by Burch, Druin
It is easy to get an impression of Ehrlich as a man consumed with microbes and chemicals, just as it is straightforward to imagine that these successful new doctors were less concerned with individual suffering than their less effective predecessors of generations before. Neither impression is true. Ehrlich was neither cold nor consumed with any imaginary omnipotence. He knew that his tuberculosis might come back at any point, and that there was little anyone could do about it. And he worked in the wards as well as the laboratories.
Whoever has seen Paul Ehrlich at a sickbed in one of the spreading wards of a large hospital, must have noticed that this extraordinary man embodied the humanist as physician. I was touched by the tenderness with which he took care of his child patients, how he joked with them and tried to soothe their discomfort by caresses, and yet, at the same time, I noticed his unease to be in the middle of an impersonal machinery whose wheels were turning in his name and by his authority.
Aniline dyes let Ehrlich understand more about the constituents of blood than anyone before him. An array of different cell types, previously unknown, appeared as he stained blood with these coal tar derivatives. They appeared in blushes of pinks and blues and greens, cells and structures gleaming into being. This was the work that led him to find the mast cells his admirer recommended he be rewarded for. They were white cells that existed plentifully in everyone’s blood; without dyes, no one had understood them to be different from the other white cells around them.
In St Petersburg, in 1891, Yuri Romanovsky took blood from patients suffering from malaria and stained it. In patients treated with quinine, the malarial parasites were clearly damaged, the first definite indication that the drug acted by attacking the invader rather than supporting the host’s defences. The same year Ehrlich, knowing that methylene blue stained the malarial plasmodium, gave capsules of the dye to two patients suffering from malaria in Berlin. Both recovered. Unable to deliberately infect animals with malaria, and busy with a project on diphtheria, he never followed the finding up.
From 1896 Ehrlich won his independence. His Institute of Serum Research and Examination was opened in Berlin. Three years later, in 1899, it moved to Frankfurt and was renamed the Royal Prussian Institute for Experimental Therapy. Ehrlich’s collaboration with the dye companies continued. They sent him samples of the new colours they produced, and he tried to turn them to new uses.
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1 One famously solved by Kekulé dreaming of a snake swallowing its own tail, then waking to the realisation that benzene was a ring.
9 Medical Missionaries
WHILE GERMANY REMAINED the homeland of the microbe hunters, other nations still played parts. With their large overseas empire, the British were particularly interested in tropical diseases. Men like David Livingstone needed to understand them in order to survive, and wanted to understand them in order to help.
Livingstone’s medical investigations went hand in hand with his efforts in quite different forms of exploration. Born in Scotland in 1813, Livingstone grew up as one of seven children all sharing a tenement room with their parents. The room was owned by the mill company where David’s father worked, and where David, from the age of ten, went to join him. His education continued, however, at school in the evenings, and in private study by himself or with Dad. By the age of twenty-three Livingstone had saved enough money to put himself through medical school – and simultaneously train as a missionary. Religion and science, he felt, were complementary, the one as much the work of God as the other. In 1840, aged twenty-seven, he qualified for both.
A poor preacher, Livingstone turned out to be a superb missionary, at least in part due to his humility. Rather than trumpeting his message to people whether they were interested or not, Livingstone was content to begin by observation and exploration. ‘Christianity, Commerce and Civilisation’ is the motto inscribed on his statue at Victoria Falls. It sounds flat and even foolish today, but for Livingstone, it was vivid and real. It meant salvation, through building communities and communication. Medicine was vital to this cause. It was a way of winning friends as well as bringing aid, and it was also essential for survival. European exploration of Africa was limited as much by disease as by the difficulties of diplomacy. From his 1865 Narrative of an Expedition to the Zambesi, here are Livingstone’s instructions for surviving malaria:
A remedy composed of from six to eight grains of resin of jalap, the same of rhubarb, and three each of calomel and quinine, made up into four pills, with tincture of cardamoms, usually relieved all the symptoms in five or six hours . . . Quinine after or during the operation of the pills, in large doses every two or three hours, until deafness or cinchonism ensued, completed the cure. The only cases in which we found ourselves completely helpless, were those in which obstinate vomiting ensued.
