I thought it was about time to leave bacteria and viruses behind for a week to look at disease caused by a very different micro-organism, Malaria. In fact by looking at malaria we can cover two diseases in one week by also looking at the effect of Sickle Cell Anaemia. It’s hard to overestimate the impact malaria has had on human populations over time but some perspective can be gained by observing that the WHO decided to try eradicating it in 1955. We gave up in 1976 because it was resistant to all our attacks and still kills nearly 100,000 people every year but it’s suspected that many deaths go unrecorded.
Very Brief History
I say brief but we can still go back to before the 5th century (BC) and find references to malaria! Hippocrates seems to have described it but combined it with symptoms of other disease so we go back to the Greeks of the 4th century BC for the first actual description. Without knowing what was happening they did notice that people that worked in the swamps developed periodic fevers and spleen enlargement, two signs characteristic of malaria.
By the 17th century the Italians had coined the name mal’ aria for the collection of symptoms meaning bad air not the award ceremony. This name presumably arose to the connection with the stinky swamps full of ‘bad air ‘people were getting sick in and probably had nothing to do with the bad musical air of the aforementioned award ceremony (he didn’t win it but to think he was even nominated). But despite the devastating effects it was already having on human populations we had also come across the first effective medicine to treat the disease. Bark from the Quinaquina tree in South America has processed in several ways and was found to alleviate the symptoms, it helped because it contained crazy high amounts of Quinine.
We had to wait till the 1880’s for the next major breakthrough, but this was followed by 20 years of frenetic advancement. In 20 years we observed the parasite Plasmodium in fresh blood (1880), observed it mating asexually and reproducing (1885), it was postulated to be carried person to person by mosquitoes by Patrick Manson (1890) then subsequently proven by the great Sir Ronald Ross by first showing the parasite could be found in mosquito guts and that the disease could spread between experimental animals by through the mosquito. He won his Nobel prize for this in 1902.
So what are we dealing with?
Malaria is caused by a protozoan (link it) called Plasmodium. There are 4 species but most disease is associated with P. falicparium and P. malariae. These parasites are able to invade our livers and red blood cells resulting in a form of systemic shock and eventually anaemia and possibly death. It’s hard to talk about the symptoms without talking about the lifecycle of the Plasmodium as the symptoms are intrinsically linked to the stage of maturity the parasites are at.
As I mentioned above, and was elegantly demonstrated by Ross, Plasmodium is carried by mosquitoes. Female mosquitoes are the only ones that feed are they are solely responsible for the spread of disease, bloody women (ha, ‘bloody’. I made a mosquitoes pun unintentionally). When the FEMALE mosquito feeds she releases saliva which has a number of properties such as being an anti-coagulant and mild anaesthetic but in the case of infected females also contains ‘haploid’ sporozites. ‘Haploid’ refers to these sporozites only containing half the genetic information of an adult mosquito, like a sperm or egg only contain half the genetic info so they have to pair up to for a zygote with the full complement of genetic material. The sporozites travel from the ‘site of the bite’ to the liver where they invade liver cells. Within liver cells the sporozites fuse together and become a single cell called a merozites. This transition can be thought of like metamorphasis, the catapillaer and butterfly are different but once became the other. The butterfly matures from its ‘caterpillar phase’ the same way the merozite matures from its sporozitic phase.
Once merozites are formed they jump out of the liver cells and back into the blood where they invade the red blood cells. The reason they do this is because Plasmodium needs a lot of oxygen to grow and there’s no better place to find it. The merozite grows in sizes and is now called a trophozite. At this stage we still have only one cell, but then, without the overall size of the cell altering, the nucleus divides multiple times and suddenly the trophozite is called a schizont made up of as many as 24 ‘mini-cells’. The schizont separates out and each ‘mini-cell’ is once again called a merozite and follows this life cycle until the resident red blood cell explodes. Then the merozites invade new red blood cells.
It is this wide scale destruction of red blood cells accompanied with malarial toxins and debris suddenly accumulating in the blood that is responsible for the periodic fevers. Upon release a fever is observed but the body cleans up and the new merozites jump into new red blood cells so the fever dies down only to spike again about every 60 hours.
However, not all merozites become trophozites. Some go one to become the gametes (generic term for cells that give rise to the next generation, the sperm and egg for example). These gametes float inside a red blood cell around until they are picked up as a female mosquito feeds. Once they are back inside the FEMALE mosquito two gametes fuse together and invade the insects gut and form a cyst. This cyst can give rise to thousands of new sporozites and the process starts again.
Malaria causes significant disease and death by forcing the body to fight the disease in the blood, always a bad idea, and by destroying the blood as part of its life cycle. Initially this causes general flu type symptoms such and general aches, sweats and lethargy but over a long enough time can proceed to anaemia and even shrinking of the liver. The combination of debris and parasites also can block blood flow to places like the brain causing cerebral malaria or the spleen. The spleen acts like a giant blood sieve and all the gunk in your veins can block it up causing it to swell and possibly rupture resulting in toxigenic shock and death.
Sickle Cell Anaemia
In the 1960’s it was observed that a population in West Africa showed some resistance to malaria. It was shown that these individuals’ red blood cells could not be infected because they carried a mutation that completely altered the cells shape.
Haemoglobin is the component of red blood cells that carries the oxygen around the body. Haemoglobin is referred to as haemoglobin-A normally but these West Africans instead had haemoglobin-S. This difference between the two types is very small but has a profound effect on the ability of haemoglobin to work properly. Haemoglobin is made up of nearly 600 amino acids and haemoglobin-S has only 1 amino acid difference to haemoglobin-A. This difference however creates a hydrophobic region that sticks to other hydrophobic regions in the presence of water (such as in blood). The result is that the red blood cells shape is changed into long ‘crescent moon’ or ‘sickle’ shapes, hence the name Sickle Cell Anaemia. Having lots of sickle cells makes you completely resistant to malaria but as these cells do not carry oxygen very well people who have lots often die very young but only having some sickle cells doesn’t actually affect you very much and confers partial resistance to malaria. It’s this partial resistance to malaria conferred by the sickle cells that has allowed the mutation to persist in human populations.
What Can Be Done?
Currently patients are treated aggressively with quinine derivatives which primarily act to prevent maturation from merozite to trophozite but this is sometime not terribly effective and its being increasingly observed that Plasmodia are becoming resistant to quinine treatment.
We don’t have a vaccine yet either. This is because designing a vaccine for malaria is very difficult, what do you target? Sporozites disappear from the blood very quickly but are probably our best hope as at all the other stages the parasite is hiding inside red blood cells. The other option is mosquito control and this is utilised heavily, particularly in South America. An interesting idea has been proposed that may have an impact on disease rates. Rather than treating the people, why not treat the mosquitoes? By breaking the life cycle we can prevent both disease and spread very effectively. We are still some way off being able to do anything like this practically but it is hoped that it might become a new weapon to fight back with.
Davidson, S. (2006). Principles & Practice of Medicine. Philadelphia, Churchill Livingstone Elsevier.
Prescott, L., J. Harley, et al. (2005). Microbiology. New York, McGraw Hill.
Raven, P. and G. Johnson (2002). Biology. New York, McGraw-Hill.