Shivers and Sweats

Mark Honigsbaum is fascinated by fever trees. The phrase may bring to mind ‘the great, grey-green, greasy Limpopo River, all set about with fever trees’. But Honigsbaum is not interested in Kipling’s trees, or in the beautiful flat-topped acacias of the Kenyan rift valley, which are called ‘fever trees’ because they grow in malarial districts. What he writes about are the many species of Cinchona that grow at high altitudes on the inaccessible eastern slopes of the Andes, in Bolivia and Peru and Ecuador and Colombia and Venezuela, whose bark is the source of quinine.

It is well known that quinine is what makes tonic water bitter, and that it has been used both to protect against and to cure malaria. What is less well known is that quinine was (with the exception of the largely forgotten Chinese qing-hao) the first drug to be discovered that provided a specific cure for an infectious disease; and the disease it cured was both a serious cause of misery and death in many parts of the world, and a major barrier to European settlement in India, Africa and the Dutch East Indies.

The first drug designed to deal with a specific infection – the arsenical Salvarsan, used to treat syphilis before the days of penicillin – was developed by Ehrlich in 1909; the sulphonamides, including the celebrated M&B 693, arose as an offshoot of the synthetic dye industry in the 1930s; and the first antibiotics became widely available at the end of the Second World War. All these modern drugs were introduced to treat diseases that were well defined and known to be caused by particular organisms. When the Spaniards used cinchona bark to treat fevers in 17th-century Peru, no one knew what caused the diseases that were being treated. Indeed, the distinction between fevers that responded to the treatment and fevers that didn’t must have helped to define what we now think of as malaria.

Until recently, the accepted story was that in 1638 the beautiful Countess de Chinchón, wife of the Spanish Viceroy of Peru, was struck down by a vicious intermittent fever, with alternate chills and sweats, that seemed about to kill her. The Governor of Loja, who eight years earlier had barely survived a similar fever, recommended a native remedy that had saved his life; it had been suggested to him by a Jesuit missionary who had himself been cured by it. The remedy was an infusion made from the bark of trees growing high in the Andean rainforest above Loja, a bark the Indians called quinquina, or ‘the bark of barks’. The Viceroy took the Governor’s advice, and the Countess was saved. When she returned to Spain, the news of her miraculous cure sparked a healthy South American export trade in ‘Countess’s powder’ or ‘Jesuits’ bark’.

The story explains why, a century later, Linnaeus called the Loja tree Cinchona officinalis (immortalising the lady’s name but, by leaving out the first ‘h’, ensuring that the English always mispronounce it). The Viceroy kept a meticulous and detailed diary, which doesn’t mention his wife’s alleged illness, and there is good evidence that she never returned to Spain but died in Cartagena. It is possible that the husband rather than the wife was the patient, as the Viceroy did have repeated attacks of an intermittent fever – attacks which, by October 1638, had become so threatening that the Countess arranged a Mass for him, and distributed candles and alms throughout Lima. On 8 November he suddenly recovered, but there is no mention in the diary of the bark of a hitherto unknown tree. It is just conceivable that the Viceroy would have thought it impolitic to attribute his sudden cure to a native remedy rather than to the Mass and the alms.

Was it, in fact, a native remedy, or was it discovered by the Jesuits? The evidence is inconclusive. There is no doubt that the native population was extremely knowledgable about the Andean flora, and the use of bark from uncommon trees growing in an inaccessible rainforest five hundred miles from Lima would certainly suggest a native origin. On the other hand, no mention of cinchona can be found in Inca records; and Humboldt, who visited Loja in 1802, wrote that ‘while agues are extremely common . . . the natives there . . . would die rather than have recourse to cinchona bark, which . . . they place in the class of poisons exciting mortification.’ By 1802, though, the natives had had plenty of time to pick up Spanish prejudices, and Joseph de Jussieu, physician, mathematician and botanist to a French expedition to Ecuador in the 1730s, points out that the Spanish would not use bark from the red-barked variety of cinchona, ‘fearing that by the strength of its heat . . . it will provoke a burning fever’. He believed that the dramatic curative powers of the cinchona were discovered by Indians from malarial coastal regions of Ecuador, and that the Spanish learned the secret only when a local chief took pity on a passing Jesuit ill with fever, and cured him with bark fetched from a nearby mountain.

