This article is the second in a series related to malaria and resistance to the disease (read the first article here). In this article, I will first explain what sickle cell anaemia is and how it affects the body. I will then move on to explore how sickle cell anaemia can give people resistance against malaria and why that is.
Sickle cell disease is a group of relatively common inherited genetic conditions that affect the haemoglobin in red blood cells. Of these (according to nhs.uk), the most serious of these is sickle cell anaemia. As I will explain later in the article, people with this genetic condition produce irregularly shaped red blood cells. This can lead to many problems as not only is the oxygen-carrying capacity of the red blood cells reduced, but the unusually shaped red blood cells can also block blood vessels, resulting in a 'sickle cell crisis' (very painful episodes).
Normal, healthy red blood cells contain haemoglobin A. This is haemoglobin that consists of two alpha and two beta chains. In people who are diagnosed with sickle cell disease, however, one of the beta chains is replaced with haemoglobin S (both beta chains are replaced in people with sickle cell anaemia). This is due to a point mutation (a single base is changed) in the beta-globin gene on chromosome 11. Since a nucleotide in the codon for amino acid 6 in the beta-globin gene is changed (from adenine to thymine), a glutamic acid amino acid is produced instead of a valine amino acid.
As such, when protein synthesis occurs to produce haemoglobin for red blood cells, a different protein (haemoglobin S) is made. The mutated gene which leads to the body producing erroneously shaped red blood cells can then be passed onto future generations.
As sickle cell anaemia is a recessive disease, you need to inherit a faulty allele from both parents. Carriers (those who receive one healthy and one faulty allele) still may have some health complications, as it causes the haemoglobin to aggregate abnormally in the cell. Normally, a fatal genetic condition like this one would kill people before they can have children, meaning that the condition would be wiped out. However, as I will explain later, carriers of sickle cell anaemia have increased resistance to malaria, meaning the condition remains prevalent.
In healthy people, the haemoglobin in red blood cells is responsible for taking up oxygen in the lungs and then carrying it through the vascular system so that all the cells in the body can receive oxygen. The normal red blood cells are also bi-concave flexible discs, meaning that they can easily squeeze through narrow blood vessels provide oxygen to respiring cells. However, sickle cells (red blood cells that have haemoglobin S) are crescent-shaped, due to the fact that non-liquid, rigid protein strands form in the red blood cell due to the mutation. Because the shape of the red blood cell has now changed, they can no longer fit as easily through blood vessels. Occasionally, the sickle cells stick to the sides of the blood vessels, causing a blockage. This results in a 'sickle cell crisis' as oxygen can no longer reach tissues beyond the blockage, causing intense pain.
As the name of the condition suggests, the most common symptom of sickle cell anaemia is oxygen-deprivation. This is because the sickle cells are much more fragile (as they can't change their shape as easily) - while normal red blood cells can last for 100-120 days, sickle cells usually die within 10-20 days. As such, there is a shortage of red blood cells in the circulatory system, meaning that enough oxygen can't be transported around the body. This is called anaemia and often leads to fatigue.
Other common symptoms of sickle cell anaemia include painful swellings of the hands and feet, frequent infections, delayed growth, vision problems and, episodes of pain due to sickle cell crises. This is where the sickle cells block blood flow through narrow blood vessels (such as capillaries) causing both chronic and occasional pain.
The treatment of sickle cell anaemia can broadly be split into two categories - taking medication to treat sickle cell crises after they occur and curing the condition itself. For the former, those with sickle cell anaemia are advised to drink plenty of fluids to avoid dehydration as well as maintaining their body temperature at a fairly warm level in order to reduce the risk of a painful episode. Further, medicine such as hydroxycarbamide can also be taken to reduce the pain during a sickle cell crisis. However, taking this medication has significant risks as it lowers the number of white blood cells and platelets your blood contains, making you more vulnerable to infections and reducing the rate your blood clots.
