The Miraculous Fever-Tree

by Fiammetta Rocco

  The very next day he made his way to none other than William McIvor, the former superintendent of the botanical gardens in Mysore who had overseen the arrival and subsequent demise of Markham’s plants in India, and who was holidaying in London while waiting to take up his new appointment as the superintendent of the government cinchona plantations at Nilgiri. He agreed to take Ledger’s seeds, and to give Money an equivalent amount of succirubra seeds in exchange. Money heaved a sigh of relief.

  McIvor carried the calisaya seeds back to Nilgiri. After travelling many thousands of miles, and withstanding all manner of hardships, Ledger’s trove was now more or less evenly divided between Britain and Holland, two nations that would fight over the commerce of cinchona just as they had fought across the centuries over so much else.

  McIvor’s new seeds were planted alongside the Cinchona succirubra that Spruce had sent from Ecuador and the ill-fated calisaya seedlings that Markham had despatched all too hurriedly via Southampton and the Red Sea. Perhaps Ledger’s seeds had been out of the ground too long, perhaps it was the climate, but the fact remains that while those McIvor planted in India failed to flourish, those George Ledger had managed to sell to the Dutch Consul-General in London grew so well in Java that they eventually transformed not just the Dutch plantations, but the entire cinchona industry. For when the time came to measure the quinine content of the young trees, Ledger’s calisaya seedlings in Java would prove richer than any tree had done before. When a consignment was put up for auction in Amsterdam in 1877, the bark fetched more than five times the price of a similar consignment of succirubra.

  While Charles Ledger’s calisaya ensured large profits for the Java plantations and the merchants who traded on the Amsterdam exchange, and even after much debate won him a Dutch pension, for Manuel Incra Mamani, who had trekked through the forests of Bolivia and waited there through frost after frost, there was no such reward.

  When Charles Ledger learned of the success of his brother George’s trade with the Dutch, he wrote a letter to Mamani in Coroico, the small mountain village that overlooked the valleys where he had collected his first batch of seeds and where he now lived. Charles asked him to set out once more in search of seed in the Bolivian forest, and enclosed a down-payment against delivery of a future consignment. On his return from the forest, however, Mamani was arrested. The chief of police of the district had got wind of the fact that he was collecting seeds for a foreign buyer who wanted to smuggle them out of the country. He ordered that Mamani be imprisoned and beaten until he revealed who he was working for. But Mamani refused to betray Ledger. The police chief ordered him to be beaten again. For two weeks he was given little water and no food. Realising that he would not break, the police finally released him twenty days later. They confiscated his donkeys and his blankets, and he was forced to make his way to his village on foot. When he reached his home, his son Santiago later reported to Ledger, he could hardly stand. His damaged organs began to bleed anew, and a few days later he died.

  When Ledger’s Cinchona calisaya seeds were fully grown, it was found that the quinine content of the bark amounted not to the normal 2 or 3 per cent, but to as much as 14 per cent. Shortly after that, botanists studying Ledger’s seeds came to the conclusion that they were a previously unknown kind of cinchona. In his honour the variety was named Cinchona ledgeriana. Charles returned to Australia, where he would die a pauper. But his reputation is slowly being rehabilitated, and in 1994 a tombstone was finally erected in his memory in Sydney. Manuel Incra Mamani, who gave his life to help Ledger’s enterprise, has no memorial of any kind.

  9

  The Science – India, England and Italy

  ‘If you would see all of Nature gathered up at one point, in all her loveliness, and her skill, and her deadliness, and her sex, where would you find a more exquisite symbol than the Mosquito?’

  HENRY HAVELOCK ELLIS, 1920

  ‘I really believe the problem is solved, though I don’t like to say so … I have hardly restrained myself … I am on it.’

