Taking the Medicine: A Short History of Medicine’s Beautiful Idea, and our Difficulty Swallowing It

by Burch, Druin

  The fallacy common to both groups of people – those who saw only harms, and those who saw only benefits – was ascribing a global value to something that was perfectly ambivalent in itself, and full of variation in its different manifestations. Two German chemists, Fritz Haber (who worked with Bunsen at Heidelberg and with Hofmann in Berlin) and Carl Bosch, spent years at the end of the nineteenth century and the start of the twentieth developing a technique for making ammonia. It meant that people could manufacture fertiliser, increasing the bounty of their land and saving themselves from starvation. The first use of the Haber–Bosch process was not to prevent famine but to worsen the slaughter of the First World War: ammonia was essential for explosives, and as early as 1914 Germany was running out. Haber helped keep the war going another four years, and while it progressed he worked on chemical weapons, and oversaw the first successful use of chlorine gas on the Western Front. His wife, objecting to such horrors, shot herself in the heart.

  Organic chemistry, like medicine, offered both therapies and injuries. The difficulty was in telling the difference, and making the choice.

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  1 The couple died in 1931, within a few days of each other. ‘If any notice is taken of my scientific work when I am gone,’ said David on his deathbed, ‘I should like it to be known that Mary is entitled to as much of the credit as I am.’

  10 Aspirin and Drug Development

  THE REVEREND STONE’S discovery of the uses of willow bark in the eighteenth century made it rapidly popular. It was much cheaper than quinine, and widely used as a result. In 1826 the Frenchman Henri Leroux had the first partial success in isolating what seemed to be the active ingredient. Johann Buchner in Munich succeeded in purifying it two years later and first used the name ‘salicin’ for the concentrated drug. Others found similar methods for the same process. Salicin turned out to be converted by the body into salicylic acid, which was itself generated directly from willow bark by the Italian chemist Raffaele Piria in 1838.

  Both salicin and salicylic acid, though, had nasty side effects. They damaged people’s guts, causing bleeding, diarrhoea and death. In 1853 a French pharmacist, Charles Gerhardt, figured out a way of buffering the salicylic acid and making it less corrosive. His interests were chemical rather than commercial and, satisfied with his success, he pursued it no further. Several German chemists repeated and improved on Gerhardt’s work, also without seeing that it had practical medical potential.

  Increases in European population during the nineteenth century meant that malaria grew less common. Swamps and marshes were drained so the land could be farmed. That meant less malaria, which was good, but it also helped to prolong people’s confusion about the difference between quinine and willow. Fewer cases of malaria meant less research into the disease, and a continuing delay in appreciating the difference between eliminating a fever and curing a disease.

  Rheumatoid arthritis was another condition that, like malaria, seemed to doctors to respond particularly well to extracts of salicin and salicylic acid. Painful swelling of the joints, often accompanied by fever, were the main symptoms of the disease. A Scottish doctor, Thomas Maclagan, wrote to the Lancet in 1876 about his experiences in using salicin for the disease. Others later argued over whether he, or a group of German physicians, first stumbled on the treatment. More important is some of the language that Maclagan used. He was initially complacent about the treatment’s side effects (‘I have never found the least inconvenience follow its use’) but encouragingly thoughtful in maintaining some doubts. ‘I shall be greatly obliged if those who try the remedy, and do not care to publish their observations,’ he wrote, ‘would kindly forward to me the results of their experience, be it favourable or otherwise.’ The notion that unsuccessful uses of the drug were less likely to get published was implicit. Some progress was being made, both in the capacity of doctors to think and also in their ability to prescribe drugs with at least some benefits.

  At the University of Munich, chemists continued to try to do what Perkin had so completely failed in doing – producing synthetic quinine. By 1882 Ernst Otto Fischer, and Wilhelm Koenigs, supervised by Ernst’s cousin Emil Fischer, produced novel compounds that they thought were similar to quinine. Although their ideas about quinine’s molecular structure later turned out to be mistaken, one of the new molecules they produced did indeed seem to share with quinine the ability to bring down fevers.

