The pigs had been dead for an hour. The cause: cardiac arrest. But six hours after researchers at Yale University connected their bodies to a machine pumping a nutrient-rich fluid, their organs began to show signs of life again.
Though the organs didn’t suddenly start working normally, some of the cellular damage brought on by loss of blood flow after death appeared to be reversed. The pigs’ hearts emitted electrical activity. Cells in their kidneys, livers, and lungs were functioning again and showed signs of repairing themselves. The discovery, published Wednesday in the journal Nature, suggests that cell death could be delayed longer than currently possible. If those processes could be slowed down, it could mean saving more organs for transplantation.
“This new system showed that not only can we slow down cellular damage, but that we can actually activate processes at the genetic level for cellular repair,” says Brendan Parent, an assistant professor of bioethics at New York University, who was not involved in the study but authored a commentary in Nature alongside it. “This might force us to reconsider what we decide is ‘dead.’”
In 2019, the Yale team challenged the idea that brain death is final when they reported that they had partially revived the brains of pigs for hours after the animals had been slaughtered. For the current experiment, the researchers wanted to see if the same method, in which a blood substitute is carried into the animal’s circulatory system, could also be used to revive other organs.
“We restored some functions of cells across multiple vital organs that should have been dead without our interventions,” author Nenad Sestan, a Yale neuroscientist, told reporters on a call Tuesday. “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 restored in multiple vital organs, even one hour after death.”
Deepali Kumar, president of the American Society of Transplantation and professor of medicine at the University of Toronto, says that with further refinement, the system could one day be used to expand the pool of human organs available for donation. “There is a significant shortage of organs for transplantation, and we certainly need new technologies that can help improve the organ supply,” she says.
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In the US, around 106,000 people are on the national transplant waiting list, and every day 17 people die waiting for an organ, according to the federal Health Resources and Services Administration. Despite the huge need, around 20 percent of organs are discarded every year due to poor quality. That could mean they’re too old or damaged, which can happen when organs are cut off from an oxygen-rich blood supply for too long.
The standard practice for preserving organs for transplant is static cold storage. Cooling organs quickly after removal reduces their oxygen demand and can prevent cell death, but doesn’t save every organ. There’s also growing interest in using a technique called extracorporeal membrane oxygenation, or ECMO, for patients who can’t be resuscitated, in order to preserve their organs for transplantation. Typically used as life support for patients whose heart or lungs are badly damaged, an ECMO machine pumps blood outside the body to remove its carbon dioxide and add oxygen, and then returns it back to the body.
The Yale system, dubbed OrganEx, is a bit more sophisticated than current ECMO machines. Whereas ECMO is a stand-in for just the heart and lungs, OrganEx also mimics the function of the kidneys. It consists of pumps, sensors, heaters, and filters to control the flow and temperature of the blood substitute it pushes through the body. And while ECMO only slows cell death, the team’s findings suggest that OrganEx may be able to reverse some aspects of cell death. When observing the pig organs, they found gene expression patterns reflective of certain molecular and cellular repair processes.
“The notion here is to try to reestablish some sort of circulation before the organ gets irreparably damaged,” says Timothy Pruett, a transplant surgeon at the University of Minnesota Medical School who wasn’t involved in the study.
The Yale team’s secret sauce is a proprietary fluid of electrolytes, vitamins, amino acids, and other nutrients, plus a cocktail of 13 drugs that reduce cell death and cellular stress and modulate the immune and nervous systems. The researchers mixed the synthetic fluid with pig blood into a series of pumps designed to control its flow and temperature throughout the circulatory system. That special substrate, the researchers surmise, helped revive the pig organs. They also found that organs treated with their system displayed fewer signs of hemorrhage and tissue swelling than those of a group of control pigs that were treated with ECMO.
One big unknown is whether the pig organs revived by the Yale researchers would begin working normally and on their own if they were transplanted into another recipient. Kumar says the next step should be transplanting the organs into other pigs to see how well they function compared with organs preserved in the conventional way.
In their study, the authors speculate that the system might also lead to new treatments for people who have had a heart attack, if it’s capable of restoring a heart’s normal function in a living patient. The idea is still far from human testing, but if it's possible, experts say, it raises some interesting ethical choices.
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Parent says a system like OrganEx could increase the likelihood of doctors being able to resuscitate patients, and he thinks researchers should explore this life-saving potential of the technology before using it to revive organs for transplant. “If this continues to demonstrate cellular recovery in unprecedented ways, it will be very important to focus on the emergency response potential first, to really determine how well the system can restore quality of life to people who, under other circumstances, we would have said died,” Parent says.
But Avir Mitra, an emergency medicine physician at Mount Sinai Health System in New York City, says decisions about resuscitating patients are often complex and come down to the wishes of patients and their families. Sometimes doctors may be able to bring people back from cardiac arrest, but their quality of life isn’t what it was before. They may never leave the hospital or walk again. They may need a feeding tube or a ventilator to breathe.
“The question is, if the outcomes are going to be really poor, should you subject them to this?” he asks. “In emergency medicine, we often say that there are fates worse than death. Just because we can bring someone back, doesn't necessarily mean that we should.”