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

by Burch, Druin

  The impact of the artificial dyes was vast, not only in terms of fashion and economics but also in stimulating the development of organic chemistry. What had been an academic field became of immense industrial importance. This was scientific progress that people could see, a visible and vivid reminder of the power of invention, and the promise it held to add colour to people’s lives.

  Worries about toxicity developed early, partly in response to the real danger posed by arsenic in the manufacture of some dyes. These concerns were almost immediately exaggerated into a widespread belief that all aniline dyes, and possibly all the products of chemists and factories everywhere, were inherently poisonous. Brewers in the north of England discovered that beer made from Thames water had a pleasantly bitter taste by virtue of a molecule it picked up from the river. Picric acid, the molecule in question, began to be added by northern brewers to produce the same effects. Even as chemists were able to establish molecular similarities – to show that picric acid added to Burton beer was the same as that which the waters of the Thames added in London – people were wondering if a molecule’s power lay not in its structure but in its provenance, whether beer with naturally acquired picric acid was safer than when someone had tipped the ingredient in from a flask.

  Most of the key steps in the developing dye industry were British. Faraday found benzene, Mansfield showed how to make it on a large scale from coal tar, Perkin and other of his compatriots came up with many of the early colours. Despite it all, in the wake of Prince Albert’s death in 1861 Hofmann found that the British were not really interested in science at all, except as an amateur hobby. He returned to Germany. The British chemists that he left behind were struck by their country’s lack of interest in encouraging competitive commercialisation of new chemical products. Britain began losing its early lead to German competition.

  During the second half of the nineteenth century, Germany led in both industrial chemistry and medical research. Bismarck Brown rapidly joined Britannia Violet in the new pantheon of colours. The industry that Perkin founded in London was adopted far more vigorously on the banks of the Rhine than the Thames. Conducive patent laws, government encouragement and more thoughtful entrepreneurs all helped. Vital, also, was the contempt that scientifically minded Britons tended to feel for commercialising their work. ‘England is not the land of science,’ said a German delegate to the 1837 Liverpool conference of the British Association for the Advancement of Science. It worshipped the gentleman amateur to a damaging degree. ‘There is only widespread dilettantism, [English] chemists are ashamed to be known by that name because it has been assumed by the apothecaries, who are despised.’

  By 1879 there were seventeen dye-works in Germany, and only six in England. When the First World War broke out, Germany was supplying three quarters of the world’s dyes. England, despite having given birth to the industry, was importing from Germany 80 per cent of what it needed.

  The immediate importance of dyes to medical research was through their power to expose the processes of both health and disease. The history of their use in this way was already old. In 1566, madder, the ancient vegetable dye, was noted to stain the bodies of the sheep that fed on it. An animal’s bones turned red. Just over a hundred years later Raymond Vieussens, a French anatomist, was injecting saffron brandy into the necks of animals, pushing it into their carotid arteries to see which bits of their brains changed colour.

  At the same time, in England, Robert Hooke was using his ‘sharpen’d Pen-knife’ to cut thin slices of cork. He went on to examine them with the use of a new tool, the microscope. Leeuwenhoek’s demonstration of ‘animalcules’ with the microscope should have alerted the world to something important. Here was the opportunity to understand crucial new things about the way in which life worked. Had it sparked the interest it deserved, it could have led to the acceptance of germ theory centuries ahead of Pasteur. A few years after Robert Hooke sliced cork, Leeuwenhoek was doing the same. Contact with the Royal Society of which Hooke was a part gave Leeuwenhoek an audience for his research. A letter from Leeuwenhoek to the Royal Society in 1674 had some of his preparations attached to it – thin pieces of cork, of quill, of elder and ‘the optic nerve of a cow’.

  In a later letter, from 1714, Leeuwenhoek told the Royal Society about his efforts to combine such slices with coloured stains. Like Vieussens, Leeuwenhoek used saffron. He wanted to compare the muscle of a fat cow with that of a thin one, and wrote that:

  Since the fibres, cut into the thinnest possible layers, were so transparent that they could hardly be recognised, I have macerated a little crocus in brandy. To make the flesh particles more visible to the artist, I have merely moistened them with this wine, whereupon they were bright with a yellow colour.

