New research is confounding 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, making the animals’ cells work again. The findings, which were published Wednesday in the scientific journal Nature, raise profound ethical questions about how medicine defines death, but also open up new possibilities for harvesting human organs for transplantation.
“My eyes widened,” Brendan Parent, assistant professor of bioethics at the NYU Grossman School of Medicine, said of the moment he first read the new findings. “My brain has gone to all the crazy places it could go in 20 or 30 years.” Parent was not involved in the study, but was invited 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 of potential use in humans. Ultimately, it could help prolong the lives of people whose hearts have stopped beating or who have had a stroke. The technology also shows the potential to dramatically change the way organs are collected for transplantation and increase their availability to patients in need.
When the heart stops beating, blood flow is cut off from the body in a process called ischemia and a cascade of biochemical effects begins. Oxygen and nutrients are cut off from the tissues. Cells start to die. It’s a path to death that causes damage that scientists consider irreversible.
The new research challenges that idea.
“The disappearance 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 have restored some cell function in various organs that should have been dead.”
The Yale researchers accomplished this feat by building a system of pumps, sensors and tubes that connect to the pigs’ arteries. They also developed a formula with 13 drugs that can be mixed with blood and then pumped into the animals’ cardiovascular system. The research builds on previous work at Yale, which showed that some damage to brain cells may be reversible after cutting off blood flow. Yale has filed a patent for the new technology, but is making its methods and protocols freely available for academic or non-profit use, the study says.
To assess the functioning of the new system, called OrganEx, the researchers caused heart attacks in anesthetized pigs. The pigs were dead for an hour, and the researchers cooled their bodies and used neural inhibitors to ensure the animals did not regain consciousness during subsequent experiments.
So the researchers started using the OrganEx system. They compared its performance to ECMO, a life support technology used in hospitals today where a machine oxygenates the blood and circulates it throughout the body.
OrganEx restored circulation and stimulated the repair of damaged cells. For example, scientists have seen heart cells contract and electrical activity return. Other organs, including kidneys, also showed improvements, the study says.
The OrganEx-treated pigs startled the researchers. During the experiment, the dead pigs’ heads and necks moved on their own. The animals remained under heavy anesthesia.
“We can say that the animals were not conscious during these times and we don’t have enough information to speculate why they moved,” Sestan said.
Researchers see neck jerking as an indication that some muscle function has been restored after death.
The OrganEx research is a unique study in a laboratory setting in which researchers had complete control over the circumstances of the pigs’ death and treatment. Even so, the first results open up possibilities that would have seemed like science fiction a few years ago.
“The assumption that the loss of oxygen to the brain or organs in seconds to minutes means that these organs are irreparably damaged and lost — that’s not true,” said Nita Farahany, a neuroethicist and professor of law at Duke University, who was not involved in 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 medical death.
“Death is a process. Technology, at various critical junctures over the past few decades, has shifted the goals to when this process begins and when we can say the dying process is over,” said Parent, a bioethicist at NYU. “All the iterations of machines that can sustain or restart lung 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 anticipate using OrganEx to treat people anytime soon.
“Before you hook this up to a person to try to undo ischemic damage throughout a human’s body, you would need to do a lot more work. Not that it can’t be done, but it’s going to take a long time,” said Stephen Latham, director of the Interdisciplinary Center for Bioethics at Yale. “There is a lot more experimentation that would be needed.”
The implications of only partially reversing the damage to a patient who has suffered a deadly heart attack or who has drowned are immense, he said.
“You would have to think about what state a human being would be restored to if they had been seriously damaged by ischemia and you gave them a type of perfusate that reversed some but not all of the damage. This can be a terrible thing, right?” said Latham.
Instead, researchers see more immediate avenues for real-world use for research. Today, transplant surgeons must strive to stay ahead of ischemia and prevent organs from being without blood supply for too long.
OrganEx can help transplanted organs travel greater distances and reach people who would otherwise be beyond the reach of a transplant, Latham said. It can also prevent organs from being lost to ischemic damage, potentially expanding organ supply.
“From a transplant perspective, when every second is critical – what if it isn’t? What if we have more time?” said Farahany.
The potential of the new technology opens up compelling new questions of medical ethics – and adds a new twist to some that remain unresolved.
Ethical experts have been debating whether it is appropriate to use technology such as ECMO to preserve organs in patients declared dead under cardiorespiratory criteria.
“If we decide that someone is dead because their heart has stopped, but we use technology to restart their heart – even for organ preservation – does that undermine the determination of death?” asked Parent, outlining the argument for what remains a rare practice.
There is no regulation on how long doctors must wait to determine death before restarting technology like ECMO to preserve organs for transplantation, Farahany said. OrganEx could allow more time between death and organ preservation.
It is also possible for OrganEx to change the threshold of when it is ethical for doctors to let a patient die and then preserve their organs for donation.
“In the short term, it is not a treatment. But if it’s that effective, it could be a treatment — you certainly couldn’t recover someone’s organs if you could keep doing things to save their life,” Farahany said.
It’s a technology that remains in its early stages, but it could be impactful enough to redefine the line between life and death.