This article is part of “Innovations In: Sickle Cell Disease,” an editorially independent special report that was produced with financial support from Vertex Pharmaceuticals.
TRANSCRIPT
How is it that you’re alive? It’s a question that we rarely ask ourselves—but it’s one that has a definite answer.
We all know our heart pumps life-giving oxygen throughout our bodies. How does that oxygen actually get to where it needs to go?
Every second of your life, two to three million red blood cells pour out of your bone marrow into your bloodstream. You have around 35 trillion of them moving around your body at all times.
Red blood cells are a marvel— not just for their incredible numbers in our body but also for what each of these cells carries inside it: hemoglobin.
Hemoglobin is an oxygen-carrying protein that makes blood red. Each red blood cell has about 100 million hemoglobin molecules in it. And each of those hemoglobin molecules is able to pick up four oxygen molecules.
It’s hemoglobin’s ability to bind to oxygen that gives it its life-sustaining properties. And normally, those 100 million or so hemoglobins in each red blood cell float freely, giving the cell its flexible biconcave shape. But what if it didn’t work like that all the time? What if hemoglobins clumped together?
This is what happens in sickle cell disease.
Sickle cell arises from a single point mutation in the human genome. That means that one DNA base pair in the HBB gene changes from GAG to GTG. This leads the body to make a faulty protein. That faulty protein causes deoxygenated hemoglobins to clump up and stick together.
When hemoglobins stick to one another, they produce stiff fibers inside the red blood cell. And those fibers stretch and distort the cell, leading to the distinctive sickle shape. For those with sickle cell disease, this is where severe health consequences begin.
The sickled cells are rigid and more likely to get stuck as they move through the vessel. This means red blood cells are less able to do the job of transporting life-giving oxygen. The sickled cells can also easily burst, releasing the cells’ contents into the bloodstream.
One of the components of hemoglobin, called heme, can trigger an immune response once it’s outside the cell. White blood cells and platelets are activated and sent to the damaged cell. These release even more damaging inflammatory signals. Sticky molecules are created on the surface of the platelets and on the walls of blood vessels. This has the unfortunate side effect of damaging the cells in the walls of the blood vessels. Such chronic inflammation can lead to long-term organ damage.
The sticky molecules can also create blockages. That can cause a “pain crisis” in people with sickle cell. It can even put them at risk of cardiac failure and other life-threatening issues.
It’s been more than 100 years since sickle cell disease was first identified in a person. Over that century, science has made major strides in understanding the disease’s basic biology and genetics.
In 1949 Linus Pauling led research that would describe sickle cell as the first “molecular disease.”
In 1954 new research found that the sickle cell trait protects against malaria,
which explains why the disease is more common in regions of Africa where the prevalence of malaria was historically high.
From the 1970s on, medicine started to develop faster ways to diagnose the disease,
and there were even some successes in treatment.
In 1973 scientists developed neonatal screening methods for sickle cell identification.
In 1978 researchers developed a DNA-based diagnostic for sickle cell.
In 1984 a child with leukemia—who also had sickle cell—was given a bone marrow and blood transplant. The treatment cured her sickle cell.
In 1998 the Food and Drug Administration approved a drug called hydroxyurea to treat sickle cell in adults.
It works by helping red blood cells stay flexible by increasing the amount of fetal hemoglobin in the blood. This rise in fetal hemoglobin, a form of the protein that is typically replaced by adult hemoglobin a few months after birth, prevents sickling and decreases the risk of blockages in small vessels.
In 2001 researchers used gene therapy to correct the disease in a lab mouse.
In 2014 researchers used a lentivirus to carry an antisickling beta-globin gene into the cells of a 13-year-old boy living with sickle cell disease. The clinical trial was halted in 2021 when two patients developed cancer.
In 2017 the FDA approved the first drug to treat sickle cell in almost 20 years: L-glutamine. It works by reducing severe sickle-cell-related complications.
The FDA also approved two other drugs for sickle cell symptom management in 2019. But with developments in the past few years, medicine finally seems to be verging on a cure for sickle cell. And gene-editing technology is central to this hope.
A new treatment approach works by first harvesting unhealthy stem cells from a patient’s bone marrow. The patient is treated with drugs that kill many of their unhealthy bone marrow cells. At the same time, scientists replace the faulty HBB gene with a healthy copy. Then the gene-edited stem cells are put back into the patient. The corrected stem cells produce healthy hemoglobin and red blood cells.
Another gene-editing technique uses CRISPR to edit a person’s stem cells to increase the production of fetal hemoglobin. At the end of 2023, the FDA approved two such gene therapies. One, called Casgevy, uses CRISPR-Cas9 to increase fetal hemoglobin. The other, Lyfgenia, uses a lentivirus to insert a gene that increases a form of adult hemoglobin in the body.
Regardless of the way sickle-cell-producing genes are modified by such treatments,
researchers hope to one day administer them inside people’s body. These treatments are and will be very expensive, raising questions about equity and access. But for the estimated 100,000 people in the U.S. and 20 million worldwide who are living with sickle cell, new treatments and a potential cure would be life-changing.
This article is part of “Innovations In: Sickle Cell Disease,” an editorially independent special report that was produced with financial support from Vertex Pharmaceuticals.