  Not many people read Leeuwenhoek’s letter, then or after. A Harvard anatomist, Frederick Lewis, coming upon it during the Second World War, was so excited by the discovery that he repeated the experiment, simmering some saffron up in Boston tap water before applying it to a thinly sliced piece of steak and finding that ‘the fibers indeed glow with a golden yellow color’.

  People had been adding dyes to the soil and water of plants for a long time before – turning lilies red with powdered cinnabar, or using saffron to make roses yellow – but it was not until the early 1700s that Nicolas Sarrabat, a Jesuit priest and natural philosopher in Lyons, made use of the technique to try to determine how plants worked. He used the Mexican pokeweed berry, finding that its colour penetrated the smallest branches of the roots. When the plant under investigation was washed, the stain remained, visibly outlining the portions of the roots where the absence of its epidermis, the plant’s skin, allowed the transfer of nutrients and water.

  Despite these hints, people were slow to catch on that a dye’s ability to stain selective parts of an organism provided a window onto life’s inner workings. Intrigued by madder, in 1736 the British surgeon John Belchier sat down to eat a pig that had been fed on the stuff. The bones and the teeth were red. ‘Neither the fleshy nor cartilaginous parts’, he recorded, ‘suffered the least alteration in colour or in taste.’

  Attempts over the following twenty years to selectively dye plant structures led to mixed success. Charles Bonnet, a Swiss lawyer with an active interest in science, used madder and rose and black ink to stain the roots of peas and beans. His efforts, he judged, were ‘only weak attempts’, but the method was ‘a rich mine’. He put camphor in brandy and infused it into a living pear – the leaves took on the camphor’s scent, but the fruit seemed not to. After reading Bonnet’s 1754 work Recherches sur l’usage des feuilles dans les plantes, a medical student named Georg Christian Reichel showed that he could use red stains to prove that the spiral ducts of a plant distributed sap rather than air.

  From here on interest accelerated. An English doctor, John Hill, used both cochineal and lead to substantiate his 1770 work The Construction of Timber. The vessels by which trees distributed the fluids essential for their lives could, by means of staining, be ‘beautifully seen’. Hill developed a machine for cutting sections of his stained wood, a great improvement on Hooke’s sharpened penknife, as well as ways of stiffening and blanching the slices that needed it.

  Wilhelm Friedrich von Gleichen, who converted his unpromising beginnings to a career of courtly and military success, spent the second part of his life on science. Moved by the work of John Hill and by Leeuwenhoek’s animalcules, in 1777 he showed that indigo and cochineal could illuminate the world of these microscopic creatures:

  The bones of animals coloured by the feeding of madder roots led me to this idea. So I coloured some water with carmine, and mixed it with an infusion of wheat in which a swarm of the largest ear-drop organisms and small oval animalcules had been living some months.

  The animalcules might be small, but von Gleichen felt that their take-up of the dye was proof that, in some manner at least, they ate and drank like larger creatures. It was a discovery advanced in 1830 when Christian Gottf
ried Ehrenberg figured out that only certain dyes were suitable for living creatures: ‘These experiments’, he noted, ‘require organic dyestuffs.’ The lead and other substances that dyers often used were too frequently fatal to the animals he wished to study.

  Plant experiments dominated, but as the nineteenth century wore on, interest in using stains on larger animals grew. In 1851 the Marquis Alfonso Corti used a carmine dye to illuminate the structure of the inner ear. ‘Under the microscope, I found that all its tissue was coloured red, being darker where it was thicker. The holes were clearly seen as small oval windows. I could easily be sure that there was really no tissue in the holes, and I could make out their borders with perfect distinctness.’ He was describing the minute holes down which nerves travelled, holes being revealed for the first time by the stain. Carmine, pointed out the marquis, showed up the nuclei of cells. It was an observation of great potential, and situated as it was ‘in a great paper in an important German journal’ it should have won attention. Instead, in a mid-nineteenth-century world where anatomy, physiology and chemistry were increasingly dominated by the successful Germans, ‘it attracted no notice: [since] it was written in French’.

