In 2012, the JCI’s Editor in Chief Howard Rockman proposed a new series focusing on the careers of today’s most accomplished physician-scientists. Since then, Editor at Large Ushma Neill has interviewed scientists as part of the Conversations with Giants in Medicine series, including Laurie Glimcher, Huda Zoghbi, and Oliver Smithies. The interviews have revealed the diverse career paths, hidden talents, and sometimes quirky personalities of this inspirational group of researchers. To reflect on her experiences, she collected her favorite moments from the series in this highlight reel.
JCI Editor at Large Ushma S. Neill shares some of the best moments from the series Conversations with Giants in Medicine, 2012–2017.
Ras GTPase activating proteins (RasGAPs) control the activation of Ras, a small GTP-binding protein that regulates signal transduction pathways involved in cell growth, survival, and differentiation. Inactivating mutations the RasGAP RASA1 cause a blood and lymphatic vessel (LV) disorder known as capillary malformation-arteriovenous malformation, though exactly how loss of RASA1 function contributes to LV leakage is unclear.
This week in the JCI, research led by Philip King at University of Michigan Medical School reports that LV development and function critically depends on RASA1 activity. Ablation of RASA1 in adult mice led to specific defects in lymphatic valves that impaired the efficiency of LV pumping. Valve closure tests revealed that RASA1-deficient lymphatic vessels failed to prevent back-leak across valves. Moreover, ablating RASA1 in embryos impaired LV valve development. Together, these findings support an essential role for RASA1 in both LV formation and maintenance.
The accompanying video visualizes LV responses to increases in downstream pressure. In the top panel, as pressure increases, LV valves in wildtype mice rapidly close to prevent backflow. In the bottom panel, valve failure in RASA1-deficient mice results in backflow into the upstream regions of the LV.
One of the leading factors in breast cancer-related death, is tumor recurrence despite apparently successful therapeutic intervention. Recurrent disease is linked to the presence of a minimal population of residual cancer cells that are hard to detect; therefore, little is known about these cells. In this episode, Martin Jechlinger and colleagues present several lines of evidence to show that residual cells have a distinct transcriptional profile that results in changes in metabolism and elevated ROS production. Together, these results provide a better understanding of these cells and suggest potential targeting strategies.
Invariant natural killer T (iNKT) cells are a prominent component of the liver-resident immune cell population. These cells are involved in both liver regeneration and regulation of the local immune response; however, little is known about how iNKT cells are maintained within the liver. In this episode, Xian Li reveals that stimulation of cell surface receptor OX40 induces a pyroptotic cell death in liver iNKT cells that exacerbates liver injury and inflammation. The results of this study support the OX40 pathway as a potential therapeutic target for limiting liver damage.