Scientists restore some brain cell functions in pigs four hours after their death

The brain is fragile, and if deprived of oxygen - for example from a massive heart attack, or through drowning - it will quickly and catastrophically degrade, leading to irreversible brain death. And that’s it - the end.

But that medical orthodoxy now must contend with a major report published Wednesday in the journal Nature that is simultaneously fascinating and disturbing: Researchers at Yale School of Medicine say they have restored some cellular function in pig brains from animals decapitated four hours earlier at a local slaughterhouse.

Over the course of a six-hour treatment, the brains were infused with a cocktail of synthetic fluids designed to halt cellular degeneration and restore cellular functions, such as metabolic activity. It worked: The brains continued to consume oxygen and glucose. Many brain cells, including neurons, which send messages within the brain and to the rest of the body, ceased decaying and appear to have been revived in dramatic and detectable ways.

The scientists detected "spontaneous synaptic activity," which means the neurons were capable of sending out signals, and the cells responded to external electrical stimulation. Cells removed from the treated brains and examined under a microscope had regained the shape of living cells, noted lead author Zvonimir Vrselja, a Yale neuroscientist.

The pig brains remained, by any traditional definition, dead. The researchers detected no signs of consciousness or any other "global" mental activity. But the study suggest that brain cells are hardier than previously thought, said study co-author and Yale neuroscientist Nenad Sestan.

"The death of a cell, or in this case, organ, is a gradual, stepwise process," Sestan said. He stressed that the revivifying system the researchers developed, which they dubbed BrainEx, may not reverse cell death and restore brains to what would be considered a stable, living state. It's possible, he said, that "we are just postponing the inevitable."

The researchers are mindful that this is controversial territory with great potential to stoke outrage, or simply the heebie-jeebies. Such a head-snapping experiment inevitably generates nightmarish scenarios involving live brains in vats, brain transplants, the Zombie Apocalypse, and other mad-scientist story lines (brilliantly crafted, somehow, by neurons firing away inside the skulls of conventionally living human beings).

The findings also lead to ethical quandaries, some of which are outlined in two commentaries simultaneously published by Nature. The ethicists say this research can blur the line between life and death, and could complicate the protocols for organ donation, which rely on a clear determination of when a person is dead and beyond resuscitation.

This startling research provides the latest reminder that science and medicine continuously create innovations that offer hope for treating dreaded diseases (such as Alzheimer's or other brain disorders) while simultaneously raising head-scratching issues about how to apply transformative technologies and procedures.

The National Institutes of Health helped fund this research as part of the BRAIN Initiative, a major research effort started during the Obama administration. The human brain is often described by scientists as the most complex object known to exist in the universe, and brains in general remain rather mysterious. Many basic questions - how does a brain create a thought? - are hard to answer.

The researchers knew they were on delicate ground. A presentation they made at the National Institutes of Health in 2018 so astonished their colleagues that word of the experiment leaked to a journalist at MIT Technology Review, and the ensuing story generated a great deal of controversy. Animal rights activists protested. Other researchers wondered why the Yale team was venturing into this edgy territory.

Speaking to reporters Tuesday in advance of publication, the Yale researchers addressed some of the objections. They pointed out that the experiment did not use live animals. These were pigs slaughtered as part of food production. They were completely dead, for hours, before their brains - drained of blood and largely removed from their skulls - were treated with the fluids.

Moreover, the experiment employed a chemical that inhibited overall brain activity. The scientists say that helped brain cells avoid stress. But the blocker also ensured the pig brain would not have any risk of awareness.

As an additional cautionary procedure, the researchers monitored the brains continuously for electrical activity that would indicate global mental operations and were prepared to chill the brains and apply anesthetic if they saw such activity. They did not.

"This is a clinically dead brain," Sestan said. He told reporters that it is premature to conjure scenarios of reviving dead people or using this technique on people who have paid to have their heads cryogenically preserved.

"I don't think it's changing anything at the moment," he said.

But this is still a big deal, to judge by the reaction of the scientific community.

"This is a huge breakthrough," said Nita Farahany, a professor of law and philosophy at Duke University and co-author of one of the commentaries in Nature warning of the ethical complications from such research. She also has served on a bioethics advisory panel for NIH. She said the research offers hope for therapeutic innovations but also raises ethical and legal challenges.

"We've built our assumptions on something that's proven to be false," she said. "Our belief was there's a point of no return. Certainly we would have believed that four hours after being decapitated, that was a point of no return. It turns out it's not."

The alive/dead divide is never simple or abrupt at the cellular level. What a molecular biologist sees is a halt in the normal flow of oxygen and other molecules that drive metabolism. Soon the whole carnival of biochemistry shuts down, and the cell loses its normal shape. But it's not like throwing an on-off switch.

Farahany said the research field needs to be careful going forward to ensure that animals studied in laboratories - even dead animals by traditional definitions - do not suffer: "Given that there's this gray zone between dead and alive we need to divine what is the appropriate use of animals in that context, to ensure that there isn't pain or distress."

Stuart Youngner, a professor of bioethics and psychiatry at Case Western Reserve University and co-author of another one of the ethics commentaries in Nature, agrees with Farahany that this is a significant breakthrough.

"What's unnerving about it is, it has really challenged assumptions that I was raised with as a physician about the fragility of the brain. It appears from this study that it's not as fragile as we thought it was," Youngner said.

He brought up the possibility of brain transplants someday:

“This is certainly not about to happen. But this study brings up possibilities that we didn’t think about before except in the most wild Sci-Fi imagination. This is a breakthrough in understanding preservation of the brain.”