The Miraculous Fever-Tree Read online

  Pharmacists in non-malarial areas of the country were asked to send all the powder, tablets and capsules of quinine, quinidine, cinchonine, cinchonidine and quinine salts they had. It didn’t matter if stocks were old, so long as they were dry. Within days, packages were beginning to arrive at the American Pharmaceutical Association. The lower floor of its headquarters was devoted to the pool, and volunteers went from shop to shop ensuring that pharmacists responded immediately. Robert Rodman, one of the editors of the Association’s journal, went on the radio to explain the pharmacists’ role in helping to save American troops who were suffering from malaria. Supplies poured in from all over the country, President Roosevelt himself forwarding a gift of one hundred pounds of quinine that he had been given by the President of Peru during a state visit.

  In five months, over three tons of quinine were collected, the equivalent of 9.6 million five-grain doses. By October, after ten months, almost five tons had been amassed, more than thirteen million doses in all. The figure comfortably exceeded the Association’s target, but donations were slowing down, in large part because America was simply running out of quinine. Something more would need to be done. With such a major proportion of the world’s quinine supply off-limits to the Allies, it was imperative, as it had been in Charles Ledger’s day, to locate a source of seeds from which to start new plantings. The US authorities thought they had just the man for the job.

  Arthur Fischer had first gone to the Philippines in 1911 with a degree in forestry and a reserve army commission. In 1917, as Director of the Bureau of Forestry in the islands, he had ambitions to develop a local source of quinine to treat the high incidence of malaria among agricultural workers. But the Dutch, like the Peruvians and Bolivians a century earlier, kept a tight embargo on all shipments of seeds and plants from their Java plantations.

  Fischer, though, was persistent. He enlisted the help of the Governor General of the Philippines, General Leonard Wood, who had trained as a doctor at Harvard, and arranged for an English sea-captain to smuggle seeds from Java. The seeds arrived in two Horlick’s malted milk jars, and the captain was paid $4000, the money coming from General Wood’s discretionary fund. By 1927, Fischer had a plantation of the quinine-rich Cinchona ledgeriana up and growing on the Philippine island of Mindanao, and nine years later the first shipment of bark arrived at a small new factory in Manila. By the time war broke out, the factory was producing 2.5 kilos of quinine sulphate a day.

  Along with thirty-eight thousand acres of Dutch plantations in Java, the factory in Manila was seized by the Japanese at the start of the Philippines campaign early in 1942. Within a short time, malaria cases on Luzon, east of Bataan, were increasing at an alarming rate. US Army correspondence reveals just how serious the situation had become: ‘There are now three thousand cases of malaria in the Luzon Force,’ the medical officer in charge of the area reported to his superior officer, the Assistant Chief of Staff, on 23 March, two months after the start of the campaign. ‘20 per cent of fighting units are not effective due to malaria and 50 per cent of some units have subclinical malaria and are considered potentially ineffective … The daily admission rate for malaria now lies between 500 and 700 cases and in the absence of quinine this rate can be expected to increase.

  ‘There is sufficient quinine in the Philippine Medical Depot to very inadequately treat 10,000 cases … this will be exhausted in three to four weeks. When stocks are exhausted, a mortality rate of 10 per cent in untreated cases can be expected. Those who do not succumb to the disease can be classed as non-effective from a military standpoint due to their weakened and anaemic condition. Blood-building foods and drugs are not available.’ Radio messages were sent to Melbourne, the nearest supply base, for fresh stocks of quinine, but without success.

  Arthur Fischer, who was interviewed shortly before his death in 1962 by Margaret Krieg while she was researching her book Green Medicine: The Search for Plants that Heal, recalled that on 18 March 1942, by which time he was serving as a colonel in the US Army, he wrote to the Assistant Chief of Staff to outline a plan that he had been considering for some weeks. ‘At the quinine plantation at Katoan, about forty kilometres west by south of Malaybalay, Bukidnon, under the supervision of Forester Altamirano,’ he wrote, ‘there should be several thousand trees over three years old from which bark can be harvested and sent to Bataan by plane. This bark should run from 7 to 9 per cent alkaloid content and can be used by grinding the bark and making an infusion with boiling water as a tea. The seed of Cinchona ledgeriana should be harvested and sent by plane to the United States for shipment to Brazil to start American sources.’

