https://www.nytimes.com/2019/04/17/science/brain-dead-pigs.html

‘Partly Alive’: Scientists Revive Cells in Brains From Dead Pigs

In research that upends assumptions about brain death, researchers brought some cells back to life — or something like it

.By Gina Kolata   April 17, 2019

In a study that raises profound questions about the line between life and death, researchers have restored some cellular activity to brains removed from slaughtered pigs.

 The brains did not regain anything resembling consciousness: There were no signs indicating coordinated electrical signaling, necessary for higher functions like awareness and intelligence.

 But in an experimental treatment, blood vessels in the pigs’ brains began functioning, flowing with a blood substitute, and certain brain cells regained metabolic activity, even responding to drugs. When the researchers tested slices of treated brain tissue, they discovered electrical activity in some neurons.
 
The work is very preliminary and has no immediate implications for treatment of brain injuries in humans. But the idea that parts of the brain may be recoverable after death, as conventionally defined, contradicts everything medical science believes about the organ and poses metaphysical riddles.

 “We had clear lines between ‘this is alive’ and ‘this is dead,’” said Nita A. Farahany, a bioethicist and law professor at Duke University. “How do we now think about this middle category of ‘partly alive’? We didn’t think it could exist.”

 For decades, doctors and grieving family members have wondered if it might ever be possible to restore function to a person who suffered extensive brain injury because of a severe stroke or heart attack. Were these brains really beyond salvage?

 The new research confirms how little we know about the injured brain and so-called brain death. Bioethicists like Dr. Farahany were stunned and intrigued by the findings, published on Wednesday in the journal Nature.

 “This is wild,” said Jonathan Moreno, a bioethicist at the University of Pennsylvania. “If ever there was an issue that merited big public deliberation on the ethics of science and medicine, this is one.”

 Until now, it has been assumed that the brain declines quickly when its blood supply is cut off. Cells deteriorate, and the connections between neurons crumble. Scientists have believed those changes are irreversible unless blood is quickly restored.

 Researchers at Yale University acquired the heads of 32 pigs killed for their meat. The scientists sawed into the skulls and removed the brains. By the time the experiment started, the brains had been without blood and at room temperature for four hours.

The team has developed a system called BrainEx that pumps an experimental solution into the intact brain. The scientists hope the technology will help point the way to new treatments for strokes, traumatic brain injuries and diseases like Alzheimer’s.

 The scientists pumped the solution into the pigs’ brains for six hours. It brought oxygen to the tissue and contained chemicals that allowed the scientists to track its flow with ultrasound.

 The solution also contained chemicals intended to block nerve signals. The scientists reasoned that brain cells might be better preserved — and their metabolisms more easily restarted — if the cells were not active.

 But the investigators also did not want to take a chance that the brains might regain consciousness, unlikely as that seemed. Had the team seen electrical activity suggesting actual consciousness, they planned to give the brains anesthetic drugs and cool them immediately to stop the process.

 In addition to the brains that got the BrainEx solution, the scientists also examined brains that did not receive infusions and those receiving infusions of a dummy substance. Brains in both groups showed no signs of activity, and their cells deteriorated.



Neurons (green), astrocytes (red), and cell nuclei (blue) in the brains of pigs. On left, brain tissue left untreated for 10 hours after death; right, brain tissue subjected to the experiment.

Credit Stefano G. Daniele and Zvonimir Vrselja, Yale School of Medicine


The National Institutes of Health, which supported the research, held a briefing to discuss its significance.

“It is not a living brain, but it is a cellularly active brain,” Dr. Nenad Sestan, a neuroscientist at Yale University who led the research, said of the revived tissue.

 “We wanted to test whether cells in the intact dead brain can have some functions restored,” he added.

 Some people who seemed dead after prolonged exposure to cold have been resuscitated and their brains continued to function, he noted. Stroke patients who had gone as long as 16 hours with a clot blocking blood to parts of the brain have regained brain function once doctors removed the clots.

 “This is a real advance,” said Andrea Beckel-Mitchener, who leads brain research efforts at the N.I.H. “This has never been done before in a large intact mammalian brain.”

 Christine Grady, chief of bioethics at the N.I.H.’s clinical center, said that the work “presents for first time an opportunity to study the whole mammal brain outside the body after death.”
 “It allows researchers to map cells and connections between them in ways that were never before possible,” she added. And the technique may broaden the study of brain injury and cellular repair, as well as how drugs affect the brain.

The ethical issues posed by research into revived brain tissue are nearly unprecedented. Among them are questions about the welfare of laboratory animals.

 “This is brand-new,” said Stephen R. Latham, a bioethicist at Yale. “This is not animal research. The brain comes to researchers from a dead animal.”

 How, he asked, will ethicists decide if suffering caused by the research — to a “partly alive” brain — is justified by the goals?

 Even though there was no electrical activity in the brains, it may be possible to restore it, Dr. Farahany and other experts said. It’s not known what would have happened if their solution did not contain nerve blockers.

 When you have a cellularly active brain, what are the appropriate protections, she asked. Do you treat it like a living animal? You can’t treat it like a dead animal, she said.

 “What does it mean to talk about consciousness in a pig? What are we looking for?” Dr. Moreno wondered.

 The work also may have implications for organ donation.

 In France and Spain, if a person has, say, a heart attack that deprives the brain of blood, emergency medical service workers try for 30 minutes or so to restart the heart, said Stuart Youngner, a bioethicist at Case Western Reserve University who was a co-author of an editorial accompanying the study.

 If they fail, emergency workers preserve the organs with a portable heart-lung machine to pump blood through the body; they also insert a balloon to prevent blood from getting to the brain. That way the person can be an organ donor, because the brain is dead.

 But “if something like BrainEx was available, why wouldn’t you do that instead of trying to get their organs?” Dr. Youngner said.

 In the United States, Dr. Youngner said, the balloon system is regarded as unethical. But a system like BrainEx would probably encourage doctors and emergency workers to try longer and harder to resuscitate patients. The result one day could be fewer brain-dead patients and fewer organ donors.

 It will take years before brain resuscitation reaches even preliminary testing in humans, researchers emphasized. But, Dr. Farahany said she can imagine a day when brain resuscitation becomes standard medical practice.

 “Maybe we will see it in our lifetime,” she said.  

Gina Kolata writes about science and medicine. She has twice been a Pulitzer Prize finalist and is the author of six books, including “Mercies in Disguise: A Story of Hope, a Family's Genetic Destiny, and The Science That Saved Them.”