When did malaria reach South America? If it arrived before the Spaniards it must have been brought by Asiatic peoples crossing from Siberia to Alaska and gradually working their way southwards, but malariologists doubt that the transmission of malaria through such protracted cold is possible. On the other hand, the prevalence of malaria in the towns and ports of Southern Europe, and in West Africa, would have made its transmission to South America by the Spanish and Portuguese and their African slaves very easy. But if this story is right, the Indians cannot have discovered the dramatic curative effects of cinchona bark before the arrival of the Spaniards – its effect on non-malarial fevers is slight.

The use of Jesuits’ bark in Europe was hindered by its variable quality (unscrupulous dealers would sometimes stain inferior barks to make them resemble that of a preferred species). In Rome in the 1640s, however, the Spanish-born Cardinal Juan de Lugo, who had been treated with the bark after nearly succumbing to a fever from the Roman Campagna, instructed the Pope’s physician to see whether the pulvis Jesuiticus stopped the alternation of shivers and sweats in his feverish patients. The tests presumably proving successful, de Lugo began to distribute the bark free to the poor; and in 1649, at a council to elect a new head of the Jesuit order, he recommended cinchona to the assembled delegates, so spreading his message throughout the Catholic world.

But 1649 was also the year in which Charles I was executed, and in Cromwell’s England Jesuits’ bark was politically suspect – even though Cromwell himself, who had been brought up in the Fens, suffered from bouts of fever that were almost certainly malarial. Some years after Cromwell’s death, Thomas Sydenham, the physician who first described scarlet fever, and whose description of an acute attack of gout was still being recommended to medical students 250 years later, openly advocated the use of the bark; but it was Charles II’s recurrent malaria that finally made its use acceptable. He was treated by Robert Talbor, a Cambridge apothecary, who, while disparaging the bark, employed a secret recipe that contained it. Charles recommended Talbor to his friend Louis XIV when the Dauphin was ill with fever. The treatment was successful, and Talbor became a pensioned Chevalier in return for disclosing the secret recipe to Louis on the understanding that it would be published only after Talbor’s death.

By the end of the 17th century the value of the right sort of cinchona bark was indisputable, but it was not until well into the 18th that Europeans seriously tried to sort out the different kinds of cinchona tree. De Jussieu, who studied the cinchonas of Loja and the rather different cinchonas (calisayas) of Bolivia, prepared a huge collection of specimens that he planned to transport via Buenos Aires to France, but he so impressed the native servant guarding the boxes with the value of their contents that the servant absconded with the lot. De Jussieu, Honigsbaum tells us, was so disheartened that he returned to Lima, where he practised medicine and consoled himself with geometry. By 1771 he had lost his memory and was confined to an institution for the insane in Paris, still clutching, so the story goes, a manuscript he had written on the cinchona tree in 1737.

Another member of the French expedition was Charles-Marie de la Condamine. A soldier turned mathematician, his primary role was to determine the length of an arc of the meridian near the Equator. A separate expedition to Lapland would make a similar measurement within the Arctic Circle, and a comparison between the two would settle the controversy between Newton’s view that the Earth was flattened at the poles, and a rival view that the Earth was constricted at the equator. Having accomplished his task – Newton was right – and dealt with various political problems, La Condamine decided to make a collection of saplings and seeds from the famous cinchona trees above Loja, descend the eastern slopes of the Andes, sail the two thousand leagues down the Amazon to Brazil, and take a boat to France, where he would present the quinine tree to his sovereign, Louis XIV. He succeeded in carrying out his plan as far as the Brazilian coast, but there a great wave carried off all his plants. As if that were not bad enough, the cinchona seeds that he took to a plantation run by Jesuits in French Guiana failed to germinate. Unlike de Jussieu, though, he made his way back to a hero’s welcome in Paris.

There were also Spanish searchers after fever trees. José Celestino Mutis came from Spain to be court physician to the Viceroy of New Grenada (Colombia) at Bogotá, and discovered new species of cinchona in the local mountains. This meant it would be possible to send plants to Spain via Cartagena, without crossing the Isthmus of Panama or sailing round the Horn. And if cinchonas grew in the Colombian Andes, might they not also grow in the Andes of central Peru and Chile? Charles III of Spain sent two botanists, Hipolito Ruiz and José Pavon, to find out. Seven years later they returned to Lima, having discovered seven new species of cinchona and filled 53 boxes with specimens. After dispatching the boxes to Spain by boat, they resumed their collecting, but a year later the house in which they kept all their records and specimens was burned down; and six months after that, they learned that the boat had been wrecked off the coast of Portugal.

