Molecules versus Malaria

The observable features of Malaria have been known to mankind since 2700BC. This mysterious condition, once thought to arise from ‘bad air’, turned cities into graveyards and vanquished armies. The great apes are highly susceptible to the protozoan infection that causes malaria. It was up to Homo sapiens to do something about it—first evolving a biologic defense, then going on offense with chemicals. We may even ‘go nuclear’ with genetic engineering.

We take our cue from the ideas presented in Napleon’s Button—17 Molecules that Changed History, by Penny Le Couteur and Jay Burreson, specifically the chapter Molecules versus Malaria. The book is a fascinating read that combines a bit of chemistry with a smattering of sociology to derive some provocative suggestions about the power of molecules to steer history.

Let’s look at the three molecules those authors identify as important to the story of malaria: quinine, DDT and hemoglobin. And we’ll toss in CRISPR technology, just to stay au courant.

Malaria

A concise history of malaria is available from the CDC and a discussion of the human impact on the WHO site. The Egyptians, Chinese, Indian, Greek and Roman ancient civilizations all wrote of it. It is primarily a tropical disease that has been especially devastating to Sub-Saharan Africa, India and parts of South America. The fact that these are all areas of European colonial conquest accounts for the British fondness for gin and tonic, how Chinchona trees got their name, and, perhaps, the reason that Africans and not Native Americans were enslaved in the New World. (You’ll have to read the book).

Napoleon's Buttons

Penny Le Couteur and Jay Burreson ... molecules that have greatly influenced the course of history.

Silent Spring

Rachel Carlson ... it's publication forced the banning of DDT.

Medical History Tour - Medical Papyri
Enable network access to view map.
• Shift-Drag any area to zoom in • Top right icon controls map style •
Pix Caption

The plasmodium parasite was discovered in 1880 by a French Army surgeon, Alphonse Laveran, stationed in Algeria. The vector of transmission, mosquitos, was discovered in 1885 by a British officer, Ronald Ross, serving in Bombay. That sickle cell disease offers relative protection from malaria was first suggested by Paul Brain, in 1952, while on duty at a mine in Rhodesia. The Europeans were ‘on the case’.

Despite millennia of awareness and over a century of research, malaria remains a devastating disease. In 2015 there were 212 million cases with 429,000 deaths, mostly in Sub-Saharan Africa.

The Making of a Tropical Disease

Randal M Packard
... why does the disease still flourish in some parts of the globe?

Humanity's Burden

James LA Webb
... the long arc of malaria out of tropical Africa into Eurasia, ... to the Americas

From a Western perspective, the first success in treating malaria came as a gift from South American Indians living in the Andes. This is memorialized in the story of how Countess Chinchon, wife of Spain’s Viceroy to Peru, was, around 1630, rescued from her death bed—cured with an extract of tree bark.

Quinine

The bark of Chinchona trees (now so named) are rich in quinine. Quinine is hard to synthesize, glows in the dark, and kills plasmodium. Catholic priests came to know about the fever tree and ‘Jesuit’s Powder’ kept Papal enclaves safe from malaria. The English would have nothing of it. For many, including Oliver Cromwell, this enmity against all things Papist resulted in death from malaria. 

 Chloroquine

Chloroquine

 Chinchona Forest

Chinchona Forest

Whatever was in this tree bark was obviously of huge social and economic importance. The urge to own it led to smuggling, international negotiations and commercial competition. In 1670 Robert Talbor sold quinine to the English by telling them it was something else. In 1735 Jussieu, a French botanist identified the tree of interest and deforestation began. Extraction of quinine was accomplished 1820 by Pelletier and Caventou, for which they were rewarded in cash by the Paris Institute of Science.

The English were discouraged by earlier attempts to grow quinine–rich trees. But the Dutch were willing to give it a go, and paid Charles Ledger $20 for seed stock, which they planted in Java. By WWII, 95% of the world’s supply of quinine came from there. The Germans confiscated a stockpile in Amsterdam and the Japanese took over Java. 

