough penicillin for the first trial in humans. On 12 February Charles Fletcher administered the first injection directly into the policeman Albert Alexander’s vein, with the results just described. Seven university graduates, including two professors and ten technical assistants, had worked every day of the week and most nights for several months to achieve these results. In June Florey travelled to America, where eventually four major drug companies took up the challenge of the mass production of penicillin.

  Come the end of the war, in 1945, Florey and Chain shared, along with Fleming, the Nobel Prize. Their achievement was not just the development of penicillin but rather the clarification of the principles by which all antibiotics were subsequently to be discovered. Florey, in his acceptance speech, spelled them out: first, the screening of microbes to identify those that produced an antibacterial substance; then, the determination of how to extract the substance; then testing it for toxicity and investigating its effect in animal experiments. And finally, tests in humans.9

  We now know, though Florey did not when he gave his speech, that penicillin was not just ‘a lucky break’. Rather the screening of tens of thousands of species of micro-organisms over the next few years revealed a handful that produced a whole further range of antibiotics (see page 23) whose profound impact on medicine has already been mentioned; but four further points are worth noting. It can be difficult to appreciate the comprehensiveness of the antibiotic revolution. There are many different types of infectious illness, from the trivial such as a sore throat to life-threatening meningitis. The bacteria involved behave in different ways, both in how they spread themselves around and how they damage the body’s tissues. So, an attack of meningitis can kill within twelve hours while tuberculosis may take ten years or more. And yet there is not one of the hundreds of different species of bacteria that cause disease in humans that is not treatable with one or other antibiotic.

  Then, while the mechanism of action of antibiotic-producing bacteria might seem simple, their effects are both very diverse and highly complex. They can interfere with the enzymes that make the cell wall, blow holes in the lining of the cell, disturb the transport of chemicals across the lining, or inhibit the manufacture of proteins in the cell.10

  Next, the chemistry of antibiotic molecules is very unusual. It was hoped in the early days following the discovery of penicillin that the drug could be synthesised, thus avoiding the necessity of growing the penicillium mould in vast fermentation plants. But that was not to be, as one of those involved, John C. Sheehan, subsequently commented:

  Behind the feat of elucidating the structure of penicillin lay the deceptively simple problem of understanding how one carbon atom is bound to one nitrogen atom. When these two atoms are properly connected this gives penicillin its antibiotic properties. When the carbon and nitrogen atoms do not connect, the penicillin compound is not penicillin. Thousands of chemists, biochemists, organic chemists, physical chemists, microbiologists, technicians and government bureaucrats struggled for years to make those atoms hook up with each other. Millions of dollars were spent from public and private treasuries. But despite the money and labour lavished on the problem, the enchanted ring of penicillin could not be mastered.11

  Dates of the discovery and sources of the more important antibiotics12

  Finally, despite the complexity and diverse mechanisms by which antibiotics work, the process of their discovery turned out to be astonishingly simple. All that was required, as Florey pointed out in his Nobel Prize speech, was the screening of micro-organisms to identify the handful that could destroy other bacteria, and then identification of the active antibiotic ingredient. Thus, though antibiotics are commonly perceived as a triumph of modern science, scientists alone could never have invented or created them from first principles. They are, rather, ‘a gift from nature’, which raises the question of what their role in nature might be.

  The most obvious and commonly accepted explanation is that antibiotics are ‘chemical weapons’ produced by bacteria to maximise their own chances of survival against other organisms in the atmosphere and the soil. This was certainly the view of Selman Waksman, the discoverer of streptomycin for the treatment of tuberculosis. Waksman was, by training, a soil microbiologist and knew more about the ways in which bacteria in the soil interacted with each other than anyone else in the world. His reason for studying bacteria in the soil as a potentially potent source of antibiotics was as follows:

  Bacteria pathogenic for man and animals find their way to the soil, either in the excreta of their hosts or in their remains. If one considers the great numbers of disease-producing microbes that must have gained entrance into the soil, one can only wonder that the soil harbours so few capable of causing infectious diseases in man and in animals. One hardly thinks of the soil as a source of epidemic. It has been suggested the cause of the disappearance of these disease-producing organisms is to be looked for among the soil-inhabiting microbes [which are] antagonistic to them and bring about their rapid destruction in the soil.13

  Waksman received the Nobel Prize in 1952 for his discovery of streptomycin, and yet in the following years he came to realise that his original perception of antibiotics as ‘chemical-warfare’ weapons deployed by bacteria in the soil must be mistaken. He noted the ability to make antibiotics was limited to a very few species and so could not play an important role in the ecology of microbial life. Further, the ability of microorganisms to produce antibiotics turned out to be highly dependent on the quality of the soil, and indeed they were only reliably produced in the artificial environment of the laboratory. And so, if antibiotics did not act as bacterial ‘chemical weapons’ in the struggle for survival in the soil, what did Selman Waksman believe their role to be? They are, he observed, a ‘purely fortuitous phenomenon . . . there is no purposeness behind them . . . the only conclusion that can be drawn from these facts is that these microbiological products are accidental.’14

  This is a very difficult concept to accept. It seems inconceivable that bacteria, the simplest of organisms, should have the ability to produce such complex molecules which then serve no purpose in their survival, but as Leo Vining, a biologist from Dalhousie in Canada, observed at a conference in London in 1992, ‘Even accepting these products [antibiotics] have a role, does not mean that we can readily agree upon or perceive what that role might be’.15

  The story of penicillin and the other antibiotics that followed is thus very different from that so often presented – and usually perceived – as the triumph of science and rationalism in the conquest of illness. The unusual climatic circumstances that led to Fleming’s discovery of the antibacterial properties of the penicillium mould were quite staggeringly fortuitous. The crucial decision that led to its mass production – Florey’s resolve to turn his university laboratory into a penicillin factory when a German invasion was imminent – was a triumph of will over reason. Las
tly the question of how, and more particularly why, a handful of the simplest of micro-organisms should have the ability to create these complex chemicals, or why they should exist at all, is simply not known. This, ‘the mystery of mysteries’ of modern medicine, will be revisited.

  2

  1949: CORTISONE

  Cortisone – commonly known as ‘steroids’ – is the second of the two drug discoveries that created the modern therapeutic revolution. Whereas the first, antibiotics, defeated an external enemy – the bacteria that caused infectious disease – cortisone mobilised the body’s capacity to heal itself. This concept requires some elaboration. The human body as a robust and self-sufficient organism must be able to heal itself. This is seen most obviously in the recovery after a wound to the skin or a fracture to the bone but it is, of course, a generalised phenomenon much exploited by doctors over the centuries. Given time, rest, warmth and adequate nutrition, many illnesses will simply get better. These self-healing properties of the body are so pervasive that it was natural to infer there must be some physical or spiritual force to guide them. For the anatomist John Hunter it was a ‘vital spirit’, for the French physiologist Claude Bernard ‘homeostasis’ and for the physician William Osler the ‘vis medicatrix naturae’.