Scientists have recovered1 Circulation and cellular activity in vital organs such as the heart and brain of pigs one hour after animal death. The study challenges the idea that cardiac death – which occurs when blood circulation and oxygen stop – is irreversible and raises ethical questions about the definition of death. The work will be carried out after the 2019 experimentstwo The same scientists revived disembodied pig brains four hours after the animals died, casting doubt on the idea that brain death is final.
The latest experiments are “amazing,” says Nita Farahani, a neuroethicist at Duke University in Durham, North Carolina. Although this research is preliminary, it suggests that some limitations in the human body may be overcome over time.
In a paper published on August 3 nature1, researchers connected pigs that had been dead for an hour to a system called OrganEx, which injected a blood substitute into the animals’ bodies. The solution, which contained 13 compounds such as animal blood and anticoagulants, slowed down the decomposition of organisms and quickly restored the function of some organs, such as heart contractions and liver and kidney activity. Although OrganEx helped preserve the integrity of some brain tissue, the researchers did not observe coordinated brain activity that would indicate the animals regained consciousness or sensation.
As with the 2019 paper, the study could reignite debates about the definition of death and the ethics of posthumous organ donation. The authors caution that these results do not indicate that the pigs somehow reanimated after death, especially when there was no electrical activity in the brain. When the animals die, “We made the cells do something they couldn’t do,” said team member Zvonimir Vrselja, a neuroscientist at Yale University in New Haven, Connecticut. “We’re not saying it’s clinically relevant, but it’s going in the right direction.”
circulation begins again
Nenad Sestan, a Yale neuroscientist and a member of the team, suggested that these experiments might work in line with the 2019 pig brain study, because the brain is the organ most vulnerable to oxygen deprivation. “If you can restore some function in the brain of a dead pig, you can do it in other organs,” he says.
To find out, he and his co-authors modified the BrainEx solution and the technique used for that study. “BrainEx is tailored for a specific organ, but we had to find a common denominator that would work with OrganEx for all organs,” says Wrselja. In the OrganEx solution, the researchers included compounds that suppress blood clotting and the immune system, which is more active elsewhere in the body than in the brain.
Sestan’s team obtained the pigs from a breeder at a local farm and monitored them for three days before sedating them, putting them on ventilators, shocking them and causing cardiac arrest. After confirming the absence of impulses, they removed the animals from the ventilators. One hour after the pigs died, they restarted ventilators and anesthesia. Some of the pigs were then connected to the OrganEx system; others received no treatment or were connected to an extracorporeal membrane oxygenation (ECMO) machine, which some hospitals use as a last-ditch effort to supply oxygen and remove carbon dioxide from the body.
After six hours, the researchers observed that the pigs that received the OrganEx solution had a much more effective resumption of circulation than the pigs that received ECMO or no treatment. Oxygen began to flow to tissues throughout the OrganEx animals’ bodies, and heart scans detected some electrical activity and contractions. But the heart isn’t fully functional, and it’s unclear exactly what it’s doing in animals, said David Andrijevic, a Yale University neuroscientist and team member.
The researchers also found that the livers of the OrganEx pigs produced much more of a protein called albumin than the livers of the other groups of pigs. And OrganEx showed that the cells of every vital organ in the pigs responded to glucose much more than animals in the other groups, indicating that the treatment kick-started metabolism.
The findings are surprising given how quickly decay begins after death, Wrselja said. Within minutes of a cardiac arrest, the body is deprived of oxygen and enzymes begin to digest cell membranes, leading to rapid loss of structural integrity of organs.
The researchers also found that more genes responsible for cell function and repair were active in all major organs in the OrganEx group compared to the ECMO or no treatment groups.
Interestingly, only the OrganEx pigs began to involuntarily shake their heads, necks and trunks after being injected with the contrast dye, which helped the scientists visualize the animals’ brains after the treatment. Scientists could not come up with a good explanation for the movements, noting that due to the lack of electrical activity, the impulses are unlikely to originate in the brain. It is possible, they say, that movements generated in the spinal cord can control some movements independently of the brain.
If the cell regeneration findings are replicated in animals and eventually in humans, their impact on human longevity could be as “profound” as the development of CPR and ventilators, Farahani said. That’s because the technique could one day be used to save failing organs for transplant or resuscitation.
ECMO is currently used to try to save organs from some dead people for donation, or to try to resuscitate people after a heart attack. For these purposes, doctors usually have to start ECMO shortly after a heart attack or death – and success rates can be low depending on the severity of the injury, says Sam Shemi, a critical care physician at McGill University Health Center in Montreal, Canada.
Given the difference in pig organs compared to OrganEx and ECMO, this is a potentially “landmark” study that “significantly increases the number of organs that can be recovered for transplantation,” says Gabriel Oniscu, a transplant surgeon at Edinburgh Royal Infirmary, UK.
Before that happens, further research to assess the viability of the regenerated organs will be crucial, says Shemi.
These potential implications pose ethical challenges, Farahani says, especially if the technique restores brain activity after death.
The researchers note that the electrical activity in the pigs’ brains may be absent because the infusion solution is cooler than normal body temperature (28 ºC) or because anesthetic compounds and neuron blockers may suppress such signals. Farahani said it will be important for future researchers to examine the recovery of brain activity, especially given the neck tremors the researchers observed during the experiment.
Arthur Kaplan, a bioethicist at New York University, said the study also emphasized that death is a process rather than a moment, making it difficult to find a single way to declare a person dead. This means that the legal definition of death will continue to adapt as medicine evolves, he adds. “People focus on brain death, but there’s no consensus on when heart death happens,” he says. “This paper brings it home in an important way.”