by Burch, Druin
The first account of Aspirin’s development by Bayer was published in 1933, the year after the Nazi Party came to power. Eichengrün, being Jewish, was not mentioned.
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1 Today, following various changes and mergers, it is a drug company called Sanofi-Aventis, with yearly sales in 2006 worth over 28 billion euros.
2 In that sense, they were natural, but dyes always involved a degree of artifice. Roots were grubbed up, shellfish gathered, juices extracted, cloths soaked. The chemical reactions of mud and vinegar, madder and indigo and cochineal, were managed by people without much aid from machines. The coal tar industry extracted colour, not from plants, but from the ancient remains of plants, and it used many machines. But natural dyes still needed the interventions of the dye makers, and factory-made ones could still be safer than naturally occurring ones containing lead or arsenic. The catastrophic history of medicine is partly the result of ascribing qualities without reasonable evidence, and one way of doing that is to think of natural as being good and artificial as being bad. In 1999 the Lancet told the story of a twenty-five-year old man found comatose in a Berlin park. His heart stopped for over seven hours, his circulation kept going all that time by chest compressions. While others did what they could for him, a nurse going through his pockets for clues about his collapse found bits of yew tree. Remarkably, the man regained consciousness and survived. He often ate plants, he explained on waking, ‘since natural foods were “healthy”’.
3 Or with meadowsweet, which was the alternative plant source for salicin and salicylic acid. The German chemist Karl Lowig had shown this in 1835.
11 Cough Medicine Called Heroin
BAYER INVESTED HEAVILY in research, and in ways of making that research as good as possible. The company spent huge amounts on well-equipped laboratories and carefully designed programmes of animal testing. They supported their scientists generously, and encouraged individuals to specialise in either drug development or testing. A dyestuff company had first released a medication in 1882 – Hoechst and Kairin – yet within a decade Bayer and its competitors were orienting themselves in a new, recognisably modern way towards the research and production of novel pharmaceuticals.
Adapting existing medications was an attractive way to begin. Often that meant finding ways to produce the same drugs in a different manner, circumventing a competitor’s patent just as Duisberg had done with dyes at the beginning of his commercial career. Actually amending compounds, in order to make them safer or more powerful, was an alternative way forwards. While Bayer continued to improve upon the willow, and continued to fail in synthesising quinine, it also looked elsewhere. With few effective drugs in the world, it was no surprise that they quickly turned their attention to the poppy.
Since the isolation of morphine by Friedrich Wilhelm Sertürner in 1805, chemists had been tinkering with it – often more out of curiosity than with any more purposeful intent. In Scotland and London a few modifications had been made. Some of these helped develop chemical theories, establishing ideas about the way different molecular structures gave rise to particular effects.
In 1874 at St Mary’s Hospital in London, Charles Alder Wright developed a new compound, diacetylmorphine, and sent it to F. M. Pierce in Manchester for testing on dogs and rabbits. A thousand years before, Rhazes in Baghdad had written on the importance of comparisons, trying to distinguish the effects of his therapy for meningitis by applying it to some patients and not others, and then comparing them. The degree to which these ideas had escaped medical thought for ten centuries was clear in Wright’s approach: although his knowledge of chemistry was far more accurate than that of tenth-century Persia, he used no control animals. As a result, he was left with no clear idea of what diacetylmorphine did and showed no further interest in it.
Carl Duisberg’s Bayer, meanwhile, were looking for ways of improving opium. The alkaloid codeine was isolated from the poppy in 1832. It showed some of the same power as morphine to suppress irritating coughs, and at the same time it had a much milder effect on the mind. This drew the interest of Bayer chemists who were seeking drugs that were gentler than the all-powerful morphine. They knew that adding acetyl groups to other compounds had produced exactly those effects, softening them and making them more useful. Felix Hoffmann was the Bayer chemist who acetylated salicylic acid on 10 August 1897 to produce Aspirin. Within two weeks he also acetylated morphine.
