Researchers have recovered1 circulation and cellular activity in pigs’ vital organs, such as the heart and brain, one hour after the animals died. The research challenges the idea that cardiac death — which occurs when blood circulation and oxygenation stop — is irreversible, and raises ethical questions about the definition of death. The work follows experiments from 20192 by the same scientists in which they revive the disembodied brains of pigs four hours after the animals died, casting doubt on the idea that brain death is definitive.
The latest experiments are “stunning,” said Nita Farahany, a neuroethicist at Duke University in Durham, North Carolina. While this study is preliminary, she says it suggests some perceived limitations of the human body could be overcome over time.
In the work, published August 3 in Nature1, researchers connected pigs that had been dead for an hour to a system called OrganEx that pumped a blood substitute through the animals’ bodies. The solution — which contains the animals’ blood and 13 compounds such as anticoagulants — slowed the breakdown of the bodies and quickly restored some organ functions, such as heart contraction and activity in the liver and kidneys. Although OrganEx helped maintain the integrity of a particular brain tissue, researchers did not observe coordinated brain activity that would indicate the animals had regained consciousness or sense.
As with the 2019 paper, the study is likely to reinvigorate the debate over the definition of death and the ethics of post-mortem organ donation. The authors caution that these results do not show that the pigs were somehow resuscitated after death, especially in the absence of electrical activity in the brain. “We made cells do something they couldn’t” when the animals were dead, 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 heading in the right direction.”
Nenad Sestan, a Yale neuroscientist and member of the team, predicted that these experiments could work in light of the 2019 pig brain study, because the brain is the organ most susceptible to oxygen deprivation. “If you can regain function in a dead pig brain, you can do it in other organs,” he says.
To find out, he and his co-authors modified the BrainEx solution and technique used for that study. “BrainEx was tailor-made for a specific organ, but we needed to find a common denominator that works for all organs with OrganEx,” says Vrselja. In the OrganEx solution, the researchers included compounds that would suppress blood clotting and the immune system, which is more active elsewhere in the body than in the brain, he says.
Sestan’s team sourced pigs from a local breeder and monitored them for three days before being stunned, put on a ventilator and inducing cardiac arrest by shocking their hearts. After confirming a lack of pulse, they removed the animals from the ventilators. An hour after the pigs died, they restarted the ventilator and anesthesia. A portion of the pigs were then attached to the OrganEx system; others received no treatment or were hooked up to an extracorporeal membrane oxygenation (ECMO) machine, which some hospitals use in a last-ditch effort to deliver oxygen to the body and remove carbon dioxide from the body.
After six hours, the researchers found that circulation had resumed much more effectively in pigs that received the OrganEx solution than in pigs that received ECMO or no treatment. Oxygen had started flowing to tissues all over the bodies of the OrganEx animals, and a heart scan detected some electrical activity and contraction. But the heart hadn’t completely rebooted, and it’s unclear exactly what it did in those animals, said David Andrijevic, a neuroscientist at Yale University and team member.
The researchers also noted that the livers of the OrganEx pigs produced much more of the protein albumin than the livers of pigs in the other groups. And cells in each of the OrganEx pigs’ vital organs were much more responsive to glucose than the animals in the other groups, suggesting the treatment had kick-started the metabolism.
The findings are striking given how soon after death decomposition begins, says Vrselja. Within minutes of the heart stopping, the body becomes deoxygenated and enzymes begin to digest cell membranes, causing organs to quickly lose their structural integrity.
The researchers also found that more genes responsible for cellular function and repair were active in all major organs in the OrganEx group compared to the ECMO or non-treatment groups.
Oddly enough, only the OrganEx pigs started involuntarily twitching their heads, necks and trunks after being given an injection of contrast dye that helped the scientists visualize the animals’ brains after treatment. The researchers did not have a good explanation for the movements, noting that the impulses are unlikely to have originated in the brain, given the lack of electrical activity. It’s possible the movements originated in the spinal cord, which can control some motor functions independently of the brain, they say.
If the findings of cellular repair can be replicated in animals and eventually humans, their implications for human lifespan could be just as “profound” as the advent of CPR and ventilators, Farahany says. That’s because the technique could one day be used to save organs for transplantation — which is in short supply — or even for resuscitation.
ECMO is currently being used in an effort to save the organs of some deceased people for donation, or to try to resuscitate people after a heart attack. For these purposes, doctors usually need to start ECMO shortly after the heart attack or death — and success rates can be low depending on the severity of the injury, says Sam Shemie, an intensive care physician at McGill University Health Center in Montreal, Canada. .
Given the difference in how the pig organs fared on OrganEx compared to ECMO, this may be a “landmark” study that “could significantly increase the number of organs that can be recovered for transplantation,” said Gabriel Oniscu, a transplant surgeon at the USO. Royal Infirmary of Edinburgh, UK.
Before that can happen, further research into the viability of the restored organs will be crucial, Shemie says.
With these potential implications come ethical challenges, Farahany says, especially if the technique could one day restore brain activity after death.
The researchers note that the electrical activity in the pig brains may have been absent because the solution they pumped was colder (28°C) than normal body temperature, or because it contained anesthetic compounds and neuronal blockers that could suppress such signals. Farahany says it will be important for future researchers to test for brain activity recovery, especially in light of the neck twitches the researchers observed during the experiment.
The study further emphasizes that death is not a moment but a process, making it challenging to come up with a uniform way to declare a person dead, said Arthur Caplan, a bioethicist at New York University. That means the legal definition of death will continue to adjust as medicine advances, he adds. “People tend to focus on brain death, but there’s not much consensus on when cardiac death occurs,” he says. “This paper brings that home in an important way.”