Results from early-phase clinical trials have indicated that recombinant adeno-associated viruses (rAAV) could potentially be used for gene therapy. In each trial, however, patients have developed T cell-mediated immune responses that may interfere with therapeutic gene expression. In this episode, Terence Flotte and Christian Mueller discuss their recent study investigating T cell responses to intramuscular injection of a rAAV encoding M-type a1-antitrypsin (AAT) in patients with AAT-deficiency. Their results demonstrate that AAT expression persists for up to 12 months and suggest that immunomodulation of T cell populations may not be necessary for long-term, rAAV-mediated transgene expression.
Much of our current understanding of calcium metabolism rests in large part on a series of discoveries made by John T. Potts Jr. of the Massachusetts General Hospital. Potts is an internationally recognized authority on calcium metabolism and parathyroid hormone (PTH) in particular. In addition to his research, he carried an enormous leadership role, serving as both Chairman of Medicine and Physician in Chief of the MGH between 1981 and 1996. Watch the full interview for stories about working with Berson and Yalow, his approach to leading the MGH, and what has changed over his 56 years there.
In order to mount an effective immune response, T cells must be primed with the appropriate antigens to help them recognize malignant or pathogen-infected cells. Tim Greten and colleagues examined how necrotic cell death influences T cell cross-priming. Here they report on a molecular mechanism that blocks antigen cross-presentation by necrotic cells. Moreover, they found that this mechanism could be circumvented to promote immunogenicity of tumor cells.
For decades, the attention of the scientific community was focused on the central dogma of biology — the decoding of the genetic information embedded in DNA. Little research was dedicated to how proteins are degraded and removed from cells. Enter onto the scene a young graduate student, Aaron Ciechanover, who with his mentor Avram Hershko, uncovered the complex and elegant ubiquitin proteolytic system. For his discovery, Dr. Ciechanover shared in the 2004 Nobel Prize in Chemistry with Hershko and Irwin Rose. Watch the complete interview for more stories about being a member of the Pontifical Academy of Sciences, the magic of “A-ha” moments, and the conflict between religion and Darwinism.
A legend within the field of innate immunity, Dr. Bruce Beutler of the University of Texas Southwestern Medical School is best known for two seminal discoveries: identifying mouse tumor necrosis factor and discovering Toll-like receptor 4, the receptor for lipopolysaccharide. With this discovery, later rewarded with the 2011 Nobel Prize in Physiology or Medicine, we finally understood how immune cells could recognize and react to bacteria. Watch the full interview for many more stories on developing etanercept, searching landfills for sequencers, and falling in love with genetics.