Livingstone’s dosages of quinine were generous enough to make him more successful than his peers, but he, his wife and his daughter eventually died of malaria all the same. The combination of so many different ingredients, in his description from 1865, was a reminder of the extent to which the chemists had not yet revolutionised therapies. The only one that helped was quinine. The others, added to produce diarrhoea, harmed.
Earlier, in a letter dated 22 March 1858, and published on 1 May, Livingstone wrote to the British Medical Journal. From the steamer Pearl, off the Senegalese coast, he apologised for having been too busy to previously tell the journal’s correspondent that ‘the employment of arsenic in the disease which follows the bite of the tsetse occurred to my own mind’. He meant that it had occurred to him to use arsenic for a disease that seemed similar to malaria, but impervious to quinine. It was called ‘nagana’. Livingstone described an opportunistic animal experiment on a mare bitten repeatedly by tsetse flies, then left to die when it became sick. ‘I gave it two grains of arsenic in a little barley daily for about a week,’ Livingstone reported, and ‘the animal’s coat became so smooth and glossy that I imagined I had cured the complaint’.
Despite this early sign of hope, the horse never fully recovered, relapsing some months later:
I tried the arsenic again; but the mare became like a skeleton, and refused to touch the barley. When I tried to coax her, she turned her mild eye so imploringly, and so evidently meaning, ‘My dear fellow, I would rather die of the disease than of the doctor,’ that I could not force her.
The horse died six months after her original illness, long enough for Livingstone to feel convinced that the arsenic had helped prolong her life.
The arsenic solution he subsequently recommended was not new. It had been used in England since 1786, not to treat any particular disease but as an all-purpose tonic. There it slowly damaged or killed all those who took it, mistakenly succumbing to its description as being helpful for fevers, malaria, headaches and a host of other conditions for which it did no good at all. (Amongst its other effects, the arsenic destroyed the small blood vessels of the face. The resulting damage gave people’s cheeks what was believed to be a healthy glow).
Livingstone’s observation of the curative effects of arsenic fell into the grand scheme of similar medical intuitions: more full of optimism than truth. The mare who refused his medicated barley probably made a wise choice, dying more comfortably of the disease than she might have done of the arsenic medicine. It was true that arsenic killed the parasites that caused the disease, but it did the same to horses and to humans.
In the 1890s David Bruce, Australian-born but Scottish-raised, wanted to be a professional sportsman. Instead, a crippling bout of teenage pneumonia sent him towards medicine. Marrying the daughter of a colleague, and a woman who shared his scientific interests, Bruce joined the Army Medical Corps. A posting in Malta gave the couple an opportunity to pursue the methods of their joint hero, Koch. They looked for the cause of an unusual local disease, Malta fever, that affected cattle and sheep and humans. By staining infected blood with the aniline dye gentian violet, they found it.
After a period of research in Koch’s own
laboratory, the couple were posted to Africa. Asked to investigate an outbreak of nagana, they travelled to what was then Zululand. Nagana was decimating the cattle that the Zulus relied on, but it affected other animals too. David Bruce described it:
The horse stares, he has a watery discharge from his eyes and nose . . . During this time the animal is becoming more and more emaciated, he looks dull and hangs his head, his coat becoming harsh and thin in places . . . In severe stages, a horse presents a miserable appearance. He is a mere scarecrow, covered by rough hair, which falls off in places . . . At last he falls to the ground and dies of exhaustion.
The Bruces, using the staining techniques they had spent so long learning, found a worm-like parasite in the blood of the affected animals. They showed that it was responsible for the disease, and was spread by the bite of the tsetse fly. In honour of them it was given the name Trypanosoma brucei.