Joseph von Mering, the doctor who had advised Bayer in 1893 that Paracetamol was not worth developing, was working for Merck by 1897. Starting in an apothecary’s shop in Darmstadt, in the south-west of Germany, what began as a family business in 1668 had continued in the same vein. From the early years of the nineteenth century Emanuel Merck, inheriting the family business, began to expand it. Unlike most of his competitors, he was in charge of a company whose interest in drugs pre-dated the work of William Perkin and his aniline dyes. Merck asked von Mering to test the acetylated version of morphine and give his opinion. Von Mering was unimpressed, and suggested Merck ignore it.
Hofmann’s acetylated morphine – diacetylmorphine or simply diamorphine – was tested with more interest by Bayer, who gave it to animals and found that their breathing became deeper and slower. In a world plagued by tuberculosis, with its chronic breathlessness and cough, this looked promising. Bayer staff tried it on themselves. It worked, they found, tremendously. Coughs vanished. People who took it felt strong and wonderful and pain-free. In fact, they felt heroic. From September 1898, Bayer began marketing their new drug for relief of the symptoms of respiratory illnesses. They called it Heroin.
It sold rapidly. Early studies showed no evidence of its being addictive. It was, of course, but the studies were too poorly designed to pick that up. But it was not so immediately addictive that the first doctors and patients who used it noticed this for themselves.1 Bayer chemists were confident, on the basis of what they knew of the drug’s structure, that addiction would not be a problem. So they never designed tests capable of proving their prejudices wrong. The powers of chemists and doctors were increasing and success was not the sort of thing to encourage humility.
It required no methodical powers of observation to see that Heroin got rid of coughs, eased pains and generally made people feel better. Often they felt a lot better, even if they had been feeling pretty good to begin with. Ideas that Heroin helped people breathe were the first ones to change. It became apparent that Heroin’s effects on breathing were exactly those of morphine, and of laudanum and opium before it. By the time it was eventually discovered that Heroin’s main action was the result of the body simply converting it into morphine, people had already noticed enough of the similarities not to be surprised. Heroin confirmed that even the world’s best chemists and doctors, acting on the knowledge of a drug’s structure, could not necessarily predict its effects ahead of time. It was not a lesson that was widely learnt, or that researchers found easy to remember.
Bayer stopped producing Heroin in 1913. It had become too linked in the public mind with addiction, particularly in America, and the profits did not justify the bad publicity. Other companies carried on making it, and the drug continues to be a useful and effective medication, although some countries, like the USA, ban it even for therapeutic use. For patients with smashed bones, failing hearts, gnawing cancers or suffocating breathlessness, it works very well. Sometimes morphine is all that is available, in which case a larger dose achieves the same effect. Bayer’s website, which proudly records the company’s production of Aspirin, makes no mention of Heroin. That seems a pity. There are worse things to be ashamed of, and Bayer, as we will see, went on to be involved in many of them.
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1 ‘You don’t wake up one morning and decide to be a drug addict,’ wrote the novelist William Burroughs. ‘It takes at least three months’ shooting twice a day to get any habit at all.’
12 Francis Galton Almost Reforms Medicine
BY THE END of the nineteenth century, the p
roductions of science were impressive. Methodologies, as well as results, were getting better. Just as some of the approaches that made up chemistry were developed in pursuit of other goals – alchemy and intoxication – so the constituents of scientific method itself often came from unlikely quarters.
‘Tall, slim, neatly dressed, with a forehead like the dome of St Paul’s’, Francis Galton possessed a mind quite remarkable enough to suit the shape of his skull. The origins and capacities of this mind, as well as their possible reflections in the shape of his head, were of great interest to Galton. Hereditary genius and phrenology were two of his interests. So, however, were mathematics, psychology, fingerprints, the weather, whistling, Shakespeare, genetics, African exploration, yawning, the Middle East, twins, families, novels and evolution.
