By looking at a problem from odd angles, Zhe Lu has upended several prevailing assumptions about ion channels. His findings may lead to better treatments for cystic fibrosis (CF) and other genetic diseases. "It used to be with cystic fibrosis…
By looking at a problem from odd angles, Zhe Lu has upended several prevailing assumptions about ion channels. His findings may lead to better treatments for cystic fibrosis (CF) and other genetic diseases. "It used to be with cystic fibrosis that a mother would notice something was wrong when her child was between two and three years old," says Lu, a professor of physiology at the University of Pennsylvania. "The child would usually be dead before grade school." Today, says Lu, "the median life expectancy for someone with CF is 37. That tremendous progress is largely due to aggressive antibiotic treatment and supportive therapy." Even with treatment, however, CF-related infections become increasingly unmanageable, and eventually fatal. Lu wants to know why, and he's finding answers by exploring unusual features of ion channels. Ion channels are proteins in the cell membrane that selectively allow ions—such as calcium, potassium, or chloride—to enter or exit the cell. The flow of ions through channels has different functions in different cell types. Movement of the ions generates electrical impulses in excitable cells, such as neurons or muscle cells, and carries salt across epithelia. Cystic fibrosis is caused by a malfunction in an ion channel that disrupts salt and fluid transport and leads to buildup of mucus in the airways. Obstruction of the airways by the mucus fosters infections, which eventually cause death. Lu began working on ion channels as a postdoctoral fellow in the lab of HHMI investigator Roderick MacKinnon when MacKinnon was at Harvard University. Lu, a native of China, received his medical degree from Beijing Medical University; he did graduate work at the University of Wisconsin–Madison, where he received master's and Ph.D. degrees in physiology. After establishing his own lab at Penn, Lu discovered that voltage-gated ion channels can be opened or closed by enzymes, providing a clue to the puzzle of how these channels are regulated in nonexcitable cells (i.e., cells that do not generate voltage impulses) such as lymphocytes. He also revealed how an unusual class of ion channels works. "Inward-rectifier" potassium channels have the odd property of allowing ions to efficiently flow in only one direction. This phenomenon allows the heart to beat and insulin secretion to respond to blood glucose levels. The mechanism flummoxed researchers until Lu demonstrated that the pore of the channel contains several potassium ions that flow freely inward, but when the voltage inside the cell becomes positive, a signaling molecule pushes these ions out of the pore. Lu began to see the potential medical impact of his research when his membrane channel work uncovered the mechanism that pathogens can exploit to exacerbate CF and other lung infections. Patients with CF eventually succumb to bacterial infections. The ion channel that malfunctions in CF is called CFTR, for cystic fibrosis transmembrane conductance regulator. Like other ion channels, CFTR is embedded in the cell membrane, tightly intertwined with lipid molecules. Lu found that bacteria can attack the lipids that regulate ion channel activity and exploit a weakness caused by a genetic defect. This discovery arose from Lu's work with an ion channel toxin he found in spider venom. The toxin, an enzyme called sphingomyelinase, snips one type of lipid (sphingomyelin) that surrounds certain ion channels. Staphylococcus bacteria, which infect CF patients, produce sphingomyelinase as well. The bacterial toxin profoundly impairs functioning of the channel. Lu thinks that the bacterial enzyme eliminates the few working CFTR channels in patients with CF, which he says is "an action that reinforces the effect of the genetic mutations." Furthermore, he made an important conceptual connection between the underlying damage in bacteria-infected lungs of CF patients and the well-known fact that the breakdown products of sphingomyelin (ceramide and ceramide-1-phosphate) trigger inflammation and cell death. He says gene therapy to replace the defective ion channels would be the best way to treat the disease, but until such a therapy is available, "finding a way to inhibit the toxins might make a significant difference. My laboratory will aggressively pursue this idea." Lu's team aims to exploit the action of the spider toxin to create new drugs that inhibit the bacterial sphingomyelinase to ameliorate the consequences of bacterial infection. "What we understand now has set the stage for addressing more practical matters," he says. Beyond that, Lu plans to explore other interactions between membrane proteins and the lipid molecules that surround them. He thinks many of the interactions may be the basis of some important regulatory functions and that pathogens may be exploiting them to cause diseases. Greater understanding of the interactions, says Lu, may one day lead to better drugs for treating diseases that current therapies are unable to combat.