  RONALD ROSS to Sir Patrick Manson, 31 August 1897

  The garrisons that the British, the French and the Dutch had established along their trading routes evolved as the nineteenth century progressed into full-blown colonies. No longer was the European footprint in the tropics limited to a small defensive presence; it grew and spread as settlements expanded and the vanguard of men was swollen with the arrival of wives and children. Yet it was not inevitable that new discoveries about tropical diseases, especially malaria, would be made in these growing tropical colonies. Malaria had, after all, existed in Europe for centuries. The centres of medicine were still to be found there, and the best hospitals. But the colonies had one significant advantage over the old European nations, and that was a vast number of malaria patients. With a ready supply of infected blood at their disposal, it comes as no surprise that the most significant steps forward in our understanding of malaria and what causes it were taken by two army officers, one French and one British, one stationed in Algeria and the other in India, men whose ambition, energy and optimism made them in every sense children of empire.

  Charles-Louis-Alphonse Laveran was born in Paris in 1845, but raised mostly in Algeria. He came from a long line of physicians, and both his father and his grandfather had been doctors. In 1867 he graduated in medicine from the University of Strasbourg, on the border between France and what was then Prussia, and not far from where Philippe Bunau-Varilla had been born five years earlier. The two countries, never the firmest of friends, were undergoing one of their periodic bouts of ill will, and Laveran joined the French army. He was captured at the fall of Metz in 1870, although before long he was released and posted back to his regiment. In 1878, at the age of thirty-three, the gentle doctor with the pince-nez was posted to Bône, the city where St Augustine had died on the Mediterranean coast of north-eastern Algeria.

  The North African coast was infested by mosquitoes that had adapted to breeding in the confined waters of the oases and the irrigation waters of coastal farms. The French had introduced rice farming when they colonised Algeria in 1830, inadvertently giving a boost to the breeding of the anophelines. In the clinic where he worked, Laveran was confronted with malaria every day.

  In addition to holding a degree in public health, Laveran had spent four years as an Associate Professor of Epidemic Medicine at the French army’s medical school in Paris, Val de Grâce, occupying the very chair that had been established for his father. There he had come into contact with four doctors who were working extensively with malaria. One of them, F.C. Maillot, had spent many years in North Africa, where he had developed a highly successful practice prescribing quinine. Two others had been investigating the pathology of malaria, using the newly invented microscope to examine glass slides smeared with human blood. Perhaps it was this that led Laveran to acquire a microscope of his own.

  The instrument he found himself working with in Bône was nothing like the microscopes we know today – Carl Zeiss’s oil-immersion lenses, which would shortly change the world of microscopy, had not yet been invented. Laveran’s eyepiece was little more than a magnifying glass, but he made good use of it.

  He spent the first two years after his arrival in Algeria in 1878 going over old ground, familiarising himself once more with the symptoms of malaria. He looked at the dark pigmentation that developed in certain organs of patients who had died of the disease. There was often so much black pigment in the liver, the brain or more commonly the spleen, that the entire organ turned grey. What caused this in malaria, he asked himself, that happened in no other disease?

  Laveran worked on material drawn from autopsies. The usual method was to apply a thin smear of blood to a glass slide, dry it, fix it chemically and then stain it. He made a huge leap forward from the work of researchers before him when he began to examine fresh blood, which he took from his patients. Although his microscope was weak, he knew immediately that the forms revealed when he looked at slides ma
de of fresh blood were completely different from anything that had been observed before. Not only could he count off the leucocytes, the white blood cells that contained the black pigment; alongside them were clear bodies, in two basic shapes, crescents and spheres. Laveran called them the No. 1 and the No. 2 bodies. He suspected they were parasites. But how to prove it?

  Laveran’s lucky break came on 6 November 1880, when a feverish twenty-four-year-old soldier from the 8th Squadron of Artillery presented himself at his surgery complaining that he had been treated with quinine three weeks earlier, but once again had the ague. Examining the soldier’s blood under his microscope, Laveran found large quantities of the crescent-shaped No. 1 bodies. Alongside them were a number of rounded bodies, whose surfaces were covered with filaments that were lashing and sinuously dancing on the slide: ‘I was astonished to observe that at the periphery of this body was a series of fine, transparent filaments that moved very actively and beyond question were alive.’