At the age of sixteen, in 1838, Francis Galton was sitting down with his wealthy and intellectually distinguished family. It was ‘chilly out of doors, while indoors our family party were assembled in cosy comfort at dessert, after a good dinner, with a brightly burning fire, shining mahogany table, wine, fruits, and all the rest’. A medical career was being discussed for Galton, and a family friend had promised to offer him a taste of it before he committed himself. So it was that a note arrived offering Galton the immediate opportunity for leaving dinner, venturing outside and going to see the post-mortem on a newly dead housemaid. ‘Oh,’ he exclaimed, ‘the mixture of revulsion, wonder, interest, and excitement!’
The girl had died, rather rapidly, from a perforation in her stomach – exactly the sort of thing that willow caused, and that doctors had not yet identified as one of the drug’s side effects. As he was sewing up her belly, the surgeon doing the autopsy pricked his finger. Germs from the girl’s corpse were inoculated into his flesh, and over the following days the infection grew worse and the surgeon’s future looked bleak. Against expectations, he eventually survived.
Impressed by these serious experiences, Galton launched himself into medicine. At the Birmingham General Hospital in the early 1840s he ‘learnt the difference between infusions, decoctions, tinctures, and extracts’ – all of which, with the exceptions of cinchona, opium and willow, varied on a scale of therapeutic value from poisonous through to useless. Galton availed himself of liquorice (used as a diuretic, a drug to make people urinate) and of poppy seeds. Both tasted pleasant, and neither had any particular effect on him. These were years ‘long before those of chloroform, and many long years before that of Pasteur and Sir Joseph Lister. The stethoscope was considered generally to be new-fangled.’
It fell to Galton to deal with the traumas that he could, and to call for help when needed. He set bones, fixed dislocations, staunched bleeding sometimes and created it often – cutting open veins and arteries in the belief that losing blood was good for people. He dressed burns, watching the neat bandages fester with pus as the patients deteriorated. He shaved heads, using the blood from the wounds as a lather, and stitched gaping scalps. And he developed the feeling that there was something to be learnt from ‘the apparently unmoral course of Nature’, this stream of misery and suffering. ‘Blind Nature seems to vivisect ruthlessly,’ he wrote. ‘Let us as reasonable creatures elicit all the good we can from her vivisections.’ The horrors of the patients watching each other die struck him, as did the uselessness of much of what he had to offer. Under orders to apply a mustard dressing to a girl sick with typhus, he heard her plead to be left alone. ‘Please leave me in peace,’ she begged him. ‘I know I am dying, and am not suffering.’ Ignoring the instructions from his teacher, Galton did as she asked.
Perhaps because of Galton’s heritage – there seemed to be no one in the family who was not a Fellow of the Royal Society, a Darwin, or a gifted scientist – he remained aware of medicine’s lacks, even as he was beguiled by its practices. A man became unconscious with drink, and as he lay on the road a wagon rolled over his legs, crushing the bones past hope of recovery. A surgeon amputated both without his waking up, and Galton could not work out why doctors did not deliberately use alcohol to knock their patients senseless before operations. It was a very reasonable question to ask, without any obviously good answer. Another man ‘stumbled into a cauldron of scalding pitch’. He was pulled away, but in places the pitch was stuck to his melted skin and could not be removed. One leg was encased with the stuff, and the doctors could do little for it. The other was not so badly damaged, and they dressed it properly with a healing poultice. As the days went by, the more severely injured and more lightly medicated leg recovered much more quickly. ‘It seemed clear’, concluded Galton, ‘that the art of dressing was far behind what was possible.’ Despite his insight, he failed to draw the full lesson: that this particular natural vivisection strongly suggested either that dressings made wounds worse or that pitch made them better. Blind belief in the utility of medications was stuck onto people’s minds, the way the boiling pitch stuck to flesh, but without any of the wholesome qualities. ‘I was so keen at my medical work,’ said Galton, ‘I began by taking small doses of all that were included in the pharmacopoeia, commencing with the letter A. It was an interesting experience, but had obvious drawbacks.’
