Using Mitochondrial Transplantation to Restore Donor Hearts
With a background in ecological physiology, in particular mitochondrial physiology, Postdoctoral Research Fellow Dr Alice Harford brings a unique skill set to CCRG.
“I undertook all my tertiary education in the Applied Surgery and Metabolism Laboratory at The University of Auckland (UoA) including my Masters and PhD, which focused on mitochondrial physiology in species inhabiting extreme and variable environments.”
“I was first introduced to CCRG by my colleague and friend Dr Jules Devaux when he was visiting Brisbane to observe a heart transplant with CCRG. I was immediately intrigued by the Group’s core emphasis on research focused on patient-outcomes,” says Alice.
For her PhD, Alice studied mitochondrial structure and function in heart mitochondria in coastal fish species and how they respond to thermal stress.
This compared fish which live in tropical environments, compared to cold-temperate species, to determine adaptive physiological differences at the subcellular level. Mitochondria have been shown to break the hot heart, and her study looked at what breaks the hot mitochondria.
From fish to preclinical donor hearts, Alice’s skills and deep knowledge in fundamental science now underpin her role at CCRG where she is the Post-Doctoral Research Fellow leading The Living Heart Project, the Group’s ongoing research program working to improve outcomes for heart transplant patients.
Heart transplant is the only effective treatment for end-stage heart disease, however, only a small number of patients are given the opportunity of a heart transplant. Donor shortages are a major challenge and, in Australia, an individual dies every 3 hours from heart failure, highlighting an urgent need for more heart transplants.
CCRG’s Living Heart Project has already revolutionised the transplant landscape in Australia and New Zealand with the use of a hypothermic oxygenated perfusion (HOPE) system for storing and transporting donated hearts. HOPE preserves donor hearts at 8˚C while continuously perfusing them with a nutrient-rich solution akin to a “medical Gatorade”. This provides superior preservation than the traditional cold static storage (ice slurry in an esky) and has allowed us to overcome major limitations for heart transplant, including time and distance as it allows a donor heart to remain outside the body for >12 hours. This is more than 3 times the previous standard with cold static storage and means donor organs can now remain outside the body and travel further to recipients in need. This is particularly important in countries as vast as Australia.
However, despite these advancements, heart transplant treatment is still limited by the number of organs donated. Most donated organs are considered too damaged to be used in transplant, meaning up to 75% of donated hearts are discarded.
“Most of the damage which causes organs to be discarded is attributed to a lack of oxygen during heart procurement, storage before transplant, as well as during transplant itself. This damage primarily occurs to the mitochondria – the powerhouses in cells - which provide 90% of the energy required by the heart to function,” explains Alice.
Her experience in mitochondrial physiology lends itself perfectly to CCRG’s work pioneering the use of mitochondrial transplant (MTx) as molecular therapy to restore damaged donor hearts immediately after transplant, in the next chapter of The Living Heart Project.
“Following the success of our HOPE research and the rapid clinical translation, we are now investigating novel therapies which may restore damaged donated hearts, effectively repairing them to be suitable for transplant. Our hope is that this leads to more hearts being considered safe for transplant, expanding the donor pool as well as improving the outcomes of heart transplants.”
Fuelling this research is an international collaboration with Dr James McCully from Harvard University and Boston Children’s Hospital. Dr McCully recently visited CCRG where he gave a special guest lecture on his team’s research, including their breakthrough technique using the patient's own mitochondria to protect the heart.
“Dr McCully’s research shows that transplanting healthy mitochondria into the damaged area of the heart shortly after transplant significantly improves the heart and, therefore, the patient’s recovery,” explains Alice.
“We are incredibly fortunate to have Dr McCully’s insights early in the development of our model and MTx research. My hope is that this is just the beginning of a new era in heart transplant research - a practice that has remained relatively unchanged in close to five decades. I also anticipate that MTx will become increasingly important in all fields of medical research.”
Away from the labs, Alice is an avid conservationist and works with her dog to track and record sightings of native Australian fauna and flora.
Read more about CCRG’s Living Heart Project
Ischemia and reperfusion injury
Dr James (Jim) McCully is Associate Professor of Surgery, Harvard Medical School, Department of Cardiac Surgery, Boston Children’s Hospital, where his research focuses on the mechanisms of myocardial cell death. In this VIP Guest Lecture, Dr McCully shares more about a breakthrough technique using the patient’s own mitochondria, the powerhouse of the cell, to protect the heart.
The McCully Lab at Harvard University studies the damage caused by ischemia/reperfusion injury in people of all ages including neonatally, with particular emphasis on the development of novel and specific cardioprotective protocols. Dr McCully's research has shown that transplanting healthy mitochondria into the damaged area of the heart shortly after blood flow is restored significantly improves the heart and the patient’s recovery. After being transplanted, mitochondria make their way into the heart and are ingested by the tissue, where they help repair and protect the cells by boosting the production of energy and proteins. This supports heart function and promotes healing after injury without triggering an immune response or rejection.