  Laveran, at that moment, became the first person to witness the parasite that causes malaria. Two days later he found more of them, as well as a number of transparent, or hyaline, ring-shaped bodies within the red blood cells. Observing them further, he noticed that the filaments, which he would later call flagella, were slightly swollen at the ends, and that now and then they would detach themselves from the spheres out of which they had emerged and swim off, like poisonous spermatozoa, stirring up the red corpuscles into a great turmoil. He also concluded that the No. 1 and No. 2 bodies he had observed were in fact the same: he watched crescents fill out and become spheres, just as he saw spheres grow hairy with filamented flagella and then despatch them off into the unknown.

  Laveran described everything he had observed in a note that he sent on 23 November, less than three weeks after seeing the sick soldier, to the Académie Nationale de Médicine in Paris. His letter was greeted with disdain and disbelief. Crescents, dancing filaments, hyaline rings – how could a single micro-organism have so many guises? And why did this prove that malaria was transmitted by a parasite, when everyone knew it came from the bacteria contained in the noxious gases of the miasma? And who was this Laveran anyway? A nobody from Bône.

  Laveran would spend four years trying to persuade the world that he was right. Leading Italian malariologists, including Giovanni Battista Grassi, Ettore Marchiafava and Angelo Celli, remained sceptical. They might have been more open-minded had they not felt so irritated that an important discovery had been made by a doctor from another country. The parasite – if it was a parasite—Grassi argued, had to have a nucleus, and none had been found; it also had to feed, and there was no evidence that it did. Others simply refused to believe. The Canadian Dr William Osler, probably the premier blood specialist of his day, who went on after teaching in Baltimore to become the Regius Professor of Medicine at Oxford University, for which he would later be knighted, wrote: ‘Nothing excited my incredulity more than [Laveran’s] description of the ciliated [flagellated] bodies. It seemed too improbable, and so contrary to all past experience that flagellate organisms should occur in the blood.’ In time, though he would get little immediate credit for his work, Laveran made individual converts, who then went on to convert others. Marchiafava was the first of the Italians to accept that Laveran was right. He showed the microscopic technique to an English doctor, who in turn passed it on to Dr Patrick Manson, who would later pass it on to Dr Ronald Ross.

  Ross, who would one day become known as ‘Mosquito Ross’, would win the 1902 Nobel Prize for Medicine for his work on how malaria was transmitted – but not before the eruption of a bitter academic quarrel such as had not been witnessed since 1653, when Jean-Jacques Chiflet’s Exposure of the Febrifuge Powder from the American World, in which he had denounced the new ague remedy as a Popish fraud, divided the Christian world in two.

  Ronald Ross spent five years in India, where he was a member of the Indian Medical Service, looking in vain through his microscope for the Plasmodium parasite that Laveran had identified in 1880. On his second furlough home, in 1894, he was advised to pay a call on Patrick Manson, a kindly and avuncular Scots doctor who had made a name for himself in London as a specialist in tropical diseases, and was a great believer in the healing properties of quinine.

  Manson’s special interest was not malaria but filariasis, now known to be a chronic parasitic infection of the lymph system, that he had first encountered while living in China, and which he believed might be spread by mosquitoes. His curiosity had led him to become adept at using the microscope; he worked hard at the laboratory bench, and made frequent dissections of the dead. Manson had devised a number of imaginative theories about how diseases were transmitted, and at the time Ross passed through London he was still working on the idea that mosquitoes could transfer other diseases, including malaria.

  As physician to the Seaman’s Hospital Society, Manson came across many tropical ailments in addition to filariasis. Malaria was one of them. As the disease had largely been eradicated in Britain by the middle of the nineteenth century, this access to a large number of malaria patients made Manson unusual among London doctors. If anyone could show Ross Laveran’s Plasmodium parasite, it was this quiet-spoken specialist in tropical diseases.