Sleeping sickness – the ‘African lethargy’ – had been known about in Europe from the fourteenth century. During the latter part of the nineteenth, it was spreading. In 1876 a French surgeon reported that it was emptying entire villages in Senegal; twenty years later it was decimating the human population around Lake Victoria. Contemporary estimates there suggested three quarters of a million dead. Together with an Italian, Count Aldo Castellani, the Bruces found a similar organism in the blood of those infected. Sleeping sickness and nagana were extensions of the same disease, both spread by the bite of the inch-long tsetse fly. Arsenic was poisonous to humans. The Bruces showed that it killed trypanosomes too.1
By 1901, researchers at the Pasteur Institute in France were able to use the trypanosome to deliberately infect laboratory rats and mice. That at least opened the way to test putative therapies more easily.
Ehrlich had shown that dyes could selectively stain certain bacteria. He theorised that there were receptors on the surface of bacteria different from those on human cells, and that if poisons gained access through these then they would kill the bacteria without killing the person who carried them. Stains provided a mentally and visually beautiful way of attempting to derive therapies of boundless benefit. ‘Initially, therefore,’ remembered Ehrlich, ‘chemotherapy was a “chromotherapy”.’ Chemotherapy – the use of chemistry to heal people – was a word that Ehrlich coined. No one better deserved to.
The problem now was how to move forward from a conceptual breakthrough – drugs that could theoretically target bacteria – to finding a practical demonstration. Some stains killed the creatures they were injected into, others accurately coloured only the infective organisms and yet were wholly harmless. If the toxicity could be tied into the selectiveness, the world would become a different place.
Vereinigte Chemische Werke, a German chemical company, started selling a new arsenic-based treatment for sleeping sickness at the beginning of the twentieth century. The compound had first been made in 1863, but nothing much had ever come of it. Now the Vereinigte chemical works thought it had potential. Without evidence, they sold it on the basis that it was as effective as previous drugs, but massively less toxic. They called it Atoxyl, to drive the message home. There were links between the chemical company and Ehrlich, and it was probably through them that a sample of the drug reached him. He tried it out on trypanosomes and, finding it useless, put it aside and turned to other things.
Then, in 1905, Ehrlich read an English paper suggesting Atoxyl really was active against sleeping sickness. Checking his work, he discovered they were correct. His mistake had been to try the drug out on the isolated organism, the trypanosome. In those circumstances it continued to show no effects. When it was given to a living creature already infected, the story was different. The Pasteur Institute’s techniques for infecting mice with sleeping sickness allowed him to see that something strange was happening. Testing his arsenic preparations on isolated trypanosomes, Ehrlich found they still had no impact – but giving them to living animals definitely did. The biological activity of trial compounds, he realised, could only be assessed in vivo, not in vitro. Life, not glass, was the tool required.
Still, though, the trouble was that the drug lacked sufficient selectivity to be safe. It damaged the infecting organism, but it did so at unacceptable expense, causing blindness and other problems. Atoxyl was badly named, and the claims for its safety that the Vereinigte company made were mistaken. Ehrlich showed that others had muddled the structural nature of the molecule. With a more accurate model, he wondered about the possibility of altering Atoxyl’s structure and therefore its effects. Could the selectivity of the molecule be somehow increased, keeping it active against sleeping sickness while making it safer to the humans who suffered from the disease? ‘We must strike the parasites and the parasites only, if possible,’ said Ehrlich, ‘and to do this, we must learn to aim with chemical substances!’
Ehrlich wanted something with a high ‘therapeutic index’, as toxic as possible for the parasite and as safe as conceivable for the host. In return for funding his research, he agreed to offer any patent rights to the nearby Cassella Dye Works. Deliberately infecting mice with sleeping sickness, Ehrlich tried out over a hundred different dyes to see if he could find any that were toxic to the Trypanosoma that caused the disease. Nagana Red became the name of the only one that seemed to work, wiping out the trypanosomes from the blood of the mice. It worked, though, for only a short time. Rather than dying after three or four days, the mice lived for five or six. Ehrlich asked his contacts at the Cassella Dye Works, soon to become part of Hoechst, to prepare him a modified version of the dye. He persuaded them to alter it, suggesting that a modification could make the dye better absorbed by the animals, thereby increasing its therapeutic power. The resulting dye, Trypan Red, was, as he expected, more powerful. Enthusiasm and desperation led to its use in humans. Again, it was not selective enough: it killed trypanosomes well enough, but it killed people too.
