A new system developed by researchers at the Yale University School of Medicine stopped the deterioration of cells in pig organs one hour after the animal’s death, a finding that suggests cells don’t die as quickly as previously understood. The researchers used the machine to successfully restore blood circulation and repair damaged cells in the pigs they treated.
The research, described in Nature today, could pave the way towards making human organs more viable for transplantation by making them last longer, and in a better condition, post-removal. It could also help scientists develop methods to treat strokes and heart attacks in humans by providing insights into how cells react after being deprived of oxygen.
The team from Yale used a computer-controlled machine called OrganEx to simulate both heart and lung function. It pumped a perfusate—a liquid mix of synthetic hemoglobin, antibiotics, and molecules to protect cells and prevent blood clots—through the pigs’ entire bodies one hour after they died. Sensors monitored circulation and measured pressures within the pigs’ arteries in real-time.
They then tested OrganEx’s efficacy by comparing pigs treated with it with pigs hooked up to a more traditional machine used by hospitals to save the lives of patients with severe heart and lung conditions by restoring their circulation, a process called extracorporeal membrane oxygenation (ECMO).
The organs treated with the OrganEx were found to have fewer signs of hemorrhage, cell damage or tissue swelling than those treated with ECMO. The researchers said this demonstrates the system can repair some functions in cells across multiple vital organs that would otherwise have died without their intervention. For example, the researchers observed how heart cells gathered from OrganEx pigs were contracting, but did not see the same contraction in samples from the ECMO group.
“These cells are functioning hours after they should not be, and what this tells us is that the demise of cells can be halted, and their functionality can be restored in multiple vital organs even one hour after death,” Nenad Sestan, professor of neurobiology at the Yale School of Medicine, told journalists on a briefing call. “But we don’t know whether these organs are transplantable.”
The research drew on a previous machine developed by the same team called BrainEx, used to partially revive pigs’ brains hours after death, which MIT Technology Review first reported in 2018. It also used a series of pumps and filters to mimic the rhythm of natural blood circulation, pumping a similar chemical mix through the pig’s brain’s blood vessels to restore oxygen flow to a dead brain up to six hours after death. It kept many of the cells inside the brain alive and functioning for more than a day, although the team did not detect any electrical brain activity that would suggest the brain had regained consciousness.
When a mammal’s blood flow becomes restricted, such as from a stroke or a heart attack, the lack of oxygen and nutrients it carries that cells need to survive causes them to die, and eventually results in tissue and organ death. After the heart stops beating, organs begin to swell, collapsing blood vessels and blocking circulation. The OrganEx perfusate fluid circumvents this because it cannot coagulate. Zvonimir Vrselja, an associate research neuroscientist at Yale School of Medicine who worked on the study, likened OrganEx to “ECMO on steroids.”
The findings, he said, suggested that cells don’t die as quickly as we assumed that they do, which opens up the possibility for interventions to, effectively, “tell them not to die.”
“We showed that this progression towards massive permanent cell failure does not happen so quickly that it cannot be averted, or possibly corrected,” he added.
Sam Parnia, an associate professor of critical care medicine at New York University Grossman School of Medicine who was not involved in the research, called the findings “truly remarkable.” OrganEx could preserve organs in people who’ve died, but in whom the underlying cause of death remains treatable, such as drowning or heart attacks, he said.
“This study demonstrates that our social convention regarding death, as an absolute black and white end, is not scientifically valid,” he said. “By contrast, scientifically, death is a biological process that remains treatable and reversible for hours after it has occurred.”
The team is planning future studies in animals, and an obvious next step is to try to study whether organs perfused using OrganEx are viable for transplantation, Sestan said.
However, the researchers are keen to emphasize that the technology is still in an experimental phase. “This is very far away from use in humans,” said Stephen Latham, director of Yale’s Interdisciplinary Center for Bioethics, who worked on the project.
While a great deal more experimentation would be required before the team could even begin to think about applying the same full-body approach to humans, that’s not to say it could never happen. The perfusate would need to be adapted to suit a human body, to ensure it didn’t damage any of the tissue, Latham said, pointing out that reversing some, but not all, tissue damage would be a “terrible thing.’
“Salvaging organs and the maintenance of organs for transplant is, I think, a much closer and much more realistic clinical goal that could be based on this study,” he added.
While the system would be potentially useful for human organ transplantation and could save more lives as a result, it doesn’t address the biggest ethical issue of consent, says Hank Greely, a Stanford law and ethics professor who reviewed the 2019 findings, but was not involved in the latest OrganEx research.
“If you do this in humans, it’ll be really important that people are told not just that they’re volunteering to have their organs transplanted, but to have their bodies kept alive for an indeterminate period of time to assist in that transplantation,” he says. “But this doesn’t answer the questions left open by the pig brain experiment: can you really bring the brain back to life? They’re resolutely not looking for the answer to that question.”
