A heavy burden genetic disorder
Sickle cell disease (SCD) is a serious inherited blood disorder that affects millions of people around the globe. In 2021, an estimated 7.74 million people were living with sickle cell disease, with prevalence growing globally. Healthy red blood cells are disc-shaped and flexible so they can move easily through blood vessels. In sickle cell disease, red blood cells are misshaped, typically crescent, or “sickle”, shaped due to a gene mutation that affects the haemoglobin molecule – the oxygen-carrying protein found in red blood cells. These malformed red blood cells are hard and sticky and do not bend or move easily. They can block blood flow to the rest of the body resulting in pain and other serious complications such as attacks of anaemia, swelling in the hands and feet, bacterial infections and stroke.
Sickle cell disease is a severe and lifelong illness that may be managed through preventive screening, care, and treatment strategies. However, options are scarce. The estimated life expectancy of those with SCD in the United States is more than 20 years shorter than the average.
So why does this inherited genetic condition persist? You might expect natural selection to weed out a gene that shortens life expectancy so dramatically. But with sickle cell disease, that doesn’t seem to be the case. That is because the negative effects of the mutated gene generally only occur in individuals who have two copies, one from each parent. A single copy of the gene actually confers health advantages in some places of the world. Not only are people with only one mutated sickle cell gene usually free from symptoms of the disease, they also have some protection against malaria, another life-threatening disease.
Where there is malaria, sickle cell genes are not far away
Malaria is a virulent disease spread by mosquitoes. In 2024 alone, there were an estimated 282 million cases worldwide, with symptoms varying from mild to life threatening. The WHO African Region carries a disproportionately high share of the global malaria burden, home to 95% of malaria cases (265 million) and 95% (579,000) of malaria deaths. It is not a coincidence that Sub-Saharan Africa is also where SCD is most prevalent, with 80% of sickle cell disease cases occurring in the region. The geographical distribution of the sickle haemoglobin gene and distribution of malaria in Africa virtually overlap. And where malaria does not occur in those regions, like in the cooler and drier climates of the highlands, neither does the gene for sickle haemoglobin.
Possessing a single mutated sickle gene reduces malaria incidence by 29% and therefore confers a survival advantage over people with normal blood in regions where malaria is endemic. People – and particularly children – infected with the parasite that causes malaria are also more likely to survive the acute illness if they have a single sickle cell gene. Therefore, they are also more likely to reach reproductive age and pass their genes on to the next generation. This explains why the sickle cell gene tends to stick around in regions where malaria is present, despite the dire consequences it can have when it leads to sickle cell disease.
Why does the sickle cell gene confirm protection?
The anti-malarial protective properties conferred by a single sickle cell gene are composed of a number of factors. In 2011, researchers used mice to uncover a few.
Miguel Soares, Ana Ferreira and colleagues, from the Gulbenkian Institute of Science in Portugal, found that haem – a component of haemoglobin – is present in a free form in the blood of mice with a single sickle cell gene, but largely absent from normal mice. By injecting haem into the blood of normal mice before infecting them with malaria, researchers found it could help guard against malaria. The mice did not develop the disease. Results also showed that the gene does not protect against infection by the malaria parasite, but prevents the disease taking hold after the animal has been infected.
In other experiments, Soares and his team demonstrated that hosts with sickled red blood cells are a naturally hostile environment for the malaria parasite. For a long time, scientists assumed people and animals with the one gene were better at fighting infection, but it turns out they are better at cleaning up after infection. Since they have to break down and detoxify misshapen red blood cells their entire lives, their molecular machinery for cleaning up mess is already active when the malarial parasite attacks. Not only do the faulty cells have a membrane that is porous, stretched by their unusual shape, and leaks nutrients that the parasites need to survive, but they are already targets of the immune system, which gets them eliminated quite fast, destroying the parasite as a side effect. The toxic T-cell build-up after a malarial infection just doesn’t happen in mice with one sickle cell gene.
Understanding the specific mechanisms of how the sickle cell mutation delays the progression of the malaria parasite in red blood cells could be fundamental in the discovery of new malaria treatments. And decreasing the malarial load could in turn weaken the evolutionary forces that encourage the sickle cell trait to stick around. A win-win situation all around, if it weren’t for the fact that malaria parasites may be adapting to the presence of the sickle cell gene. Research is still very much needed to understand all the evolutionary forces at play.
Last edited: 24 June 2026 11:08