In 1783 Charles III, whom Mutis had been petitioning for years, appointed him to a post that enabled him to gather together a group of scientists and artists dedicated to studying the flora of Colombia. The brightest of the scientists was the Colombian-born Francisco José de Caldas, a young polymath who not only differentiated 22 species of cinchona in Colombia and Ecuador, and kept systematic records of the altitude, climate and soil conditions to which they were suited, but also discovered for himself the method of measuring altitude by determining the boiling point of water. When the Colombians revolted against Spain he joined the rebels, became a captain under Bolívar, and ended his life in front of a Spanish firing squad. Whether or not there was a curse on those who joined the fever trail, the statistics were not encouraging.

By the turn of the century the military importance of cinchona bark was recognised, and in 1803 Nelson directed that ‘a dose of Peruvian-bark in a preparation of good sound wine or spirits’ be given to sailors in the morning and evening if they were going ashore in marshy areas. But in August 1809 Napoleon defeated an initially successful British raid on the marshy shores of the Scheldt, at Walcheren, by breaching the dykes so that forty thousand English troops found themselves surrounded by pools of stagnant, mosquito-infested water. The supplies of bark were inadequate, the quality was not always good, and over the next three months the death toll rose to four thousand with nearly three times as many sick – an early example of germ warfare.

It became much easier to ensure quality after 1820, when the young French pharmacists Pelletier and Caventou identified the active agent in cinchona barks as quinine. Honigsbaum finds it incredible that they did not patent their discovery, but discoveries of naturally occurring substances are not patentable, and it is not clear that their method of extraction would have justified a patent.

As the relative value of the different cinchonas was gradually established, a new worry arose. In 1844 the Bolivians, whose calisayas turned out to be particularly rich in quinine, set up a national cinchona bank and banned the export of cinchona bark without a licence. But neither here nor elsewhere were effective steps taken to preserve the stock of cinchona trees. During the second half of the 19th century, European countries found themselves dependent on a small number of producers whose supplies were liable to run out. For Great Britain and Holland, with their tropical colonies, this was a nightmare, and the most exciting part of Honigsbaum’s book describes the extraordinary adventures of two Yorkshiremen, a Cockney and a Dutchman, who managed to smuggle plants or seeds back from the Andes. As a result, flourishing cinchona plantations were established in Java by the Dutch, and on the Nilgiri hills in Madras and later elsewhere in India by the British.

Two-thirds of the way through his book, Honigsbaum switches from fever trees to the malarial parasites themselves – single-celled animals of the genus Plasmodium. I remember, as a medical student fifty years ago, making drawings of the animal’s complicated life-cycle, with three stages of asexual reproduction, and with sexual reproduction that starts in human blood and is completed in the mosquito. The parasite was first seen in human blood cells by the French army surgeon Charles-Louis-Alphonse Laveran; a role for the mosquito was suggested by Patrick Manson’s studies, in China, of another mosquito-borne disease, elephantiasis; and Ronald Ross, a British army surgeon, first demonstrated the presence of the parasites in the stomach wall of mosquitoes that had fed on malarial patients. Later (working with bird malaria, which is transmitted by mosquitoes of a different species), Ross succeeded in following the migration of the parasite from the mosquito’s stomach wall to its salivary glands, ready for injection into the next victim. Honigsbaum spares his readers the full horrors of the life-cycle, but he gives a much fuller and more colourful account of the steps by which the cause of the disease came to be understood, starting with a sixth-century BC Vedic text blaming mosquito bites, and including a splendid 19th-century cartoon of Laveran on a camel charging a crowd of huge mosquitoes with a lance. He is, though, quite unfair to Ross in implying that the award of his Nobel Prize depended on the lucky chance that his observations on the mosquito responsible for transmitting malaria in birds appeared before related observations by Giovanni Grassi, in Rome, on the mosquito responsible for transmission in humans. It is clear from Ross’s memoirs that the quarrel with Grassi over priority rankled unduly in his later life, but there is no doubt that he deserved the Prize.

In the last part of the book, Honigsbaum gives an interesting, if breathless, account of current difficulties in controlling malaria, caused by the evolution of strains resistant both to quinine and to many of the new synthetic drugs; and he discusses the attempts, so far only partly successful, to create a vaccine. What is abundantly clear is that the scale of the current problem is vast, with more than a million people, most of them children under five, dying of malaria each year in sub-Saharan Africa alone. With global warming, the problem is likely to grow worse and to spread to more temperate areas.