In 1905, while he was still continuing with his efforts to develop a drug for sleeping sickness, the cause of syphilis was uncovered. Treponema pallidum was the latest germ to be exposed by the new techniques of staining. It took up colour poorly and even with the brightest stains kept a pallid look. Despite that, it appeared a similar organism in many ways to the trypanosomes. Every compound that Ehrlich had produced was fetched out again, and tested for potency against this other disease. Sleeping sickness was important, but it was not much of a problem for the developed world. Syphilis was altogether different.
At first the work went slowly, the only animal model for syphilis being apes, and work with them being laborious and time-consuming. In 1909, though, the biologist Sacachiro Hata arrived from Tokyo to work with Ehrlich. Hata found a way of infecting rabbits with syphilis, making the work quicker and more practical. Testing the 606th of Ehrlich’s existing preparations, one that had been abandoned two years earlier as useless against sleeping sickness, Hata found that it worked for syphilis.
Ehrlich insisted on extensive animal experiments to make sure that compound 606 – or Salvarsan, as it came to be called – was free enough of toxicity to do more good than harm. He spoke about magic bullets, but he wanted to be sure he had not produced something more like buckshot, damaging everything around it. Finally convinced that he had not, from 1910 Ehrlich released samples widely, in return for full case information on every patient treated. Syphilis was sexually transmitted, chronic, incurable and eventually fatal. It held a position a hundred years ago roughly equivalent to that of AIDS before the development of the anti-retrovirals that keep that disease at bay. In syphilitics whose infections reached their brains and spinal cords, producing a condition called General Paralysis of the Insane, the effect of Salvarsan was unmistakably miraculous. (A related compound, developed a few years later specifically for trypanosomiasis, was similarly effective for that disease.)
Ehrlich showed that the molecular structure of a drug determined its effects, and he developed the concept of the cell surface receptor, the means by which compounds were sel
ective for certain targets. For all that, Salvarsan was a wonderfully clear indication of science’s inability to accurately predict a drug’s effect without experimentation. As with Atoxyl, culture dishes were not enough. The breakthrough had required rabbits, and lots of them.
Sometime later, the Zionist and chemist Chaim Weizmann met Ehrlich, wanting to enrol his support for the proposed Hebrew University in Jerusalem:
I have retained an ineradicable impression of Ehrlich. His figure was small and stocky, but he had a head of great beauty, delicately chiselled; and out of his face looked a pair of eyes which were the most penetrating that I have ever seen – but they were eyes filled with human kindness. Ehrlich knew that I was a chemist, but he did not know what I was coming to see him about. He therefore plunged at once into the subject of his researches. He introduced me to some of his assistants (since become famous) and especially to his rabbits and guinea pigs.
The animals were valuable in themselves, for their colour and their character. And beyond that they were keys to opening up the world, and discovering ways of making it better. Ehrlich loved them.
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It was not only in Germany and Britain that the aniline dye industry flourished. The New World was getting involved as well. The bays and harbours around New York, once famously full of oysters, wildlife and natural beauty, were becoming polluted and lifeless. In the 1880s, residents of Brooklyn noticed the effects of the blossoming dye industry on the Gowanus Canal, a channel reaching in from the bay. They ‘complained of the smell but were more struck by the colours. Dye manufacturers turned the waterway a different pigment every day. The canal was nicknamed “Lavender Lake”.’
Odd health beliefs about the industry were not confined to people whose minds exaggerated the fears. For all those who believed without proof that everything which came from industrial processes was unhealthy, there were others who believed the opposite for as little reason. Brooklynites took their asthmatic children to the waters of Lavender Lake, standing them on its bridges in the belief that the rising fumes must have healing powers.
