Whole heart suspended animation: leveraging the zebrafish to solve the organ shortage

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There are currently over 123,000 patients on the organ transplant waiting list in the US, a number that far exceeds the supply of available organs, and that continues to grow ~5% each year. In Canada, every ten minutes someone is added to the waitlist and ~22 people die each day while waiting for a transplant. A major reason is the limitations of our current organ preservation and handling practices, which severely restricts preservation duration and disallows the transplantation of marginally injured organs. This project aims to develop a protocol to bank hearts for several weeks to enable global organ matching and overcome limitations of ischemia tolerance to increase the donor pool of hearts. I propose that strategies to solve current barriers in heart transplantation, including ex vivo preservation and recovery of marginal organs, should look to nature for inspiration. More specifically, the ability to descend into a state of “suspended animation”, characterized by the slowing of life processes and improved stress tolerance, holds promise. I will systematically leverage two methods of suspended animation; 1) freeze-tolerance, and 2) high-temperature hibernation. Using inspiration from freeze-tolerant wood frogs in nature, I seek to develop a protocol for whole heart preservation which will achieve high subzero storage temperatures in the presence of extracellular ice, and storage durations of weeks to months. Further, I will identify pharmacological agents which will strategically lower metabolic demands to match oxygen/nutrient availability, and increase warm ischemia tolerance from minutes to hours, using inspiration from hibernating primates in nature. To accomplish this goal, I propose to introduce the zebrafish as a novel model system for cryobiology and organ transplantation. While zebrafish has become a favored research animal for studying human disease, it has never been used as a tool to develop innovative approaches for organ handling and preservation or to understand the underlying biology of organ transplantation. Classical model organisms such as the zebrafish offer many advantages including robust genetic/biochemical tools, ease of real-time imaging, compatibility with high-throughput studies, and are cheap and easy to maintain. Complimented by scale-up experiments and validation in mammalian model systems, including rats, the present proposal will mend a critical gap in the research field.