It seemed to him that progress was being made. ‘The signs of advance were all about and in the air. The microscope had rather suddenly attained a position of much enhanced importance.’ This was in 1839, almost two hundred years after Leeuwenhoek had come across his first magnifying glass and gone on to describe microscopic life. The microscope was an impressive piece of technology, but the only thing it helped a doctor to offer was an extra bit of pomp: there were no benefits for the patients.
‘There is still much lack of exact knowledge of what Nature can do without assistance from medicine,’ wrote Galton shrewdly, ‘if aided only by cheering influences, rest, suggestions, and good nursing.’ The lack of knowledge was because nobody had yet thought of the right way of seeking for it. Without asking nature the proper questions and in reliable ways, doctors received no useful answers. Galton suggested a way that they might – if they had a mind to – approach the world much more effectively. ‘Suppose two different and competing treatments of a particular malady,’ he suggested. ‘Let the patients suffering under it be given the option of being placed under Dr. A. or Dr. B., the respective representatives of the two methods, and the results be statistically compared. A co-operation without partisanship between many large hospitals ought to speedily settle doubts that now hang unnecessarily long under dispute.’ Doctors, however, thought differently. Dr A. could see no reason for such an examination, since it was clear to him that his methods worked. Dr B., for all that he felt Dr A. to be sadly mistaken, was equally sure in his own designs. They disagreed over many things, but were equally sure their own ideas were correct. Neither could see the need for a trial of them.
What follows, in Galton’s autobiography, is a passage that can sound a little bland if you read it too quickly. In fact it is a summary of why doctors had always failed their patients, an explanation for why unstructured observations, and a reliance on experience and intuition, are misleading:
Medical statistics are, however, the least suitable of any I know for refined comparisons, because the conditions that cannot be, or at all events are not taken into account, are local, very influential, and apt to differ greatly. It is, however, humiliating to find how much has failed to attract attention for want of even the rudest statistics. I doubt whether the unaided apprehension of man suffices to distinguish between the frequency of what occurs on an average four times in ten events and one that occurs five times.
In other words, people and their diseases vary so much that using your own personal experience to compare them is generally useless. This man’s tuberculosis is not the same as that woman’s; this child’s sore throat is different from her mother’s. The prospect of making accurate comparisons becomes hopeless. Galton is making the point that if you have seen ten episodes of a disease – often spread over a period of time – you are unlikely to notice
the difference between an outcome that occurs four times as opposed to five. In other words, if your medicine increases someone’s likelihood of living by a quarter – or, similarly, makes them more likely to die – you will not see it. This was why doctors in the seventeenth century had been so slow to notice that cinchona, so brilliant at treating malaria, was better than Peruvian balsam bark, which was useless: many people who got malaria recovered anyway, and many of those given cinchona died all the same. The Jesuit bark made more than a quarter’s difference and yet many doctors were unsure if it really helped.
Galton gave examples of the medical errors he could see, of connections overlooked and causes of disease that were misunderstood. He was particularly struck with the medical habit of declaring, with absolute conviction, for the superiority of particular diets – convictions which varied drastically between doctors. Alcohol was something else that the medical profession always thought it knew the best use for. Galen, acting as physician to the Roman emperor Marcus Aurelius, worked his way through the imperial cellars, searching for the healthiest wines to offer his patient. He was convinced that there was a difference between them. After much research, dutifully undertaken, Galen concluded that the healthiest wine was the one that tasted best. A friend of Galton’s, searching through the records of his ‘very old and eminent firm of wine merchants’, had looked at what doctors prescribed over the years for his company’s customers. He found ‘that every class of wine had in its turn been favoured by the doctors’. No one, in other words, had the faintest clue. By advocating statistical trials, Galton was suggesting the way in which proper comparisons might help them to try and find out.
