29 gennaio 2015

Fighting malaria: tonic water, quinine and sickle cell anemia

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(You may want to read first the first part of this article, on how people get infected with malaria's parasite)

When left alone to fight against malaria, our body often gets in troubles. Our immune system finds it very difficult to get rid of the parasite which causes malaria (the plasmodium) and, differently from what happens with most other bugs, it can't even properly generate an acquired protection against it.
Only after several repeated infections, the body manages to organize a defence system that cannot eradicate plasmodia, but can at least reduce the severity of malaria symptoms and complications. That's why young - and still non-immunized - children are more at risk, and are the most common victims of the disease.

A treatment for malaria does exist: it's quinine, which has been known and used for four centuries. This is how it works.
Malaria's plasmodium spends most of his human stay hidden inside blood's most abundant cells, the red blood cells.
Upon entering a red blood cell, the parasite is seized by an extraordinary hunger, and starts eating all he can find, especially a protein very abundant in these cells, called hemoglobin. Being a protein, hemoglobin is quite nutritious. But its core, made of iron, is hard, definitely not edible - and also poisonous.

As he eats hemoglobin, the plasmodium carefully sorts the iron waste, compacting it, and stocking it into a dedicated container for special garbage. This behaviour may seem quite psychotic, as in a few hours, when the plasmodium will leave the cell, he'll forget about the iron waste, letting it diffuse in the blood, where it will cause great environmental damage.
Antimalarial drug quinine mixes with the iron waste within red blood cells and disrupts its compacted organization. Free to diffuse within the cell, the waste becomes very toxic, and kills plasmodia.

[Note. Quinine has a very bitter taste and is also used to flavour drinks such as Italian "chinotto" or tonic water. Tonic water was originally a "tonic" against malaria, and contained a much larger amount of quinine. Englishmen living in India had to drink tonic water as a prophylaxis for malaria; at some point, somebody had the brilliant idea of adding gin to the bitter drink, to improve its taste. That's how gin tonic was born].
Therefore, there is a cure for malaria. But if you are an African baby covered since birth with a continuous layer of mosquitoes, the chance you'll get enough quinine to save your life is quite low. Unless you have an alternative mechanism of defence, for example a specific mutation in the hemoglobin gene.

In standard conditions, mutated hemoglobins behave normally; but if exposed to stress, they become peculiarly sticky and tend to aggregate, forming hard and elongated crystals that make red blood cells very stiff. Affected cells become locked in a funny conformation, which makes them look like a sickle or a crescent: therefore, they are referred to as sickle cells. As soon as sickle cells get to the spleen, they are withdrawn from circulation and sent to scrapping.

Now: what's more stressing than being infested with a parasite? Nothing (anybody who's travelled in the tropics will agree). Indeed, plasmodia infested mutated red blood cells get extremely stressed, become easily sickle shaped and are rapidly eliminated - together with the parasites they host - by the immune system: not because they are infected, but because they are ill-shaped. This impairs plasmodium's replication and protects the body from the most severe consequences of malaria. Thus people carrying one mutated hemoglobin gene have a very low probability of dying from malaria.

However, if you have both hemoglobin genes mutated, because you got one from each parent, you are in serious trouble. In these people, red blood cells are a complete disaster: stiff, very fragile and constantly sickle shaped, even in normal conditions - that is, when not infected. This leads to anemia - due to systematic elimination of red blood cells - and other serious and life-threatening consequences. This genetic disease is called sickle cell anemia and it's widespread in all countries where malaria is (or was) endemic.

The case of malaria is a perfect example of evolution and selection.
Chance introduced a potentially lethal defect (hemoglobin's mutation), which was retained and propagated only because it helps to fight an even more lethal threat (malaria).
[The mutation is so advantageous that has been separately invented five times during human evolution]
In countries where malaria still is a problem, and appropriate treatment is not available, carrying the mutation is still an advantage.
In countries like Italy, where malaria was eradicated, sickle cell mutation is just a genetic defect and might at some point disappear.

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