Tuesday, August 24, 2010

Killer disease and foreign cure: the story of malaria and quinine

Nowadays one tends to think of malaria as an African problem. But in centuries past malaria was the scourge of the Mediterranean, and of Rome in particular. Even places as far a field as France, southern England and Russia were affected by it. Originally an ‘Old World’ disease, it was carried by explorers and settlers into the Americas. Its cure – the quinine found in the bark of the cinchona tree – was discovered in the C17th in the foothills of the Peruvian Andes, an elevated area where there had never been any malaria. The fact that quinine was ever actually discovered is something of a miracle.

Malaria is a parasite that is carried by the Anopheles mosquito (right). It is transmitted to humans through the bite of a contaminated mosquito. The parasite enters into the bloodstream and the infected human suffers from intense fever and icy shivering. The spleen becomes painfully enlarged. Those who recover often suffer relapses and they seldom regain their prior strength. Many die, especially when the parasite reaches the brain, causing cerebral malaria. Malaria-carrying mosquitoes breed in stagnant pools of water.

Malaria has been around since at least late antiquity.* Nobody quite knows why, but it appears to have abated in the Middle Ages before flaring up again in the seventeenth and eighteenth centuries. The problem for so many centuries was that the Europeans had no idea what caused malaria. To them it was simply an intermittent fever that took hold of many in the summer months. They did not know it was caused by a parasite, they did not know the mosquito was its carrier and dispenser, and they thus had no real idea of how to prevent or cure it. The best idea they had of this fever was that it was some type of contagion that basically ‘hung about’ in the miasma (i.e. the summer mists). In Rome, where malaria was the most rampant, one was said to catch the fever from the ‘bad air’ (the mal’aria) of the marsh mists.

Malaria – variously known as the Roman marsh fever, the intermittent fever, or the tertian/quartan ague – was the ever-present enemy of the Roman Campagna. The Tiber frequently breached its banks in summer and left the countryside covered in stagnating pools of water. Numerous popes, cardinals and ordinary Romans were laid low or killed by malaria; six visiting cardinals died from malaria during the disastrous conclave of 1623. The wealthy citizens would desert the city during the worst of the summer heat, fleeing to the cooler climate of the surrounding hills in an effort to avoid catching the fever. Malaria was only really eradicated in the area in the 1930s when Mussolini had the Pontine marshes drained and the mosquitoes’ breeding ground in western Italy was thus finally eliminated.

The Italian Jesuit Agostino Salumbrino arrived in Lima, which was then part of the Spanish Viceroyalty of Peru, in 1605. Salumbrino witnessed how the Quechua people (Incas) would take cinchona bark - ground into a powder and drunk in hot water - to stop from shivering when the winter cold had seeped into them. Salumbrino was well acquainted with the symptoms of Roman marsh fever, and the shivering of the locals caused him to think of the shivering phase caused by the fever back home. So he sent a small sample of cinchona bark to Rome in 1631, where it proved to be a cure for the marsh fever.

Cinchona bark and flowers

In a short time the Jesuits, with the aid of the local Indians, would begin to search for and strip the bark of the cinchona tree in order to send it to the Old World. The Jesuits showed the locals how to strip the bark in vertical pieces so as not to kill the tree. They would plant five new cinchona trees for every one they cut down, and they would plant them in the shape of the cross in the hope that God would then bless their growth. In 1767 the Jesuits were expelled from the Spanish Empire by Charles III as the latter had grown fearful and jealous of their accrued power and properties. With time the local people would forget the conservational practices taught to them by the Jesuits, and the cinchona trees would begin to be over harvested.

Soon after the discovery every ship travelling from the New World to the Old would carry a consignment of “Peruvian bark” or “Jesuit powder”. Though nobody knew how it worked, its reputation as an effective cure for the intermittent fever soon began to spread throughout Catholic Europe. But the Protestants viewed it with great suspicion. The Reformation and counter-Reformation were in full swing, and many Protestants suspected the so-called remedy to be part of a Popish plot. In addition, the foul taste of the bitter bark led many to think they were being poisoned, and cinchona bark was thus not universally accepted for a long time.

