By: Aarushi Sant
Sickle Cell Disease
Imagine a highway where traffic is flowing smoothly– until some cars come close together and become stuck, blocking the incoming vehicles. This is very similar to what happens inside the body of someone who suffers from Sickle Cell Disease. This is also what makes Sickle Cell Disease so dangerous, something as straightforward as blood flow can become interrupted and have devastating effects on the body.
Sickle Cell Disease, also known as Sickle Cell Anemia, affects hemoglobin in the red blood cells. Hemoglobin is a protein that is responsible for carrying oxygen around the body, delivering it to different tissues and organs. Normally, the red blood cells in your body are disc-shaped, allowing them to move easily through blood vessels. But for people who have Sickle Cell Disease, a genetic mutation causes the blood cell to become inflexible and stiff, in a “sickle” or crescent-like shape.The issue with sickled red blood cells is that they do not bend, or move easily through blood vessels, which can restrict blood flow to different parts of the body.
What exactly happens?
The main cause of this disorder is a genetic mutation in the HBB gene, which affects hemoglobin, a protein in red blood cells. A DNA section is swapped from GAG to GTG (adenine to thymine). Though this change seems small, even a small shift in DNA can completely change the way proteins like Hemoglobin acts. This change in DNA swaps glutamic acid (a hydrophilic amino acid) to valine (a hydrophobic amino acid). Sickle Cell Disease can only be inherited, meaning that a child can only have this disease if they receive two sickle genes, one from their mother and the other from their father.
As a result, the genetic mutation causes the body to produce an abnormal type of hemoglobin called Hemoglobin S. This type of hemoglobin ‘sickles’ when it is deoxygenated. When oxygen is released to the tissues, the valine is exposed. Since the valine is hydrophobic, and needs to escape water, it binds to another hydrophobic patch on the same blood cell.
Sickled cells are stiff and inflexible, and are not able to pass through blood vessels easily. They become stuck, which blocks the flow of blood to tissues and organs. The blockages lead to intense pain episodes called crises, organ damage, and in some cases, stroke.
According to an article by Mayo Clinic, a few complications associated with Sickle Cell Disease include:
- Stroke: Sickle cells are known to block blood flow to parts of the body. Blocked blood flow to the brain can lead to stroke. Some signs of stroke include loss of consciousness, numbness in arms or legs, seizures, and sudden difficulty speaking.
- Acute Chest Syndrome: A painful complication caused by vaso-occlusion (blocked blood flow) in the lungs. Symptoms of this include chest pain, fever and difficulty breathing.
- Organ Damage: Sickle cells that block blood flow to parts of the body deprive certain organs of blood and oxygen. Over time, the lack of blood and oxygen to the affected organs leads to damage in nerves and organs.
Who is affected?
Sickle Cell Disease affects over 100,000 Americans, and over 7 million people worldwide. It is most common in people who come from areas where Malaria has been widespread. This is a prime example of adaptation: the Hemoglobin S gene protects against Malaria, showcasing how genetics and the environment are related.
- Approximately 1 out of 13 Black babies are born with sickle cell trait (they inherited the trait from one parent)
- Around 1 in every 365 Black babies are born with Sickle Cell Disease (they inherited the sickle cell gene from each parent)
In the United States Sickle Cell Disease affects around 100,000 people. As stated by U.S. Centers for Disease Control and Prevention, “more than 90% are non-Hispanic Black or African American, and an estimated 3%–9% are Hispanic or Latino [in the United States.]”
The Use of CRISPR in Treatment
CRISPR-Cas9 is a tool that allows scientists to carefully cut and change DNA. In treatment for Sickle Cell Disease, the main objective is to get rid of or fix the mutation in the HBB gene. CRISPR works by changing the DNA in the bone marrow so that instead of sickled blood cells, healthy ones are made instead.
A type of therapy called Casgevy uses CRISPR to target the root cause of Sickle cell Disease. Casgevy is the first FDA approved treatment that uses gene editing technology.
In Casgevy, CRISPR is used to turn on the production of Fetal Hemoglobin, a type of hemoglobin that is made in the body before birth but stops being produced later in life. Shortly after you are born, the body stops producing Fetal Hemoglobin and starts producing adult hemoglobin. For people who have Sickle Cell Disease, adult hemoglobin does not work properly. Fetal Hemoglobin does not cause red blood cells to sickle. CRISPR is used to target the root cause of the disorder, instead of just the symptoms.
In order to do this, doctors remove stem cells from the patient’s bone marrow and use CRISPR to edit their DNA. Once the cells have been edited, they are returned to the patient’s body. Over time, the edited cells begin to produce healthy blood cells, which contain fetal hemoglobin. This process can serve as long term treatment, in some cases.
Technologies like CRISPR offer hope for more effective and different types of treatments in the future. As research continues, new medical advancements can completely change the way disorders like Sickle Cell Disease are treated.