Synthesis became paramount. Chloroquine was discovered in 1934 at Bayer Labs but not exploited at the time. Reports from Harvard in 1944 were spurious, true synthesis ultimately achieved only in 2001. But Ledger did take some of his seeds to Australia. And the Allies won the War.

 Caventou and Pelletier

Caventou and Pelletier

Today quinine and its derivatives still play a role in treating malaria, cardiac arrhythmias andgiving the tang to ’tonic’ (see the Slate article).

Chloroquine can be had now for 4 cents a dose. To this day the antimalarial mechanism remains unknown.

DDT

In 1955 the World Health Organization mounted a campaign to eradicate malaria by killing mosquito infestations. The reduced malaria rates by 40% in 14 years—all using an agent, DDT. DDT (dichloro-diphenyl-trichloro-ethane) is essentially non-toxic to humans but for mosquitos it is a lethal ‘nerve gas’. The effect on the environment was only later realized, starkly documented in Silent Spring. Birds were especially imperiled by the effect on egg shells. The ban of DDT is why America still has Bald Eagles. And why spring is not silent.

 DDT

DDT

 DDT Spraying Operation

DDT Spraying Operation

Although synthesized in 1874 by Othmer Zeidler, it would be 1939 by the time that Paul Muller, tasked with finding an insecticide at Geigy Pharmaceutical in Switzerland, found that the 350th agent tested—DDT—did in fact kill insects.. It was used to de-louse people for typhus control before it gained prominence in malaria prevention. 

Hemoglobin

Oxygen is delivered to tissues by blood, via the red cells, specifically in a pocket of heme, surrounded by two pairs of folded protein chains—hemoglobin. Hemoglobin exists in mutated forms. The study of sickle cell disease led to the first ever description of a point mutation, where a single amino acid substitution is responsible. This earned Linus Pauling the Nobel prize. 

The geography of malaria and hemoglobin mutations overlap. It was a bit of a mystery why the gene for sickle cell disease, deadly in those with two copies of the gene, had been so well preserved in tropical areas. The reason we accept today started as mere speculation, based on the observations of a doctor working for a mining company in Souther Rhodesia (now Zimbabwe).

 Hemoglobin

Hemoglobin

 Shibanie Mine, Rhodesia

Shibanie Mine, Rhodesia

He wrote a letter to the British Medial Journal a letter: “I have recently produced figures which, although inadequate, suggest that the mechanism may be one of positive selection for the heterozygote-that is, that bearers of the trait enjoy an advantage in health over normal people.”

People with one copy of the gene do not die of sickle cell disease. They remain healthy and enjoy some resistance to malaria. The reason for the resistance has been the subject of much speculation (‘the sickled cells spear the protozoan’). Very recent research suggests that it is an alteration in circulating heme levels that allows small amounts of carbon monoxide to accumulate, thus preventing malaria from taking hold. 

In any case, the relative resistance to malaria by slaves taken from endemic areas was common knowledge to the enslavers. Make of it what you will as to the consequences.

CRISPR Mosquitos

A genetic technology that can kill off mosquito species could eradicate malaria. But is it too risky to ever use?

So begins “The Extinction Invention”, an excellent survey of the prospects in the MIT Technology Review. At the Target Malaria project at the Imperial College, London, there is housed a population of mosquitos endowed, by man, with a selfish gene. It is one that would result in ‘gene drive’, a CRISPR related form of genetic engineering. Gene drive would cause the gene to be passed on not 50% of the time, but 99%. This gene will cause female mosquitos to be sterile. About one year after introduction of a bucket full of such mosquitos, the target population would cease to exist.

What we don’t know of course is what are the unintended consequences. But then, we Great Apes are known more for inventiveness than caution.

  Plasmodium

Plasmodium

 Anopheles mosquito at  lunch

Anopheles mosquito at lunch

Leave a comment, email us at info@medicalhistorytour.com.

SqXprntIcon_malaria.png