[Image from iStockphoto.com/GuidoVrola]
BrainEx is an open-source device originally based on CaVESWave, a system developed by Biomed Innovations of North Carolina to preserve donated organs for research or transplantation.
The scientists perfused the pig’s brain with a specially designed chemical solution to restore circulation and cellular activity, challenging long-held assumptions about the timing and irreversible nature of the cessation of some brain functions after death. Their study was published April 17 in the journal Nature, and a detailed report on their work appeared July 2 in the New York Times Magazine.
The Times article described BrainEx as “roughly eight feet wide and mounted on the shelves of a long metal hospital-style cart… less a single machine than a bristling collection of individual machines, each connected to the next, in a simulacrum of the human body.” A pulse generator mimics the heart, filters work as mechanical kidneys. Another portion works like lungs to add oxygen to the perfusate.
The research, funded primarily by the National Institutes of Health Brain Initiative, has raised ethical concerns about the possibilities for future studies — including those on the human brain.
The Yale scientists said they harbor no such plans, and have not published photos or exact descriptions of the BrainEx device. They also stressed that the treated brain lacked any recognizable global electrical signals associated with normal brain function.
“The intact brain of a large mammal retains a previously underappreciated capacity for restoration of circulation and certain molecular and cellular activities multiple hours after circulatory arrest,” senior author Nenad Sestan, professor of neuroscience, comparative medicine, genetics, and psychiatry, said in a Yale news release.
“At no point did we observe the kind of organized electrical activity associated with perception, awareness, or consciousness,” added co-first author Zvonimir Vrselja, an associate research scientist in neuroscience. “Clinically defined, this is not a living brain, but it is a cellularly active brain.”
The researchers never aimed to restore consciousness to a brain, according to co-author Stephen Latham, director of Yale’s Interdisciplinary Center for Bioethics.
“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 said. “Everyone agreed in advance that experiments involving revived global activity couldn’t go forward without clear ethical standards and institutional oversight mechanisms.”
The researchers said that it is unclear whether this approach can be applied to a recently deceased human brain. The chemical solution used lacks many of the components natively found in human blood, such as the immune system and other blood cells, which makes the experimental system significantly different from normal living conditions. However, the researchers stressed any future study involving human tissue or possible revival of global electrical activity in postmortem animal tissue should be done under strict ethical oversight.
The Yale researchers’ work prompted Stanford University law professor Hank Greely, Duke University legal scholar and ethicist Nita Farahany and Duke scientist Charles Giattino to write an essay for Nature that accompanied Sestan’s findings.
“New guidelines are needed for studies involving the preservation or restoration of whole brains, because animals used for such research could end up in a gray area — not alive, but not completely dead,” they wrote. “We’re reminded of a line from the 1987 film ‘The Princess Bride’: ‘There’s a big difference between mostly dead and all dead. Mostly dead is slightly alive.’ ”
On a more positive note, the new system could help studies into the roots of brain disorders, as well as neuronal connectivity in both healthy and abnormal conditions. It could even help doctors find ways to help salvage brain function in stroke patients or test the efficacy of novel therapies targeting cellular recovery after injury, according to the researchers.
“Previously, we have only been able to study cells in the large mammalian brain under static or largely two-dimensional conditions utilizing small tissue samples outside of their native environment,” said co-first author Stefano G. Daniele, an M.D./Ph.D. candidate. “For the first time, we are able to investigate the large brain in three dimensions, which increases our ability to study complex cellular interactions and connectivity.”
“This line of research holds hope for advancing understanding and treatment of brain disorders and could lead to a whole new way of studying the postmortem human brain,” added Andrea Beckel-Mitchener, chief of functional neurogenomics at the NIH’s National Institute of Mental Health, which co-funded the research.
There is an ethical imperative to use tools developed by the Brain Initiative to unravel mysteries of brain injuries and disease, said Christine Grady, chief of the Department of Bioethics at the NIH Clinical Center.
“It’s also our duty to work with researchers to thoughtfully and proactively navigate any potential ethical issues they may encounter as they open new frontiers in brain science,” she said.
