This post is the second in a series on evolutionary medicine, the application of the principles of evolution to the understanding of health and disease. Read the previous entry here.
It's a basic tenet of biology that natural selection picks the most advantageous traits and passes them on to the next generation. Why, then, do people still suffer from debilitating genetic diseases? Shouldn't the genes that code for these diseases be removed from the population over time? How did they manage to keep themselves around during the course of human evolution? It turns out that there may be a reason that genes for harmful diseases survive evolutionary selection and pass from generation to generation.
One disease that has stood the test of time is sickle cell anemia. Sickle cell disease is a nightmare for the millions living with the symptoms of the disease, yet the genes that cause it may be a blessing for many others. The sickle cell gene has the potential to cause intense pain, delayed growth, and even organ damage or stroke. But, it can also provide a measure of protection against an entirely different illness: malaria, a potentially fatal blood infection. How can the sickle cell have such different effects in different people? The answer is all in the genes.
Sickle cell relates to the gene for hemoglobin, the protein in the blood that carries oxygen throughout the body. Instead of inheriting a normal hemoglobin gene, babies with sickle cell inherit mutated hemoglobin. These abnormal hemoglobin molecules clump together, causing red blood cells, which are normally round, to become crescent-shaped.
A baby normally inherits two copies of a gene, one from each parent. In the case of sickle cell, inheriting two abnormal copies of the hemoglobin gene causes symptoms of the disease to appear. But babies who inherit only one copy of the sickle cell hemoglobin gene and a copy of the normal hemoglobin gene do not show sickle cell anemia symptoms.
Unlike kids with two copies of normal hemoglobin, though, kids with just one copy of the sickle cell gene are protected against the worst symptoms of malaria. Since malaria infection can cause flu-like symptoms, bleeding problems, shock, or even death, being able to diminish those effects has obvious advantages. In areas of the world where malaria infection rates are high, like Africa, South Asia, and Central and South America, this protection becomes even more important.
Dr. Anthony Allison was the first to discover that the sickle cell trait provided protection against malaria. In 1954, Allison collected blood samples from children in Uganda in order to compare hemoglobin types and rates of infection with the malaria-inducing parasite Plasmodium falciparum. He found that individuals with the sickle cell trait--that is, just one copy of the mutated gene--had lower P. falciparum parasite counts than than those with normal hemoglobin. They were also less likely to die of malaria.
Allison also discovered that the sickle cell hemoglobin gene is most common in parts of the world where infection with the P. falciparum parasite is very high. Since Allison's initial work, further research has supported his notion that the sickle cell gene, although the cause of fatal disease in young children, has stuck around because of the survival advantage it provides for malaria.
How exactly does sickle cell save many around the world from the deadly effects of malaria? Dr. Rick Fairhurst of the National Institute of Allergy and Infectious Disease suggests that it may be related to how the malaria parasite affects red blood cells. In normal red blood cells, P. falciparum parasites leave a sticky protein on the surface of the cell. The sticky protein causes blood cells to adhere each other and to the sides of the blood vessel, leading to a build up that blocks blood flow and causes the blood vessel to become inflamed. The stickieness also keeps the parasites from being flushed out of the blood stream.
Kids who have the trait for sickle cell hemoglobin, however, see a different end to this story: It's sickle cell to the rescue. Their infected red blood cells with the sickle cell trait are not as "sticky" as infected normal red blood cells. This allows blood to flow more freely and quells inflammation.
Sickle cell hemoglobin is not the only type of hemoglobin that shields against malaria. "Alpha-thalassemia, HbE, and HbS are all different mutations, but they're doing the same thing," Fairhurst says. These hemoglobin gene mutations yield abnormal red blood cells and cripple the health of many kids. But, just like sickle cell hemoglobin, they also decrease the severity of malaria after parasite infection.
Mother nature, explains Fairhurst, found ways to change hemoglobin to weaken the stickiness of red blood cells caused by parasites. He hopes to use this knowledge to develop new medicines to treat--or even prevent--malaria. "If the strength of binding is what's killing you, develop therapies that can weaken that binding," Fairhurst explains.
Natural selection seems to have had a hand in preventing serious malaria infection by maintaining the sickle cell and other abnormal hemoglobin genes, despite the potentially deleterious ramifications. It can help explain why other debilitating diseases are still around, too. Huntington's chorea is a genetic disease that causes degeneration of neurons in the brain, eventually resulting in the inability to carry out many everyday tasks, like walking, swallowing, and speech. Unlike sickle cell disease, which requires you to inherit two copies of an abnormal gene to develop the disease, Huntington's only requires one copy of the defective gene. In other words, as long as you receive a copy of the Huntington's gene from at least one of your parents, you will show symptoms of the disease. Huntington's is also fairly common--about one in 20,000 people worldwide has the disease. Why does this disease, which has such devastating neurological consequences, still affect so many people?
Huntington's can escape natural selection because it does not appear until later in life--typically between ages 40 and 50. Because this is after reproductive years are over, there is no evolutionary drive to weed it out. Natural selection optimizes reproductive success, not health as an end in itself. Huntington's is therefore able to survive generation after generation because it is invisible to natural selection. Pretty sneaky.
But this may not be the whole answer to why Huntington's is still around. Surprisingly, the prevalence of Huntington's has actually increased over the years. Evolutionary "invisibility" cannot explain this increase. It turns out that the gene for Huntington's might actually provide a health advantage during reproductive years by protecting against a entirely different disease: cancer.
A recent study at the Centre for Primary Health Care Research at Sweden's Lund University found that individuals with Huntington's disease and other genetically similar diseases exhibited lower-than-average incidences of cancer. The decreased cancer risk was even greater for younger patients, suggesting that the greatest health benefit of Huntington's disease occurs right around the reproductive years.
Thus even Huntington's disease, which kept itself around by cheating natural selection, may be a double-edged sword. In one way or another, natural selection seems to maintain and even favor some truly dreadful diseases. By understanding both the good and bad, we may gain insights into how to treat--or even prevent--disease.