Sickle cell anaemia can also be cured by a bone marrow transplant. This works as your bone marrow produces stem cells which differentiate to produce red blood cells. As such, when the bone marrow of someone who has sickle cell anaemia is replaced, they begin producing healthy blood cells and the unhealthy sickle cells are filtered out. The first stage of a bone marrow transplant involves harvesting the healthy stem cells from a donor, usually a family member with the same tissue type as the recipient (so that the immune system doesn't reject them). The body is then treated with chemotherapy or radiotherapy to destroy any existing bone marrow cells and stop the immune system from working, thus reducing the chance that the donor cells get rejected. The donor stem cells are then passed slowly into your body through a central line, similar to how a blood transfusion is carried out.
The link between sickle cell anaemia and malaria is very well documented and helps explain why the disease is still prevalent today. As sickle cell anaemia is a recessive trait, if you only have one faulty allele then you will be a carrier for the disease - while you can pass on the mutated gene to your children, you can't have the disease yourself. However, while those who suffer from the disease are more likely to not have children, carriers are just as likely to have children as non-carriers of the faulty allele. Further, as being a carrier of the disease means that you have resistance to malaria, this trait is selected as beneficial in malaria-prone areas, meaning the disease continues to exist. Meanwhile, being a carrier of sickle cell disease is not beneficial in areas without malaria, meaning that the disease prevalence is low in areas without malaria.
Before reading on to my analysis of the current ideas around how sickle cell anaemia confers resistance to malaria, I would suggest reading my article on malaria which will help explain the mechanism body which malaria spreads around the body.
There are many conflicting beliefs as to why being a carrier for sickle cell anaemia confers resistance to malaria. One theory published in 2011 suggests that it is related to the actin filaments on the red blood cells. The internal skeleton of healthy red blood cells contains many actin filaments (threads of protein) that allow the red blood cell to squeeze through the small blood vessels. However, when a person is infected with malaria, the malarial parasite takes the actin from the red blood cell and uses it to form a bridge by which the parasite can transport a protein to the cell. As such, the cell loses its flexibility. Meanwhile, red blood cells containing haemoglobin S prevent the malarial parasite taking the actin, preventing the protein from being polymerised to form long chains. As such, those who are carriers of sickle cell anaemia make enough normal red blood cells to not have symptoms of sickle cell anaemia, while simultaneously increasing their resistance to malaria.
A further theory suggests that sickle cells are just as affected by the malaria parasite, but are worse hosts for the parasite. This is because the unusual shape of the sickle shape means that its membrane is stretched, resulting in it becoming more porous. As such, nutrients such as potassium are lost from the cell, meaning the parasite can no longer survive in the cell. Furthermore, sickle cells are also worse hosts for the parasite as the body sends sickle cells to the spleen to be destroyed, thus meaning that malarial parasites in sickle cells are more likely to be destroyed.
The most convincing theory that I found, suggested and proved using mice by the Gulbenkian Institute of Science in Portugal, was that haem (the iron-containing, non-protein part of haemoglobin) is present in a free form in the blood of sickle cell disease carriers. This haem then stimulates the production of an enzyme called haem oxygenase-1, which in turn releases small quantities of carbon monoxide gas. While carbon monoxide gas is usually poisonous, since it binds irreversibly with haemoglobin, heavily restricting the transport of oxygen around the body, in small quantities, the gas can actually have therapeutic properties. This is likely because carbon monoxide naturally exerts anti-inflammatory effects, which oppose the inflammation caused by malaria. Carbon monoxide also exhibits cytoprotective properties in vascular endothelial cells, making it harder for cells lining the blood vessels to be damaged. Regardless of the precise mechanism by which the carbon monoxide combats malaria, a study by Ferreira (a researcher at the Gulbenkian Institute) has previously shown that the carbon monoxide helps prevent mice from succumbing to cerebral malaria.
In conclusion, I would contend that it is a combination of the theories above that result in carriers of sickle cell anaemia having resistance to malaria. Nevertheless, I believe that further research in this field needs to be completed, especially with regards to the role of haem (particularly regarding the fact that too high concentrations of haem actually led to malaria being more prevalent).
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