From the Experts

Science Simplified: Gene Editing for Human Health Improvement

Dr.  Sujan Mamidi
Sr. Scientist
HudsonAlpha Institute for Biotechnology

In a recent development, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene editing has been used to improve human health. This new technique helped cure people with sickle cell anemia and another serious blood disorder, beta-thalassemia. This research would create more avenues for the treatment of other human and plant diseases. It marks the beginning of using genomics and molecular biology to solve human problems.

Defining the function of a gene and its effect on phenotype by disrupting a gene using various techniques is an important tool in molecular biology. These techniques are important for understanding how a gene and its product contributes to the development and cellular identity of organisms. NGS (next generation sequencing) along with genome‐editing techniques has increased the possibilities of understanding biology in many organisms. On the other hand, the identified genes if altered can help cure genetic disorders. CRISPR-Cas9 is one such assay.

CRISPR is a genetic mechanism used by some bacterial species for antiviral mechanism. Now, as a gene-editing tool, CRISPR/Cas9 is revolutionizing functional biology and biomedical research. Given the growing importance, Jennifer Doudna and Emmanuelle Charpentier were awarded noble prize in
chemistry in 2020. CRISPR/Cas9 edits genes by precisely cutting DNA and then letting natural DNA repair processes to take over. The system consists of two parts: the Cas9 enzyme and a guide RNA.

Sickle cell anemia is an inherited disease affecting about 100,000 persons in the United States, mostly of African origin. It is estimated that about 400,000 infants are born in the world with this disease. People born with sickle cell disease have mutations in their two copies of a gene for hemoglobin (the oxygen-carrying protein in red blood cells). Sickle shaped hemoglobin (HbS) is a variant of normal adult hemoglobin (HbA). This is produced when a single missense mutation (mutation that causes change in amino acid sequence) in the β-globin gene (HBB) occurs. Functionally, on deoxygenation, HbS polymerizes and leads to abnormally shaped red cells. These cells clog blood vessels, and cause severe pain, leading organ damage and strokes, ultimately leading to early death. The standard treatment for sickle cell disease is a bone marrow transplant. With a matched sibling donor transplantation, it is about 90% effective in patients. However, there is an increased risk in older patients, a risk of severe graft-versus-host disease, and scarcity of matching donors.

Contrary to this, patients suffering with beta-thalassemia make little or no functioning hemoglobin. This is because of the mutations that affect the same subunit of the protein as sickle cell anemia. It is estimated that about 60,000 babies are born each year globally with this disease. This is prevalent in
Mediterranean, Middle Eastern, and South Asia. Transfusion is an optional cure but is limited due to various factors.

In the two new treatments, that target the above two diseases, researchers modified the genes to counter the malfunctioning hemoglobin. For this, they removed a patient’s blood stem cells (found in bone marrow) and in the lab, disabled a genetic switch called BCL11A. The patient then received chemotherapy that wipes out most of their diseased cells, and then the altered stem cells are infused. When the fetal gene is active, the fetal protein restores missing hemoglobin in thalassemia using the altered stem cells. In sickle cell disease it replaces some of the flawed adult hemoglobin. Among the six-sickle cell patients treated for at least 6 months, it has been a success in 5 of them and the 6th patient just needed additional transfusion. However, all the patients treated in both trials have begun to make sufficiently high levels of fetal hemoglobin and no longer have sickle cell crises.

Reference (Dec-20-A8)


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