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.