  Looking at the names of those who were working in microscopy, you get an impression of the reasons for much of the German success. The work there was being done by professionals, greatly supported by academies and universities. England relied on hobbyists. Lord Osborne demonstrated the staining of wheat cell nuclei to London’s Microscopical Society in 1857, while pointing out that as a ‘mere amateur’ he ‘made no attempt to resolve any question in chemistry’. The same year, Hermann Welcker, the gifted German doctor and anatomist, showed the value of stains in illuminating the nuclei of cells in frogs. Leading authors in England and elsewhere heard about Welcker’s findings even as Osborne’s failed to reach them.

  *

  Adolf von Baeyer was fascinated by dyes from a young age. He dallied with physics and mathematics as a student at the University of Berlin, then went back to chemistry. From 1856 he was working for Bunsen in Heidelberg, and from the next year for Kekulé, of the benzene-ring dream, in Heidelberg and then in Ghent. From 1866, responding to the urging of Hofmann, the University of Berlin appointed von Baeyer as a senior lecturer, giving him no money but plentiful lab space. He worked on dyes, developing several new classes of chemical and industrial importance. Success, including a Nobel Prize in 1905, firmed rather than dissolved his belief in the essential humility required of a man in possession of theories rather than evidence. Those who designed experiments simply to confirm their prejudices were in danger, he felt, of designing bad ones, of misinterpreting their results, or even of fatally convincing themselves that their theories were too good to need such testing. ‘I have never set up an experiment to see whether I was right,’ said von Baeyer, ‘but to see how the materials behave.’

  Methylene blue is an aniline dye. In its powdered form it is a dark deep green; diluted in fluid it looks something like a clear and hopeful sky. It was discovered in 1876 by Heinrich Caro (involved in the development of Bismarck Brown) in collaboration with Baeyer. Caro was laboratory director at Badische Anilin & Soda-Fabrik – BASF. Set up in 1865 in response to the great opportunities for industrial chemistry in Germany, BASF’s patent on methylene blue was Germany’s first on a coal tar dye, and it became crucially important, through the work of Robert Koch and Paul Ehrlich, in the development of modern medicine.

  Pasteur performed marvels in France in the 1860s, persuading the world of the truth of germ theory. A host of incomprehensible diseases were suddenly made clear by the idea of infection, the notion that invisible micro-organisms could invade the body and turn health into illness. Here was suddenly a key to understanding, preventing and potentially treating a host of diseases in previously unthought-of ways.

  Despite Pasteur’s start, it was once more in Germany that the new techniques really shone. Robert Koch found the organism that caused anthrax in 1877, tuberculosis in 1882 and cholera in 1883. He even developed rules for other microbe hunters: ‘Koch’s postulates’ – intellectual devices for reliably tying together diseases with their causative micro-organisms. Together with a climate of support for seriously conducted science, Germany forged ahead.

  One of those supported and inspired by Koch was Paul Ehrlich. He was born in 1854, in Strehlen, Upper Silesia – then part of Prussia, now Poland – and his childhood passions were tied up with this new discipline of microbiology. As a schoolboy he tinkered with microscopes and was introduced to tissue-staining by his cousin, Karl Weigert, whose Breslau laboratory he later worked in. Weigert showed him how aniline dyes could colour cells and tissues, revealing their structure and relationships. Ehrlich was enthralled, ‘awakened’, as he later remembered, ‘to the love and understanding of dyes that have accompanied me throughout my career’. He pursued the subject for his doctorate. Classmates remembered him as the man with the multi-coloured fingers. Over the next five years he used his dyes to explore blood cells, then bacteria. Frustrated after a time with injecting dyes into dead creatures, Ehrlich further developed ‘vital staining’, showing how methylene blue and other dyes could be injected into, as well as ingested by, living creatures. With encouragement, Ehrlich found, Nature not only showed her secrets, but did so in the most glorious of colours:

  If a small quantity of methylene blue is injected into a frog, and a small piece of the tongue is excised and examined, one sees the finest twigs of the nerves beautifully stained, a magnificent dark blue, against a colourless background.