The bark was also denounced by many hard-line conservatives. Medicine at the turn of the C17th was still an essentially medieval affair. The old-school doctors clung to the ancient ideas of Galen (a 2nd century Greek physician). Galen had advocated the idea that all disease is caused by an imbalance of the humours (i.e. blood, phlegm, black bile and yellow bile). Fevers were thought to be the result of too much bile, so bloodletting and purging were the most common curative measures. The debate that raged over cinchona bark was heated to say the least, but with time, and the help of a few discreet Catholics, the bark found its way into even the most Protestant of places, such as England, where it was used to cure both Oliver Cromwell and Charles II.

“Cinchona revolutionised the art of medicine as profoundly as gunpowder had the art of war.”** It ushered in a new age of medicine and quinine can be seen as the first modern pharmaceutical drug.

The next big problem was finding a way of producing plentiful, affordable and easily accessible quinine. The cinchona tree grew across northern South America, within the Spanish Empire. If you wanted to travel in Spanish territory, you had to obtain the permission of the King, who was determined that Spain should be the sole benefactor of the intellectual and financial rewards of the cinchona tree. Inadequate quinine supplies would hamper the efforts of explorers, missionaries, settlers, scientists and armies the world over. To be a missionary was a courageous thing – for centuries malaria felled them in their droves, in both Africa and Asia. The exploration of West Africa was only really made possible after the use of quinine as a prophylactic became common in the mid C19th. Before that, West Africa had been known as “the white man’s grave”. Malaria was sometimes also referred to as the “pioneer shakes”.

The worst malaria epidemic the world had yet to see attacked the British in 1809 when their expeditionary force of 40,000 men – the largest England had ever sent abroad – landed on the Zeeland coast in Holland in order to fight the forces of Napoleon. Napoleon, who was well aware of their impending arrival, is reported to have written to a commander, saying: “We must oppose the English with nothing but fever, which will soon devour them all.” When the English had landed, Napoleon ordered that the dykes of the Scheldt estuary be breached. Brackish water flooded the area and, with no medical corps, the British troops dropped like flies.

Malaria was most probably introduced to the New World by the early European explorers and settlers. American settlers then took the disease inland with them as they moved westward. It even found its way into Canada. During the Civil War, the Yankees, who had little natural resistance to the disease, suffered greatly from malaria when the fighting took them south into the heart of malarial country, such as Carolina. The Union army said that by the end of the war over a million of its soldiers had contracted malaria, and more than 10,000 had been killed by it.

The Panama Canal (above) was begun in 1881 by the French Compagnie Universelle du Canal Interocéanique. At that time, supplies of quinine were irregular and expensive the world over. The Compagnie managers thus considered it more economically viable to replace dead workers with fresh ones, rather than provide the current workers with adequate quinine doses. The incessant downpours in Panama meant that thousands were affected by malaria. Additionally, the legs of hospital beds were placed in water-filled glass bowls in order to prevent ants from reaching the patients, but in so doing those who went into hospital for reasons other than malaria were sure to contract the disease whilst there. Under French administration of the canal, which lasted eight years, more than 20,000 workers died from malaria or yellow fever.

When the Americans took over construction of the canal in 1903, thorough efforts were made to eradicate the area of malaria and adequate quinine supplies for all workers was a priority. Quinine was given as a prophylactic and those who did not take their daily dosage were punished. The Caribbean workers were particularly resistant to taking it. So the authorities did as the British in India had done: they mixed it with something very sweet to make it more palatable. The British officers in India had added sugar and gin to the quinine, creating gin and tonic.

