What shape are your cells? Squishy cylinders? Jagged zig-zags? You probably don’t think much about the bodies of these building blocks, but at the microscopic level, small  changes can have huge consequences. And while some adaptations change  these shapes for the better, others can spark a cascade of  debilitating complications. This is the story of sickle-cell disease. Sickle-cell disease affects the  red blood cells, which transport oxygen from the lungs  to all the tissues in the body. To perform this vital task, red blood cells are filled with hemoglobin proteins to carry oxygen molecules. These proteins float independently inside the red blood cell’s pliable,  doughnut-like shape, keeping the cells flexible enough to accommodate even the  tiniest of blood vessels. But in sickle cell disease, a single genetic mutation alters the structure of hemoglobin. After releasing oxygen to tissues, these mutated proteins lock  together into rigid rows. Rods of hemoglobin cause the cell  to deform into a long, pointed sickle. These red blood cells are  harder and stickier, and no longer flow smoothly through  blood vessels. Sickled cells snag and pile up– sometimes blocking the vessel completely. This keeps oxygen from reaching a variety of cells, causing the wide range of symptoms experienced by people  with sickle-cell disease. Starting when they’re  less than a year old, patients suffer from repeated episodes of stabbing pain in oxygen-starved tissues. The location of the clogged vessel determines the specific  symptoms experienced. A blockage in the spleen,  part of the immune system, puts patients at risk for  dangerous infections. A pileup in the lungs can produce  fevers and difficulty breathing. A clog near the eye can cause vision  problems and retinal detachment. And if the obstructed vessels  supply the brain the patient could even  suffer a stroke. Worse still, sickled red blood cells  also don’t survive very long— just 10 or 20 days, versus a  healthy cell’s 4 months. This short lifespan means that patients live with a constantly depleted supply of red blood cells; a condition called sickle-cell anemia. Perhaps what’s most surprising  about this malignant mutation is that it originally evolved as a beneficial adaptation. Researchers have been able to trace the origins of the sickle cell mutation to regions historically ravaged  by a tropical disease called malaria. Spread by a parasite found  in local mosquitoes, malaria uses red blood cells as incubators to spread quickly and lethally  through the bloodstream. However, the same structural changes that turn red blood cells into roadblocks also make them more resistant to malaria. And if a child inherits a copy of the mutation from only one parent, there will be just enough abnormal  hemoglobin to make life difficult for the  malaria parasite, while most of their red blood cells retain their normal shape and function. In regions rife with this parasite, sickle cell mutation offered a serious  evolutionary advantage. But as the adaptation flourished, it became clear that inheriting the  mutation from both parents resulted in sickle-cell anemia. Today, most people with  sickle-cell disease can trace their ancestry to a country where malaria is endemic. And this mutation still plays a key role in Africa, where more than 90% of malaria  infections occur worldwide. Fortunately, as this “adaptation” thrives, our treatment for sickle cell continues  to improve. For years, hydroxyurea was the only  medication available to reduce the amount of sickling, blunting symptoms and  increasing life expectancy. Bone marrow transplantations  offer a curative measure, but these procedures are  complicated and often inaccessible. But promising new medications  are intervening in novel ways, like keeping oxygen bonded to  hemoglobin to prevent sickling, or reducing the stickiness  of sickled cells. And the ability to edit DNA has raised the possibility of enabling  stem cells to produce normal hemoglobin. As these tools become available in the areas most affected by malaria and sickle cell disease, we can improve the quality of life for more patients with this  adverse adaptation.