  It was Koch who showed how to use methylene blue to stain the tubercle bacillus. With the right dyes the cause of tuberculosis, this ancient and terrible disease, was not only discovered; it was displayed to the world in hues of beautiful pink and blue. Ehrlich was present at the meeting when Koch announced his discovery, and sat close enough to notice what years of work had done to Koch’s hands. Their skin was dark and wrinkled, damaged by the stains and disinfectants that the tasks required. Ehrlich listened to Koch’s announcement in wonder. ‘I hold that evening’, he said later, ‘to be the most important experience of my scientific life.’

  That was in 1882. Largely unwelcome in Berlin’s Charité Hospital, where neither his ideas nor his Judaism were popular, Ehrlich became ill. Nevertheless he refined Koch’s technique, and, in 1887, used the latest techniques to prove to himself that the spittle he was coughing up contained the tubercle bacillus. The discovery of the bug had not yet led to treatments. Ehrlich went to Egypt, hoping the climate would help his lungs heal. Two years later he returned, feeling somewhat better, this time to work as an assistant at Koch’s new Institute for Infectious Diseases.

  In Koch’s laboratory, Ehrlich was at the heart of the world of medical research – a world that was still small. August von Wasserman, who found his own success researching syphilis, remembered the excitement of the concentration of talents:

  If a comparison of any sort is appropriate among such great men, I have to say that Paul Ehrlich was the champagne among the wines. While Koch appeared as the eternally serious-minded academic who thoughtfully weighed and stressed every word, disdaining all theory, observing only what was factual, and describing it in studied terseness, Ehrlich was literally bubbling over with brilliant ideas and views . . .

  Ehrlich’s laboratory, lined with the palette of his aniline dyes, was a startling sight. ‘The visitor was confronted with a symphony of colours,’ said Wasserman:

  without exaggeration, thousands upon thousands of glass bottles stood around, all filled with the brightest aniline dyes. Ehrlich . . . was involved in a highly stimulating exchange of ideas with the coal-tar industry. Thus, the industry sent him a sample of each new dye as soon as it appeared, and it was from that time onwards that his lifelong friendships and profound admiration for the creative geniuses and great names in the German dye industry derived.

  For a time, Ehrlich left his beloved dyes behind, concentrating instead on the way
in which animals seemed able to fight off infection. Serum is the name given to the fluid that blood moves in, the clear liquid turned red by the cells it contains. By exposing animals to infections, then bleeding them, Ehrlich found that their serum developed healing properties. Something in it contained the ingredients of immunity.

  Serum therapy set Ehrlich wondering again about his coloured stains. It was clear that something in serum worked as an anti-toxin, specifically capable of fighting off infections like tetanus and diphtheria. These ‘antibodies’ must work, Ehrlich reasoned, something in the manner of ‘magic bullets’, ones with the power to find a particular target and destroy only that. He described, sketchily but for the first time, the way living cells could produce antibodies. A letter from 1901, arguing that Ehrlich should be awarded the inaugural Nobel Prize for medicine, noted that his ‘explanation is vastly different and much more innovative than anything that has been thought or written on the origin of antibodies so far’. It was, despite that, only one amongst a large number of deeply original pieces of work, including Ehrlich’s ‘earlier haematological work, the discovery of the mast cells, the histo-chemical staining of living nerve fibres with methylene blue, [and] his vital staining’. In the event the award of medicine’s first Nobel was blocked by a chemist who incorrectly disagreed with some of Ehrlich’s ideas, and who disliked the ‘markedly Jewish atmosphere’ he created.

  When Ehrlich injected living rats with methylene blue, he found that the dye was taken up particularly by nerve cells. The stain had some selectivity for that bit of the body, a property that reminded Ehrlich of the manner in which antibodies seemed to pick out their targets. He set out to find chemicals that would work in the same way, mimicking the body’s own ability to fight off infection, binding themselves only to the infecting organisms and killing only them.