New research confounds conventional wisdom about life and death.
Researchers at Yale University used a new technology to restore cells in some organs of pigs that had just died, bringing the animals’ cells back to work. The findings, published Wednesday in the scientific journal Nature, raise deep ethical questions about how medicine defines death, but also tease new possibilities for harvesting human organs for transplantation.
“My eyes widened,” Brendan Parent, an assistant professor of bioethics at the NYU Grossman School of Medicine, said of the moment he first read the new findings. “My mind went to all the crazy places we could go in 20 or 30 years.” Parents were not involved in the study, but were asked by Nature to write a commentary discussing the implications of the new technology.
The research is still in an early, experimental phase and many years away from potential use in humans. It could ultimately help prolong the lives of people whose hearts have stopped beating or who have had a stroke. The technology also shows potential to dramatically change how organs are collected for transplantation and increase availability for patients in need.
When the heart stops beating, blood flow from the body is cut off in a process called ischemia and a cascade of biochemical effects begins. Oxygen and nutrients are cut off from tissues. Cells begin to die. It is a path to death that causes damage that scientists have deemed irreversible.
The new research challenges that idea.
“The outcome of cells can be stopped,” said Dr. Nenad Sestan, professor of neuroscience at the Yale School of Medicine and author of the new research, during a press conference. “We restored some functions to cells across multiple organs that should have died.”
The Yale researchers achieved this feat by constructing a system of pumps, sensors and tubing that connect to pig arteries. They also developed a formula of 13 medicinal drugs that can be mixed with blood and then pumped into the animals’ cardiovascular systems. The research builds on previous work at Yale, which showed that some damage to brain cells can be reversible after blood flow is cut off. Yale has applied for a patent on the new technology, but is making the methods and protocols freely available for academic or non-profit use, the study says.
To evaluate how well the new system, called OrganEx, works, the researchers induced heart attacks in anesthetized pigs. The pigs were dead for an hour, and the researchers cooled the bodies and used neural inhibitors to ensure that the animals did not regain consciousness during subsequent experiments.
The researchers then began using the OrganEx system. They compared its performance to ECMO, a life-support technology used in hospitals today, where a machine oxygenates blood and circulates it throughout the body.
OrganEx restored circulation and led to the repair of damaged cells. For example, the researchers saw heart cells contract and electrical activity return. Other organs, including kidneys, also showed improvements, the study says.
The pigs treated with OrganEx alarmed scientists. During experimentation, the dead pigs’ heads and necks moved under their own power. The animals remained under heavy anesthesia.
“We can say that animals were not conscious at those moments, and we don’t have enough information to speculate why they moved,” Sestan said.
The researchers consider that the jerking of the neck is an indication that some muscle functions were restored after death.
The OrganEx research is a single study in a laboratory environment where the researchers had total control over the circumstances surrounding the pigs’ death and treatment. Nevertheless, the early results open up possibilities that would have seemed like science fiction a few years ago.
“The assumption that loss of oxygen to the brain or organs within seconds to minutes means that those organs are irreparably damaged and lost — that’s not true,” said Nita Farahany, a neuroethicist and law professor at Duke University, who was not involved in the the study.
The definition of death is a moving target that has changed as new life support technologies such as ventilators or ECMO have been developed. Ethicists see OrganEx as ECMO on steroids and something that could change the definition of what medical death means.
“Death is a process. Technology has, at several critical moments over the past few decades, shifted the goalposts of when that process begins and when we can say the death process has ended, said Parent, the NYU bioethicist. “All the iterations of machines that can maintain or restart lung function and or heart function have changed our perception, our experience, of when we can say it’s worth trying to save someone’s life.”
The Yale researchers do not foresee using OrganEx to treat humans anytime soon.
“Before you connect this to a person to try to reverse whole-body ischemic damage in a human being, you have to do a lot more work. Not that it couldn’t be done, but it’s going to be a long way off,” says Stephen Latham, director of the Yale Interdisciplinary Center for Bioethics. “There’s a lot more experimentation that will be needed.”
The implications of only partially reversing damage in a patient who suffered a fatal heart attack or who had drowned are enormous, he said.
“You have to think about what is the condition a human being would be restored to, if they had been severely damaged by the ischemia and you gave them some kind of perfusate that reversed some, but not all, of the damage. That could be a terrible thing, wouldn’t it ?” Latham said.
Instead, the researchers see more immediate avenues of real-world application for the research. Today, transplant surgeons must fight to stay ahead of ischemia and prevent organs from going too long without a blood supply.
OrganEx can help transplant organs move longer distances and reach people who would otherwise be out of reach for a transplant, Latham said. It may also prevent organ loss due to ischemic injury, potentially expanding the organ supply.
“From a transplant perspective, when every second is critical — what if it’s not? What if we have more time?” Farahany said.
The potential of the new technology opens up new and compelling medical ethical questions—and adds a new twist to some that remain unresolved.
Ethicists have debated whether it is appropriate to use technology such as ECMO to preserve organs in patients declared dead under cardiorespiratory criteria.
“If we determine that someone is dead because their heart has stopped, but we use a technology to restart their heart — even for organ preservation — does that undermine the death determination?” parent asked, outlining the argument for what remains a rare practice.
There is no regulation on how long doctors must wait to determine death before starting new technologies such as ECMO to preserve organs for transplant, Farahany said. OrganEx can provide more time between death and organ preservation.
It is also possible that OrganEx could change the threshold for when it is ethical for doctors to let a patient die and then preserve their organs for donation.
“In the short term, it’s not a treatment. But if it’s that effective, it could be a treatment — you certainly couldn’t recover organs from somebody if you could keep doing things to save their life,” Farahany said.
It’s a technology that remains in its earliest stages, but could be impactful enough to redefine the line between life and death.