The pigs had been dead in the lab for an hour – no blood circulating in their bodies, their hearts were immobile, their brain waves flat. Then a group of Yale scientists pumped a custom solution into the bodies of the dead pigs with a device similar to a heart-lung machine.
What happened next adds questions to what science sees as the wall between life and death. Although the pigs were by no means believed to be conscious, their apparently dead cells resurrected. Their hearts started beating as the solution, which the scientists called OrganEx, circulated through their veins and arteries. Their organ cells, including heart, liver, kidney and brain, were working again and the animals never stiffened up like a typical dead pig.
Other pigs, dead for an hour, were treated with ECMO, a machine that pumps blood through their bodies. They became stiff, their organs swelled and damaged, their blood vessels collapsed, and they had purple spots on their backs where blood pooled.
The group published their findings Wednesday in Nature.
The researchers say their goals are to one day increase the supply of human organs for transplantation by allowing doctors to obtain viable organs long after death. And, they say, they hope their technology could also be used to prevent serious damage to the heart after a devastating heart attack or to the brain after a major stroke.
But the results are only a first step, said Stephen Latham, a bioethicist at Yale University who has worked closely with the group. The technology, he pointed out, is “very far from being used in humans”.
The group, led by Dr. Nenad Sestan, professor of neuroscience, comparative medicine, genetics and psychiatry at the Yale School of Medicine, were stunned by its ability to revive cells.
“We didn’t know what to expect,” said Dr. David Andrijevic, also a Yale neuroscientist and one of the paper’s authors. “Everything we restored was amazing to us.”
Others not associated with the work were also astonished.
“It’s amazing, mind-blowing,” said Nita Farahany, a Duke law professor who studies the ethical, legal and social implications of emerging technologies.
And, Dr. Farahany added, the work raises questions about the definition of death.
“We assume death is one thing, it’s a state of being,” she said. “Are there reversible forms of death? Or not?”
The work began a few years ago when the group did a similar experiment with the brains of dead pigs from a slaughterhouse. Four hours after the pigs died, the group infused a solution similar to OrganEx which they called BrainEx and saw that brain cells that should have died could be reanimated.
This led them to ask if they could revive a whole body, said Dr. Zvonimir Vrselja, another member of the Yale team.
The OrganEx solution contained nutrients, anti-inflammatory drugs, drugs to prevent cell death, nerve blockers – substances that dampen the activity of neurons and prevent any possibility of pigs regaining consciousness – and artificial hemoglobin mixed with blood of each animal.
When caring for the dead pigs, investigators took precautions to ensure the animals did not suffer. Pigs were anesthetized before being killed by stopping their hearts, and deep anesthesia continued throughout the experiment. Additionally, the nerve blockers in the OrganEx solution prevent the nerves from firing to ensure that the brain was not active. The researchers also refrigerated the animals to slow the chemical reactions. Individual brain cells were alive, but there was no indication of organized overall nerve activity in the brain.
There was a startling discovery: pigs treated with OrganEx shook their heads when researchers injected iodine contrast solution for imaging. Dr Latham pointed out that although the reason for the movement was not known, there was no indication of any brain involvement.
Yale filed a patent on the technology. The next step, Dr. Sestan said, will be to see if the organs are working properly and could be successfully transplanted. Sometime after that, researchers hope to test whether the method can repair damaged hearts or brains.
The journal Nature asked two independent experts to write comments on the study. In one, Dr. Robert Porte, a transplant surgeon at the University of Groningen in the Netherlands, discussed the possible use of the system to expand the pool of organs available for transplantation.
During a telephone interview, he explained that OrganEx could in the future be used in situations where patients are not brain dead but are brain damaged to the point that life support is unnecessary. .
In most countries, Dr. Porte said, there is a five-minute “no touch” policy after the ventilator is turned off and before transplant surgeons remove the organs. But, he said, “before you rush into the operating room, extra minutes will pass,” and by then the organs may be so damaged that they will be unusable.
And sometimes patients don’t die immediately when the life support system is disrupted, but their hearts beat too weakly to keep their organs healthy.
“In most countries, transplant teams wait two hours” for patients to die, Dr Porte said. Then, he says, if the patient isn’t dead yet, they don’t try to retrieve organs.
As a result, 50-60% of patients who died after life support was shut down and whose families wanted to donate their organs cannot be donors.
If OrganEx could revive these organs, Dr. Porte said, the effect “would be enormous” – a huge increase in the number of organs available for transplantation.
The other comment was from Brendan Parent, a lawyer and ethicist who is director of transplant ethics and policy research at New York University’s Grossman School of Medicine.
In a phone interview, he spoke about what he called “sensitive questions about life and death” raised by OrganEx.
“According to the accepted medical and legal definition of death, these pigs were dead,” Parent said. But, he added, “a crucial question is: what function and what type of function would change things?”
Would the pigs still be dead if the group didn’t use nerve blockers in their solution and their brains worked again? This would create ethical issues if the goal was to preserve organs for transplantation and the pigs regained some degree of consciousness in the process.
But restoring brain function might be the goal if the patient had had a severe stroke or was a drowning victim.
“If we’re going to get this technology to a point where it can help people, we’ll have to see what’s going on in the brain without nerve blockers,” Parent said.
In his opinion, the method should eventually be tried on people who could benefit from it, such as victims of strokes or drowning. But that would require a lot of thought from ethicists, neurologists, and neuroscientists.
“How to get there is going to be a critical question,” Parent said. “When does the data we have justify taking this leap?”
Another issue is the implications OrganEx might have for the definition of death.
If OrganEx continues to show that the time after blood and oxygen deprivation before which cells cannot recover is much longer than previously thought, then there must be a change in when it is determined that a person is dead.
“It’s weird but no different than what we’ve been through with ventilator development,” Parent said.
“There’s a whole population of people who in another era might have been called dead,” he said.