Research into cell death offers path to decrease wait times for liver transplants

Several times a month, Dr. Blayne Amir Sayed, a liver transplant surgeon at The Hospital for Sick Children (SickKids), begins his day a short walk away at Toronto General Hospital, one of the busiest transplant centres in the world. His purpose: to secure a donor liver for a child awaiting transplantation at SickKids. 

With the waiting child and anxious family at SickKids are anesthesiologists Drs. Neil Goldenberg and Benjamin Steinberg, who help to ensure that the child is ready to receive the donor liver as soon as it arrives. 

This kind of work is happening almost every day at SickKids and Toronto General Hospital, and yet many critically ill children can wait up to 10 months for a liver. Paediatric patients require high-quality organs from young donors, which are not frequently offered, and despite the prioritization of children on the wait list they still have to compete with very sick adults for those same organs. 

“There is a critical organ shortage that is having an immense impact on the paediatric population,” explains Sayed, who is also an Associate Scientist in the Cell Biology program. “We always want to use the best available organs to improve our patient outcomes, but we also need to focus on increasing the number of organs available for the many patients who need them.” 

In a study published in Nature, a research team led by Drs. Sayed, Goldenberg and Steinberg at SickKids and scientists at Genentech, a biotechnology company, identified a means of targeting the molecular mechanisms involved in cell death as a way to potentially increase the pool of suitable donor organs.

Preventing cell death may improve outcomes

There are many ways cells may become stressed during a liver transplant, from the condition of the donor, the time an organ spends cooling outside of the body, or injury that may occur when rewarming the organ. 

When these stressed cells die, they have the potential to rupture and release specific molecules that act as a red flag signal to neighbouring cells, triggering an inflammatory response. 

This mechanism plays a significant role in the clinical challenges faced during liver transplantation. When these signals are produced in a newly injured transplanted organ, the recipient's cells react by propagating inflammation, leading to dysfunction in the organ system and, in severe cases, even resulting in death. 

This type of cell death is not a passive occurrence; rather, it is an orchestrated molecular process involving a protein called Ninjurin-1 (NINJ1). Sayed, Goldenberg and Steinberg have been studying the intricacies involved in cellular death for many years, propelled by what they see as an urgent need to increase the pool of viable donor organs. 

“Our findings present a potential way forward to reduce the risk associated with transplanting livers that would otherwise be deemed ‘marginal’ or less-than-perfect, decreasing competition on the wait list and helping patients access donor organs earlier,” says Sayed.   

In the study, the team showed that by using anti-NINJ1 antibodies in a pre-clinical model they could intervene in this process and prevent cells from rupturing when they die, stopping the red flag signal from ever being raised. 

“Using anti-NINJ1 antibodies, our research showed that we could reduce inflammation associated with liver injury and improve outcomes in a mouse model,” says Steinberg, a Scientist-Track Investigator in the Neurosciences & Mental Health program. 

Research driven by clinical questions

The SickKids team says their passion for pursuing this research is directly connected to the life-saving care provided to children waiting for transplant, inspiring collaborations across the hospital and the SickKids Research Institute.  

“One of the biggest benefits to working at SickKids is the protected academic time and support given to us to pursue scientific answers to real challenges we see every day in the clinic,” explains Goldenberg, a Scientist in the Cell Biology program. “We wanted to find a way to help children waiting for a liver transplant, and now through research, we have found a potential path to improve patient outcomes across all ages and transplant types.” 

The research team hopes to translate the findings from this study into a clinical study in the future and help improve access to organs for every child waiting for a transplant. 

Funding for this study was provided by the Canadian Institutes of Health Research (CIHR), the University of Toronto, the Ajmera Transplant Centre and SickKids Foundation. The study used resources and expertise from Genentech.