  The Munich chemists took out a patent and sought a company to back them. They chose a dyestuff manufacturer. The Frankfurt company Farbwerke, vorm. Meister, Lucius & Brüning, had never made a drug before. No dyestuff company ever had. They knew enough about chemicals and markets, however, to spot an opportunity. In 1882, selling their anti-fever drug under the trade name Kairin, from the Greek word for ‘timely’, they went into this new business. By the following year the company formally created a pharmaceutical division, and soon it became so successful that it needed a simpler name. It became Farbwerke Hoechst, or, in practice, just Hoechst.1

  Hoechst’s new product was the start, not only of dyestuff companies getting heavily involved in drug manufacture, but also of a range of medications for fevers. Seeing Hoechst’s production of Kairin, which was soon attracting bad publicity for the drug’s toxic side effects, a group of independent chemists offered Hoechst their alternative drug. It was called Antipyrine, and was introduced on the basis of what the chemists knew about it, which was not a great deal. As with the group that developed Kairin, there were basic mistakes about this drug’s structure. Both were largely based on two benzene rings. The first was a tetrahydroquinoline – as quinine was also incorrectly thought to be – and the second was believed to be a tetrahydroquinoline but turned out later, in fact, to be a derivative of pyrazolone, an unrelated molecule. Since a drug’s overall effects can even now be predicted only poorly on the basis of its function, these mistakes were less serious than they seemed. The key error was that only a few unstructured tests were performed on animals, and a handful of test doses of each drug given to small numbers of healthy and febrile people. The idea that drugs might do harms, subtler and harder to see than their ability to reduce a fever, did not readily occur to people. ‘Among the many remedies that have been discovered to alleviate the ills of suffering humanity,’ said the New York Times on the first day of 1886, without much evidence, ‘none is more important than Antipyrine.’ The paper endorsed its safety without justification, but added an important caveat. ‘It should be understood that Antipyrine does not claim to cure a disease, it simply reduces temperature.’

  Hoechst showed some initial caution in using the drug. After the pre-release tests, they sent it only to hospitals willing to report back on how it performed. By 1884 there were more than forty academic papers, and the majority were positive. For everyone involved in the drug, that felt like enough.

  Naphthalene, a coal tar derivative, is poisonous to humans. Not terrifically: it makes up the main ingredient of mothballs, and you need dedication to eat enough of them to kill yourself. Swallow enough mothballs, however, and your red blood cells begin to split apart. Doctors at the University of Strasbourg in the 1880s had no way of knowing this when they started giving naphthalene to patients suffering from worm infestations. Their ignorance of its full effects sounds like a reasonable excuse for their actions; in the context of their time it is usually accepted as being so. Animal experimentation, however, had already been shown to be useful at spotting unexpected toxicity. The willingness of doctors to try novel treatments on their patients, rather than on rabbits, should still grate. It was possible to test extensively for drug safety in animals by the end of the nineteenth century, but few doctors or chemists did.

  When Adolf Kussmaul, the head of Strasbourg University’s medical department, asked two of his juniors, Arnold Cahn and Paul Hepp, to try out naphthalene’s effects on patients with worms, they did so. There appeared to be neither obvious benefits nor harms. Consumed with optimism, and the spirit of haphazard
trial and error, they gave it to a patient suffering from a fever rather than from worms. The fever vanished. Publicly, they attributed their discovery of the drug’s effect to ‘a fortunate accident’, a curious euphemism for their willingness to take chances with other people’s health.

  Naphthalene, however, was meant to smell, just as mothballs do. The drug that successfully treated the patient’s fever did not. Cahn and Hepp discovered that what the hospital pharmacy had labelled as naphthalene was not naphthalene at all. They contacted the dye works that had made the product, Kalle & Co., wanting to know what they had got hold of. The drug turned out to be acetanilide, a sweet-tasting, white-coloured derivative of aniline. The company learnt from Cahn and Hepp that they possessed a potential product. But it was a tricky one to sell. Acetanilide was a common compound, meaning there was no way they could secure a patent on it. The solution seemed to be to give it a different name – Antifebrin – and to hope that made it smell a little sweeter. Remarkably, it worked. The branding was enough. Doctors preferred ‘Antifebrin’ to the cheaper ‘acetanilide’, and were happy enough to prescribe it by its expensive trade name, even knowing exactly what it was.