In the mid 1900s the British, Dutch and French were all extremely eager to get their hands on cinchona tree seeds so they might grow their own trees. As already mentioned, the cinchona trees were far less numerous than they had once been, and so there was a sense of urgency to the matter. The Dutch botanist, Justus Karl Hasskarl, triggered the rush to smuggle cinchona seeds out of South America when he disguised himself as a German businessman in an attempt to obtain seeds that he would then take to Java. Britain, after many ups and downs, eventually managed to lay hold of some cinchona seeds. They planted them in India. But the Dutch were by far the most successful: by the 1930s their Java plantations were producing 97% of the world’s quinine supply.

It was only in the C19th that scientists actually started to get a handle on the disease. The first milestone came in 1880 when the Frenchman Charles-Alphonse Laveran (right), working in Algeria and using what was essentially a magnifying glass, caught sight of the parasite that causes malaria in the human bloodstream. He spent years trying to convince his contemporaries that he wasn’t just some nut job. Those who advocated a link between malaria and mosquitoes were similarly ridiculed. In the last days of the C19th, whilst working out of a shed in India, Major Ronald ‘Mosquito’ Ross (far right) discovered through his dissections that the mosquito is responsible for transmitting malaria. For his efforts he was awarded the Nobel Peace Prize in 1902.

The need to grow more cinchona trees and/or develop synthetic substitutes became painfully apparent during the Second World War. Soldiers were fighting in malarious regions in West Africa, Sicily, the eastern Mediterranean, Singapore, China and the south-west Pacific. In the Pacific countries malaria was a bigger killer than combat. For the Allied powers, the German occupation of Holland in 1940 was disastrous, as the latter seized control of the quinine headquarters in Amsterdam, with its essential machinery and supplies. Furthermore, the Japanese then took control of Java and its plantations of cinchona. The Japanese kept the Axis powers supplied with quinine, but the Allies were left high and dry. The Americans began growing their own cinchona forests in Costa Rica, but not in time to help with the war effort. The Allies’ only supply of quinine came from the eastern Congo, where plantations had been grown from cinchona seeds that had been smuggled out of Bolivia and brought there in 1933 by Prince Leopold. It is the Congo that today has the largest cinchona forest in the world.

Quinine frequently has undesirable side effects, such as vomiting, headaches and tinnitus. The synthetic and much-hailed alternative chloroquine eradicated these. But the malarial parasite eventually mutated and chloroquine became ineffective. Other drugs have since been placed on the market, but none of them have proved as effective as the natural quinine found in the bark of the cinchona tree, to which the parasite appears to have developed no immunity. (As an aside, in 1856, the synthetic organic dye mauveine – a purplish colour which became known as ‘mauve’ by the public – was accidentally discovered by 18-year-old British chemist William Henry Perkin when he was trying to find a synthetic alternative to quinine.)

Malaria is today primarily a disease of the tropics, thriving in places where the smart new drugs on the market are too expensive for the average person. Two hundred million Africans, from Botswana to Chad, are at risk. Malaria is a disease that can be cured and even prevented through education and quinine, yet the UN’s World Health Organisation estimates that 3 million people die every year from malaria. In other words, it kills one person every fifteen seconds.

* There are those historians who believe that the problem of malaria in the Mediterranean was one of the main reasons the Roman Empire collapsed.
** Bernardo Ramazzini, 1717.

Main source:
- Fiametta Rocco’s The Miraculous Fever-Tree: Malaria, Medicine and the Cure that Changed the World

Further reading:
- Michael Finkel. Malaria, in National Geographic. http://ngm.nationalgeographic.com/ngm/0707/feature1/text2.html

- Anopheles mosquito. CDC, public domain.
- Cinchona bark. A. Zell, 03/09/09. GNU Free Documentation License.
- Cinchona calisaya flower and leaf. Public domain.
- Panama Canal. Public domain.
- Charles-Alphonse Leveran. Public domain.
- Ronald Ross. Public domain.