In this episode of JCI's Author's Take, Donald Kohn of UCLA describes his group's efforts to develop a method to safely and effectively modify patient bone marrow to treat sickle cell disease. Sickle cell disease (SCD) is an autosomal recessive disorder caused by mutations in hemoglobin (HBB) that leads to rigid, deformed red blood cells, as seen in the accompanying image. A small number of patients have been successfully treated with allogeneic hematopoietic stem cell (HSC) transplantation; however, there are several drawbacks and complications associated with this procedure. Many complications could potentially be avoided by performing an autologous HSC transplant in combination with gene therapy to over-ride the defective hemoglobin gene. Zulema Romero, Donald Kohn, and colleagues investigated the utility of a lentiviral vector encoding a human b-globin gene engineered to impede sickle hemoglobin polymerization. The vector efficiently transduced bone marrow cells from SCD patients and expressed the engineered globin gene to prevent sickling of red blood cells and the transduced cells were successfully transplanted into immunocompromised mice, indicating that this method could potentially be used to treat SCD.
Dr. Christine Seidman of the Harvard Medical School has uncovered the genetic basis of many human cardiovascular disorders, from cardiomyopathy and heart failure to congenital heart malformations. In this interview, she speaks about her early intrigue with atrial natriuretic factor and her more current gene-intensive investigations. She also shares many more stories about her interest in the ear, an early inspirational patient, and her thoughts on work-life balance.
Tsonwin Hai and colleagues discuss how the transcription factor ATF3 acts as a key regulator of the host immune response and as a contributor to co-option of the host by cancer cells to promote metastasis. Highlights:
Professor Stephen O’Rahilly’s research has led to an increased understanding of the genetic causes of human obesity and insulin resistance. Using modern biochemical approaches and classical clinical observation in humans with profound metabolic disorders, O’Rahilly, from the Departments of Medicine and Clinical Biochemistry at the University of Cambridge, has shown that a person’s appetite and feeding behavior can be linked to specific genes. His work has challenged long-held dogmas and led to new treatment avenues. The full interview includes many more stories about how you can learn more from reading Chekhov than medical school and why he has stayed in Cambridge all these years.
More than almost any other scientist in the field of obesity and metabolism research, the work of Bruce Spiegelman, from the Dana-Farber Cancer Institute and Harvard Medical School, has informed potential targets for drug discovery that could burn fat and even turn fat into muscle. He was the first to suggest that inflammation underscores insulin resistance, and also the first to find the key regulator of adipogenesis, PPAR-γ.