  General Jonathan Wainwright, the American Chief of Staff in the Philippines, called Fischer immediately for a first-hand report on how this could be achieved. He quickly gave his approval. Fischer was suffering from blood poisoning as a result of a wound in his arm. He was feverish and in considerable pain from recurring malaria. His weight had dropped from its usual 150 to just ninety-six pounds, but he did not let that deter him, and left Bataan immediately for Mindanao to supervise the harvesting. With local help, he stripped bark, ground it up in a corn grinder, and packed it into old petrol drums. A first cargo was despatched, but the plane carrying it was shot down. Meanwhile, a Catholic priest with a smattering of chemistry improvised a laboratory equipped with two old bathtubs and some ether and sulphuric acid begged from a nearby hospital. Within days, though, the weakened American force on Bataan was obliged to surrender, leaving Fischer, the priest and a small guerrilla force to fight a rearguard action against the Japanese on Mindanao on their own.

  The group’s one thought was how to escape with a supply of Cinchona ledgeriana seeds. General MacArthur, who had ordered the withdrawal from Bataan and was by now stationed in Australia, ordered three B-17 Flying Fortresses to be despatched to the island to bring back the American military personnel. The first two were shot down, but the third made its escape from Mindanao. Colonel Fischer was aboard, and so was a large tin of Cinchona ledgeriana seeds. It was the last Allied plane to leave Mindanao before the peninsula was overrun by the Japanese.

  From Australia, Fischer’s seeds were flown back to the Americas, from whence the species had come seventy years earlier. After being carefully germinated in the US Department of Agriculture’s laboratories at Glen Dale, Maryland, four million cinchona seedlings were sent to Latin America. One of the larger plantations was started in Costa Rica, where ten thousand acres of land had been leased to grow cinchona. Other seedlings were sent to Ecuador, one of the very countries from which they had originated.

  Although the war was over by the time Colonel Fischer’s trees were ready to harvest, one of his youthful dreams—to make quinine available in underdeveloped countries as a ‘good neighbour policy’ – had been achieved. Echoes of his philanthropic ambition would be seen fifty years later in a cinchona project in Africa. For his wartime services, Fischer was awarded the United States Order of Merit and the Distinguished Star of the Philippines.

  The fact that it had been so easy for Germany and Japan to annex virtually all the quinine that the world produced, and so difficult for the Allies to get any of it back, proved to the American military in particular that the time had come to pursue other ways of curing malaria. No longer was a tree that grew far away going to be the answer.

  What was needed was a drug that was easy for manufacturers to produce and for doctors to administer. The Plasmodium vivax strain of malaria was particularly prone to recur, but taking quinine over long periods caused many unpleasant side-effects. Patients complained of ringing in their ears, vomiting, deafness and acute headaches. In their search for an anti-malarial drug that could be manufactured artificially scientists alighted on a compound that had first been synthesised in Germany in 1930. Called 9-aminoacridine, it was licensed under the name Atabrine.

  Atabrine was one of several anti-malarial drugs developed by scientists working in the dye industry. For more than a century, ever since the French
chemists Pelletier and Caventou first synthesised quinine, scientists had been trying to find a way to manufacture synthesised quinine commercially. In 1834, Friedlieb Runge, a German chemist, succeeded in manufacturing quinoline, an organic-based compound, out of coal tar, though the manufacture of quinine defeated him. Two decades later, an energetic eighteen-year-old British chemist, William Perkin, put his mind to the same problem. Perkin too was foxed by quinine, though he did manage to formulate mauveine, a distinct colouring agent that became the first of the aniline dyes and launched the craze for pale purple.

