Some aspects of death are not entirely irreversible. On Monday, Yale scientists announced that they successfully restored circulation and cellular activity in pig brains four hours after the animals had died. The restored brains, the team emphasizes, were not alive — but they did become cellularly active.
The experiment hinges on a newly developed system called BrainEx. In an issue of Nature scheduled to be published Thursday, the team explains that BrainEx involves connecting the brain’s vascular system to a solution developed to preserve brain tissue. The solution acts as a substitute for blood and contains a hemoglobin-based oxygen carrier and a range of pharmacological agents to keep a dead or dying brain alive.
"The researchers were prepared to intervene with the use of anesthetics."
In the experiments, the team took 32 brains collected from a United States Department of Agriculture slaughterhouse and hooked them up to the BrainEx system four hours after the pigs were killed and their brains were removed. The team didn’t observe any electrical activity associated with perception, awareness, or consciousness — that was never the goal of the study — but they did witness a different sort of miraculous result: BrainEx restored and sustained circulation to major arteries, small blood vessels and capillaries.
Furthermore the system reduced cell death, preserved anatomical architecture, ignited spontaneous neural activity and active cerebral metabolism. Meanwhile, the untreated control brains rapidly decomposed.
The team stopped the experiment after six hours because of the limited availability of the BrainEx solution — which means they still don’t know how long these functions could have been sustained.
Not an Attempt to Restore Consciousness
The goal of the study was not to restore consciousness, and the research was conducted under strict ethical guidelines: They didn’t want the brains to become aware, co-author and bioethicist Stephen Latham, Ph.D. said Wednesday, but they were prepared to deal with that scenario if it occurred.
“The researchers were prepared to intervene with the use of anesthetics and temperature-reduction to stop organized global electrical activity if it were to emerge,” Latham says. “Everyone agreed in advance that experiments involving revived global activity couldn’t go forward without clear ethical standards and institutional oversight mechanisms.”
This study’s findings sharply contrast with what we know about dead brains. The established idea is that once oxygen and blood flow cease, basic cellular functions stop within seconds and in that moment, neural activity is irretrievably lost. From there, the brain is expected to begin a trajectory towards cell death and decay.
The new research disrupts the idea that the demise of a dead brain is rapid and concrete. The team hopes that in the immediate future, this research can lead to a new way of studying the postmortem brain, allowing scientists to study complex cell and circuit conditions after the life of a specimen is lost.
In a more hypothetical future, the BrainEx system could help salvage the brain function of stroke patients, though it’s currently unclear whether this approach would have the same result when applied to human tissue.
What Is a Dead Brain?
What is clear is that these findings open up a future that is difficult to navigate. In an accompanying commentary, ethical scholars including Duke professor of law and philosophy Nita Farahany, Ph.D. write that the study “throws into question long-standing assumptions about what makes an animal — or a human — alive.” Now that scientists are capable of this, Farahany and her co-authors argue that new guidelines are needed for studies involving the restoration of brains. What is considered an alive brain — or a dead one — needs a better definition.
In another commentary, bioethicists Dr. Stuart Youngner and Insoo Hyun, Ph.D., raise the point that this study could “exacerbate tensions between efforts to save the lives of individuals and attempt to obtain organs to donate to others.” Brain resuscitation, they argue, seems increasingly reasonable, and we may eventually have to revise our definition of a legally dead brain.
That’s a far-off scenario, but it’s increasingly obvious that our idea of what the brain is capable of — and how scientists can manipulate it — is changing. Life, for now, cannot be restored after death — but the definition of death is now a question that’s on the table.
The brains of humans and other mammals are highly vulnerable to interruptions in blood flow and decreases in oxygen levels. Here we describe the restoration and maintenance of microcirculation and molecular and cellular functions of the intact pig brain under ex vivo normothermic conditions up to four hours post-mortem. We have developed an extracorporeal pulsatile-perfusion system and a hemoglobin-based, acellular, non-coagulative, echogenic, and cytoprotective perfusate that promotes recovery from anoxia reduces reperfusion injury, prevents oedema, and metabolically supports the energy requirements of the brain. With this system, we observed preservation of cytoarchitecture; attenuation of cell death; and restoration of vascular dilatory and glial inflammatory responses, spontaneous synaptic activity, and active cerebral metabolism in the absence of global electrocorticographic activity. These findings demonstrate that under appropriate conditions the isolated, intact large mammalian brain possesses an underappreciated capacity for restoration of microcirculation and molecular and cellular activity after a prolonged post-mortem interval.