Dr. O’Halloran and his collaborators have established principles and defined mechanisms that maintain tight control over the cellular metallome. Each cell must acquire millions (bacteria) to billions (eukaryotes) of metal ions, monitor and balance the levels of these ions to prevent excessive accumulation while simultaneously keeping metals flowing into essential catalytic and signaling processes. The body of work emerging from his lab supports a larger thesis; i.e., that metal insertion is a posttranslational protein modification requiring trafficking via metallochaperone proteins and sensing activities via metalloregulatory proteins.
A second research project in the O’Halloran laboratory is to investigate the mechanisms underlying zinc signaling pathways in mammalian reproduction. In collaboration with Dr. Teresa Woodruff, the laboratory has described a new and central role for the transition metal zinc in control of the cell cycle and development of the mammalian egg. The presence of a network of metal receptors in the egg that control compartmentalization and metal insertion laid the groundwork for this recent discovery. Together the O’Halloran and Woodruff groups have published a series of papers that illuminate how the mammalian egg employs zinc fluxes to establish metaphase arrest and subsequently re-enter the cell cycle after fertilization. Most recently, we discovered that mammalian oocyte maturation, fertilization and cell cycle control are directly mediated by these novel zinc-signaling pathways.
Another goal of the O’Halloran research group is to develop a molecular level understanding of how nanoscale therapeutics target and then release their cargo within tumor cells, with the overarching goal of increasing the therapeutic index of some of the most potent anticancer drugs. The group’s strategy revolves around the development of targeted nanoscale lipid drug delivery systems that are uniform in size and are readily produced on a large scale. These methods allow enable the team to load hundreds of thousands of molecules of a given anticancer drug (including those in the arsenic and platinum families) per each 100 nm liposome. The group has repeated demonstrated targeted delivery of multi-functional metal-based therapeutic agents for treatment of hematological cancer and solid tumors: these agents are moving towards clinical applications. The laboratory’s formulations protect the drugs from early release, decrease off target toxicity in vulnerable organs, and are easily modified with targeting ligands thorough bioconjugation chemistry