  In the 1920s, after their experience of trying to defend their East African colony Tanganyika during the First World War, the Germans turned once more to trying to find a synthetic substitute for quinine. Scientists working for IG Farben, part of the Bayer dye works in Elberfeld, began testing thousands of compounds. In 1926 they discovered one that appeared to kill off malaria parasites in human blood. Named Plasmochin, it was also discovered to be highly toxic, and was discarded. But the search continued.

  Six years later, the scientists at Farben alighted on the compound which they named Atabrine. Others followed, but it was Atabrine that endured, because, although it turned patients’ skin yellow, it appeared to be almost identical in its action to quinine, only with even better results. It remained in the blood for at least a week after the first dose, and could thus be used as a prophylaxis.

  Farben sent examples of its new compounds to its American sister company, Winthrop Stearns, and in 1938 the US Army began testing Atabrine on soldiers in Panama. In the autumn of 1942, soon after the landing on Guadalcanal, Atabrine was issued to troops in the south-west Pacific ‘by the roster’, as the Navy Medical Department described it later, with one tablet every day except Sundays.

  The unpleasant side-effects made the drug highly unpopular among the soldiers. Some suffered from diarrhoea; others could not take it without vomiting; nearly all found that it turned their skin a violent yellow. But it was only when rumours began to circulate that Atabrine caused impotence that the troops began refusing outright to take it. They threw their tablets into latrines, or hid them under mattresses; anything rather than swallow it down.

  With nothing better to prevent their men from catching malaria, the authorities did their best to stress the positive aspects of taking Atabrine regularly. The truth was that there was no perfect anti-malarial available. Nor would there be until after the fall of Tunis in May 1943, when a group of French doctors suggested the Americans prescribe a drug called Sontochin, which they found had worked well against malaria in North Africa.

  Sontochin, the Winthrop researchers recalled, was one of the many compounds that had been passed on by their German sister-company IG Farben before the war, and had been gathering dust on Winthrop’s shelves through the intervening decade. Another, which soon became much more popular, was a similar compound named Resochin, better known nowadays as chloroquine.

  Researchers analysing chloroquine found that the drug was a solution to many aspects of the malaria problem. It was fast-acting and easy to administer, and its side-effects were relatively mild. It takes less than thirty minutes for the malarial sporozoites that are injected into the bloodstream when a person is bitten by an infected mosquito to make their way to the liver. The parasite needs to absorb some of the proteins that exist within the human liver before it looses itself back into the bloodstream in search of red blood cells. It ensures an adequate supply of protein by wandering from cell to cell within the liver. Once it has found what it wants it simply replicates over and over, many thousands of times, until as an army it re-enters the bloodstream in a form that is able to invade the red blood cells that carry oxygen to various parts of the body.

  Once it succeeds in piercing the outer wall of a red blood cell, the parasite once again sets about finding and synthesising the proteins it needs. It uses them to form tiny protrusions, called ‘knobs’, on the surface of the red blood cell. The effect is to anchor the cell to the wall of a capillary, like a boxer against the ropes, and prevent it from being carried to the spleen, where damaged red blood cells are normally destroyed. Once inside the red blood cell, the parasite can keep changing the configuration of new surface proteins so that the body’s immune system doesn’t have time to identify each new variant. By forcing the red blood cell to change its disguise over and over, the parasite effectively hides its kidnapped host from the immune system for just long enough to absorb the iron that the haemoglobin contains, and which the parasite needs in order to reproduce itself.

  If a patient with malaria were to remain untreated, the parasite would reproduce over and over for as long as forty-eight hours, when the wall of the haemoglobin, or red blood cell, would be ruptured, and the newly multiplied parasites released into the bloodstream to search for more red blood cells to invade. In some cases, the parasite then accumulates in the capillaries of the brain, causing cerebral malaria and, within hours, death. Meanwhile, the wreckage of the spent red blood cell on which the parasite had been feeding would be cleared by phagocytic cells, whose job it is to carry away spent cells to the spleen, causing it to swell and turn black. It is this that gives malaria patients the hard spleens – what early physicians knew as ‘ague cake’—that are so characteristic of the disease.