  In 1889, when an influenza epidemic hit Europe, the habit of taking a drug to banish a fever became cemented in Western culture. Thanks to companies like Kalle and Hoechst, almost everyone could afford to take something. Whether it affected their chances of survival, for better or for worse, was not a question that was seriously addressed. They liked it, their doctors liked it, the drug companies liked it – everyone was happy. The drugs made people feel better, therefore they believed they must be doing them good.

  In 1896, Hoechst began selling a slightly adjusted version of Antipyrin under the name Pyramidon. It was three times as powerful – which sounded good, even if the only actual difference it made was that you needed to swallow less of it to achieve the same effect. Like Antipyrin, it became a bestseller. By 1908, Hoechst were doing very well indeed. Since the company making Antifebrin was also doing well, Hoechst bought them. Life looked promising for those making pharmaceuticals.

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  Friedrich Bayer was born in 1825 near Cologne. His father was a silk worker, and at the age of fourteen Bayer began an apprenticeship with a dyestuffs dealership. William Perkin’s discoveries were years ahead, so the dyes they used came from animals and vegetables rather than aniline.2

  Bayer was successful, setting himself up in business and trading dyes across Europe. He met a like-minded fellow named Johann Weskott, and the two men joined forces. Perkin’s innovations were sweeping across their business, and they needed to respond. They imported some of the early aniline dyes and tried to understand how to produce them themselves. In 1863 they founded the firm of Friedrich Bayer & Co.

  It grew steadily, and when Bayer died in 1880, and Weskott in 1881, it employed over 300 people. Weskott’s and Bayer’s descendants inherited the company. They renamed it (not with notable linguistic flair) as Farbenfabriken vormals Friedrich Bayer & Company – ‘the Dye Factory formerly known as Friedrich Bayer & Company’ – and raised money by a sell-off of shares. Part of their purpose was to invest more capital in research, which meant paying for laboratories and for chemists to fill them.

  One of the new chemists was named Carl Duisberg. On his twenty-third birthday, having previously struggled to scratch a living with his chemistry qualifications, Duisberg became a full-time Bayer employee. Within a short space of time he developed new ways of arriving at two existing colours (thereby circumventing patent law) and discovered a third colour that was entirely new – to the productions of organic chemists, at least. He was rapidly promoted. From being handed research projects became able to give ones of his own devising to other staff.

  Reading the descriptions of Antifebrin in 1885, Duisberg realised that this was something Bayer should be competing with. He had the company produce slightly altered versions of the compound. One seemed to work well, and the following year Bayer put Phenacetin onto the open market. It sold prodigiously, but Duisberg continued directing the company to try to develop alternatives. By 1890 he was largely in control of Bayer. In 1893, in collaboration with an eminent physician named Joseph von Mering, Duisberg and Bayer tried out a compound structurally similar to Phenacetin. N-(4-hydroxyphenyl)ethanamide was soon renamed Paracetamol, but just as quickly rejected. It worked well, concluded von Mering, but it was toxic to the blood. Paracetamol was shelved as useless.

  Meanwhile, Hoechst’s Antipyrine was selling well. It took until 1934 for doctors to notice that Antipyrine killed people. Not many, but some. Their realisation did not come as the result of a careful trial, comparing those who took it with those who did not. Instead it came because the blood disorder it caused was rare enough to get attention. In contrast it took until 1948 for people to notice the toxicity of Antifebrin. The liver and kidney damage it caused was far less remarkable. Not that it did less harm, it was just that slow failure of liver and kidneys was relatively common, so without structured trials capable of recognising the cause of these extra deaths, it took longer for anyone to connect them with the drug. The same was true for Phenacetin, discovered in the 1880s, where concerns over kidney damage took the best part of a century to surface. In 1949 a group of American researchers reported their discovery that the body turned Phenacetin into two different compounds. One, phenetidine, was responsible for most of the toxicity, the other, which was actually Paracetamol, for most of the benefits.