  Manson was out when Ross first called on him at his home in Queen Anne Street, London, on 9 April 1894, but he sent a note entreating him to call again, ‘tomorrow if possible’, and suggesting that the reason Ross had missed seeing the Plasmodium was perhaps because ‘of the technique you employ’. He added: ‘It will give me great pleasure to be of any service to you for I am quite sure you can do good work and have the patience to do it.’

  Although the two men had never met, Manson had already formed a shrewd judgement of Ross’s character. Photographed in his black frock-coat and high wing-collar, Ross looks every inch the confident Victorian soldier in civilian dress. He has fierce black eyes and a high, domed forehead. It is easy to imagine him pacing up and down before his drawing-room fire, deep in thought, curling his moustache in a masterful way. Manson was right: Ross could do good work, and he was certainly patient. But Ross the man was a far more complex creature than his photograph suggested.

  Born in India and, like so many sons of the Raj, schooled in England, Ross had been equivocal about following his father and training to be a doctor. He had tried to become a painter, then in turn a composer, a mathematician, a poet and a novelist. Having failed to make a living at any of these, he enrolled at the age of thirty at his father’s alma mater, St Bartholomew’s Medical School on the edge of the City of London, only to dawdle once he got there, and qualify two years late.

  The Ross who emerged was a competent clinician who would go on to expand his medical knowledge, taking further degrees in bacteriology and public health. But he retained a profound insecurity, a tendency to depression and a deep sense of being misunderstood, or more precisely underappreciated, traits which combined to show themselves in a certain touchiness and arrogance whenever he felt crossed.

  For years after their first meeting, Ross in his letters home to Manson would rail about the dunderheads in the Indian Civil Service who were impeding his research, the medical establishment that failed to recognise sufficiently the contribution his discoveries had made, and the foreign scientists he believed were trying to pass off those discoveries as their own. All too often, Ross regarded his own knowledge as superior to that of his colleagues. When he looked through his microscope and could not find the Plasmodium parasite, he did not conclude that perhaps he was using the equipment incorrectly. Rather he decided that Laveran’s so-called parasites were probably nothing more than misshapen cells, even though the parasite had by then been observed for nearly a decade, and much was already known about its life cycle. Yet despite his shortcomings, which grew more pronounced as he grew older, Ross was possessed of enormous energy and drive.

  Ross visited Manson many times after their first encounter in April 1894. He was drawn by Manson’s deep kn
owledge and gentle Scottish humour; perhaps even by the older man’s fatherliness. Manson, for his part, found that he liked his young acolyte more and more. And Ross, for the time being at least, seemed happy to play a subordinate role.

  In his research into the spread of filariasis, Manson had made only intermittent observations of the life cycle of the parasite. He realised that it did not seem to develop much while in the blood, and thus probably needed outside help to complete its life cycle. Could the bloodsucking mosquito be that outside agent? Manson threw himself into dissecting mosquitoes. Opening up hundreds upon hundreds of their abdomens, he saw that the parasite underwent a number of subtle changes there; but he was unable to understand how, or why. He had read somewhere that mosquitoes fed only once during their short lives, an observation that was incorrect, and so failed to see the importance of the mosquito’s bite. To make up for that gap in his knowledge, Manson devised his own ideas on how the parasite made the transition from human to human.

  In the course of his conversations with Ross, Manson transferred ever more of his filarial theory to malaria. The parasite that caused malaria, Plasmodium, enclosed in a patient’s red blood cells, needed an outside agent to develop, just as the filariae did. In sucking up human blood, the mosquito ingested the filariae, which then began to metamorphose. Surely the Plasmodium parasite would do the same? That still left a large gap in the life cycle of the parasite. To fill it, Manson posited that shortly after laying its eggs the female mosquito died, and its decayed body re-entered the chain. The female, having fed, he wrote, ‘seeks out some dark and sheltered spot near stagnant water. At the end of six days she quits her shelter, and, alighting on the surface of the water, deposits her eggs thereon. She then dies, and, as a rule falls into the water alongside her eggs.’ Humans would become infected by drinking the water.