  The development of chloroquine was able to stop the parasite developing, and to explain for the first time how quinine, to which it is closely related, actually worked.

  If a patient had been taking chloroquine regularly as a prophylactic, the parasite that had reproduced within the liver would find, once it reached the red blood cells, that the drug had got there first. The haeme – or iron-producing part of haemoglobin – is actually toxic to the malaria parasite. But it has learned to render it harmless by converting the haeme into something called haemozoin, the black pigment that colours the spleen. What quinine and chloroquine do is to block the parasite from being able to convert the haeme into haemozoin, so that instead of being made harmless it remains poisonous to the parasite. Trapped within its toxic prison and unable to develop any further, the parasite soon dies.

  Easy to administer and relatively cheap to produce, chloroquine had the advantage of causing far fewer side-effects than quinine. Thus it appeared to be what American researchers like to call a ‘magic bullet’. Chloroquine, at first, was effective against all four species of the parasite, including the deadly falciparum. The quinine tree, it seemed, could be consigned to history.

  The discovery of chloroquine came too late to help the Allied soldiers who took part in the war in the Pacific or the landings in Sicily. But news of its effectiveness spread rapidly. Among the British and French colonies in Africa and Indochina it was soon the drug of choice.

  In Italy, meanwhile, a massive campaign was under way to repair the damage that the tanks of the German Panzer divisions had wreaked upon the elaborate constructions put up through the ages to drain the marshes of the southern Italian countryside. At the same time, the Italians were keen to begin trying out a Swiss-made discovery which, it was hoped, would eradicate the mosquito from the Campagna Romana forever. The new pesticide was called DDT, a killing compound that proved so successful in eradicating disease-carrying insects that it allowed man for a while to believe that he had become invincible. The eventual eradication of malaria, went the mantra, was inevitable. It was only a question of when.

  In time, though, DDT would arouse enormous controversy about its long-term effects on other animals. Chloroquine for some years remained free of taint, but as early as 1961 doctors treating malaria patients in Cambodia, Thailand and Vietnam began to notice that it was not working as well as it had done. It was as if the malaria parasite refused to be outdone, and had redoubled its efforts to find a way around the onslaught of the drug; which is exactly what had happened. The parasite had developed a mutation that rendered it resistant to chloroquine.

  Resistance could be seen when, despite repeated treatment at different dosages, the blood still sho
wed the presence of live parasites. Why wasn’t chloroquine working any more? Many theories have been put forward for this change, but the most plausible is that the resistant parasite has somehow managed to block the uptake of chloroquine into its system. Why has this happened? No one is quite certain. What is clear, however, is that over the past forty years resistance to chloroquine has become so widespread that in many countries it is now likely to be of no help to a doctor treating a malaria patient. In at least ten Eastern and Central African countries, including Kenya, Rwanda and Congo, prescribing it has become illegal.

  Chloroquine’s long-term failure has had two salutary effects. First, it has shifted the perspective of doctors and researchers by proving to them that some drugs may be effective for only ten years or so, and it has forced them to consider using combination treatments to attack the parasite on several fronts at once. Thus, a patient who falls ill with malaria and is fortunate enough to be able to afford the best treatment will find that, depending on where he is and which species of malaria he has, he is likely to be treated with aminoquinolines, such as chloroquine, in conjunction with other anti-malarial drugs – such as anti-folates, quinoline-methanols and phanthrene-methanols, all of which act on the parasite at slightly different points in its reproductive cycle – and even with an antibiotic.

  Within this vast new cocktail of cures is one drug that is being regarded with new deference. Cheap to produce and easily manufactured in the developing world, it has shown itself to be highly effective as a treatment for the most virulent attacks of falciparum malaria. If a patient with this strain of malaria is treated in the world’s most sophisticated hospitals, this cheap medicine will be the drug of choice. Even more remarkable is the fact that the malaria parasite has not yet developed more than a token resistance to it. Known for centuries as a treatment against fever, it is none other than natural-growing cinchona, the Jesuits’ cure.