Since World War II, just about every aspect of healthcare, from surgery to radiology to record keeping, has undergone sweeping change. Blood banking is a notable exception. Blood today is collected, typed, screened and stored much as it was in the late 1940s, when a nationwide system of blood banks was first organized.
While this system works relatively well, it has significant flaws, says Eric E. Bouhassira, Ph.D., professor of cell biology and of medicine (hematology), the Ingeborg and Ira Leon Rennert Professor of Stem Cell Biology and Regenerative Medicine and director of the Pluripotent Stem Cell Unit.
With its brief shelf life, blood can’t be stockpiled, resulting in local shortages. And while all units of donated blood are screened for a variety of pathogens, nothing can be done to prevent the transmission of new ones, which is what happened with HIV in the 1980s. In addition, some people with sickle cell anemia and other conditions requiring chronic transfusions develop sensitivities to antigens in blood, making it difficult to find suitable blood matches.
Genetically modified stem cells offer perhaps the best hope for curing thalassemia.
Dr. Bouhassira is trying to use iPS to produce red blood cells (RBCs) on an industrial scale—a seemingly far-fetched idea that may not be so far off. In a 2011 study published in PloS One, he showed that various types of adult human cells could be reprogrammed into iPSCs, which could then be made to produce large quantities of fetal-like red blood cells. Unfortunately, fetal RBCs have a form of hemoglobin (the oxygen-carrying protein in RBCs) that differs from the kind in mature RBCs, and they would not sustain an adult’s oxygen needs.
“Our next challenge,” says Dr. Bouhassira, “is to induce iPSCs to differentiate far enough along the blood-forming pathway that we can create RBCs that possess adult hemoglobin.”
In addition to their freedom from ethical problems, iPSCs offer another key advantage over human embryonic stem cells: replacement tissues derived from iPSCs are unlikely to provoke an immune response resulting in tissue rejection. New nerve cells for a patient with Parkinson’s disease, for example, should be a good match for that patient, since they come from iPSCs derived from the patient’s own skin cells rather than from an embryo with a different genetic makeup. Dr. Bouhassira is taking advantage of this trait in work aimed at transforming iPSCs into cures for genetic blood disorders such as thalassemia.
People with thalassemia make an abnormal form of hemoglobin that causes mild to severe anemia, depending on the underlying genetic flaw. Thalassemia is typically treated with repeated blood transfusions. But over time, such transfusions can cause elevated blood levels of iron, which must be removed with costly chelation therapy.
Selected cases of thalassemia can be cured with bone marrow transplantation, in which the patient receives high doses of drugs or radiation to destroy the diseased hematopoietic (blood-forming) stem cells, followed by a marrow infusion from a compatible donor. But the risky procedure is generally reserved for patients with severe disease who have well-matched donors—typically siblings—available.
Genetically modified stem cells offer perhaps the best hope for curing thalassemia. In one approach, doctors harvest a patient’s hematopoietic stem cells, use viral vectors to insert normal copies of the affected gene into them and then return the cells to the patient. But using viral vectors risks inducing cancer-causing mutations in the stem cells.
Dr. Bouhassira is developing a potentially safer stem cell cure based on iPSCs, which can be genetically modified without viruses. The idea here is to convert the patient’s skin cells into iPSCs and then modify the iPSCs with a gene-insertion technique using zinc finger nucleases—synthetic proteins that carry little or no risk of causing cancer. Scientists would then induce the corrected iPSCs to develop into RBCs, which would be transfused back into the patient.
In a study published last year in Blood, Dr. Bouhassira showed that this technique could potentially correct the genetic flaws responsible for alpha thalassemia major, the most severe form of the disease. But as with the effort to form RBCs for transplantation, the genetically corrected iPSCs must progress beyond the fetal RBC stage and develop into adult RBCs before this therapy can be brought to clinical trials.