  Paracetamol’s rediscovery in this manner prompted a revision of von Mering’s opinion that it was too dangerous to use. Most of the explanations for its peculiar rejection in the 1890s suggest that there were impurities in the compound that von Mering tested, which accounted for his mistaken conclusion. His eminence kept anyone from noticing this for another fifty years.

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  In the late nineteenth century coal tar, along with its derivative phenol, was being used as an external antiseptic. Observations that the two compounds prevented decay in meat and vegetables led on to their application to human wounds. On that basis the Scottish surgeon Lister developed antisepsis – which, developed by extension into asepsis, revolutionised surgery. Antisepsis meant deploying compounds that were toxic to the micro-organisms causing infectious diseases; asepsis meant keeping operating theatres and surgical wounds so scrupulously clean that the bugs never got a chance to establish themselves in the first place. Not only was Lister able to make theatres safer places to be than ever before, enabling surgeons to open up chests and skulls and abdomens with every hope that their patients would survive, he also used numbers to demonstrate the power of his new techniques effectively, comparing survival percentages before and after his technique’s introduction. The gradual increase of statistics in medicine was subtler than that of asepsis, but every bit as powerful.

  By the 1870s, doctors had realised that phenol and coal were too corrosive to be useful wound dressings, and certainly too toxic to take internally. Their potential, however, was something these doctors were very interested in. They were learning about the impact of bacteria on the outside of the body, and speculating about their influence within. Disinfecting the gut seemed to hold out therapeutic promise. Getting people to swallow phenol was similar to having them swill down bleach – it killed the germs well enough, but the overall effect on the patient was not good. It was too corrosive to the guts. Salicylic acid become popular as an alternative. It was antiseptic and, although it was still caustic, it was mild in comparison with phenol. In 1853 the German chemist Hermann Kolbe figured out how to make salicylic acid directly from coal tar, without having to trouble with the willow.3 From 1874 the process was successfully industrialised, and salicylic acid became very much cheaper as a result.

  By 1897, Bayer chemists had developed versions of salicylic acid that they hoped would provide all the benefits with fewer of the harms. Salicylic acid could irritate the stomach lining to the point of dissolving a hole in it. One of the alternative versions that
Bayer investigated, acetylsalicylic acid, was the buffered compound previously made by the French academic chemist Charles Gerhardt in 1853. Gerhardt had done nothing with his discovery besides publishing it.

  Bayer employees showed great interest in the substance, until a leading member of the company, Heinrich Dreser, rejected it as being damaging to the heart. His colleague, Arthur Eichengrün, thought he was wrong. Eichengrün pushed for clinical experiments, but was overruled. Ignoring this, he arranged for acetylsalicylic acid to be secretly tested by doctors in Berlin. The image of evil drug company employees, risking the lives of helpless patients, is not appropriate. Eichengrün shared his generation’s complacency about the long-term risk of drugs, and its mistaken optimism in the power of chemists to correctly predict effects on the human body, but his ignorance was sincere rather than manipulative. Before having the drug tested on Berlin patients, Eichengrün tried it out on himself.

  The drug performed better in Berlin than even Eichengrün expected. It eased fevers as well as the symptoms of rheumatoid arthritis, and it seemed to have fewer side effects than either salicin or salicylic acid. Given that Eichengrün had tested the drug behind Dreser’s back, it was unsurprising that the latter took against it. The news of the drug’s benefits came from independent doctors, but when the reports reached Dreser, he decided that his own prejudices were more reliable. ‘This is the usual Berlin boasting,’ Dreser wrote on the report, ‘the product has no value.’

  Carl Duisberg settled the argument by ordering a second study done. When it supported Eichengrün, he put Bayer’s weight behind the product. Since the product had been created by acetylation, and one of the sources for salicin had originally been not just willow but also meadowsweet – Spirea ulmaria – Eichengrün put an ‘a’ in front of ‘spirea’, jiggled the letters around a little, and came up with the new drug’s trade name: Aspirin.