Reperfusion technologies that revive the brain may make death reversible, even after cardiac arrest.
- Scientific advances suggest that death may be a treatable condition, and with the use of new technologies, the concept of death may one day change.
- Resuscitation technologies can revive the human brain after cardiac arrest, blurring the line between life and death.
- The use of new devices such as BrainEx and OrganEx helps to revive organs after death, and could lead to saving the lives of patients in need of organ transplants.
The severed head of the pig had come from a local slaughterhouse. It was usually thrown away, but Yale School of Medicine neuroscientist Versilia Zunimir and her colleagues had a different idea. Four hours after the animal was beheaded, they removed the brain from the skull. They then connected the dead brain’s vessels to tubes that pumped a special mixture of preservatives into its blood vessels and turned on the perfusion machine.
That’s when something incredible happened. The color of the cerebral cortex changed from gray to pink. Brain cells began producing proteins. Neurons came back to life, showing signs of metabolic activity that were indistinguishable from those of living cells. The cell’s basic functions, activities that were thought to cease irreversibly when blood flow was cut off, were restored. The pig’s brain wasn’t exactly alive, but it certainly wasn’t dead either. Now the team is using the new technique on a human brain for the first time.
Reviving a dead human brain would have many medical benefits. Researchers could test drugs on a brain that is still cellularly active, which could lead to improved treatments.
Similar techniques are already being used to better preserve other human organs for transplant. In perhaps the most useful application, resuscitation technology could save people from the brink of death. The problem is that it raises ethical issues, and by demonstrating the brain’s extraordinary plasticity, it raises the question of when a person actually died.
What We Thought We Knew About Death
A study by Versilia and colleagues on pig brains five years ago shocked the medical community. “I was stunned when I heard about it,” recalls Hank Greeley, a biomedical law expert at Stanford University in California. He was not alone.
The idea that you could remove the brain from the body, deprive it of oxygen, and keep it at room temperature for four hours was contrary to popular belief about death, and that we are at a critical moment in defining life and death, says Lance Becker of the Feinstein Institute for Medical Research in New York.
Determining the time of death has never been as easy as you might think. The ancient Greeks considered the cessation of breathing to be a sign of death, and to check for this, they held a candle near the person’s mouth. Later doctors confirmed death by trying to shock the person to see if they were dead or alive. For example, they would hold a person’s finger over a flame or stick a needle into their body.
In the early 1800s, after several cases of false deaths and improper burials, bodies were kept in mortuaries and hospitals for several days to confirm decomposition. Skilled inventors began to patent safe coffins with air ducts and bells that could be rung from the inside.
These days, a person is usually declared dead when their heartbeat has stopped (known as cardiac arrest) and cannot be revived. The UK does not have a legal definition of death. Instead, it accepts medical opinion. In the US, on the other hand, doctors in most states rely on a law that states that a person is dead when there is irreversible cessation of circulatory and respiratory function or irreversible cessation of the functions of the entire brain, including the brainstem.
The key word here is “irreversibility.” Until recently, we thought we knew two things about death. First, when the heart stops beating, electrical activity in the brain stops within seconds or minutes. Second, the brain suffers irreversible damage within 5 to 10 minutes of the onset of oxygen deprivation. But recent studies have called both of these assumptions into question.
Let’s start with the idea that the brain’s electrical activity slows down after cardiac arrest. For a study published in 2023, Jimo Borjigin, a neuroscientist at the University of Michigan Medical School, and his team analyzed the electrical activity of four deceased people before and after they were removed from life support. “Instead of slowing down, the whole brain seemed to be active,” Borjigin says.
In two of the people, areas of the brain that were silent when the person was on life support suddenly became active after they were removed. High-frequency brain waves called gamma waves, which are a sign of consciousness, also became active.
The synchronous activity, similar to that associated with memory and perception, persisted for up to six minutes. Some brain regions suddenly tried to communicate with the heart. These waves of activity first slowed down, then tripled in intensity. In some areas, the activity was 12 times greater than when the person’s heart was still beating and they were breathing. “The dying brain actually starts this massive rescue effort,” says Borjigin. “If we can understand what’s happening at this stage, maybe we can revive it.”
Because the subjects did not survive, it is impossible to know what they experienced in those final moments of brain activity. But this study, along with others, suggests that the line between life and death is not a perfectly clear one.
“We’re all used to thinking of death as a binary phenomenon, where we’re alive and then we’re dead. Most people don’t want to accept that biology doesn’t work that way,” says Sam Pernia, a cardiologist at New York University. His team in 2023 recorded brain activity in 53 people undergoing resuscitation after cardiac arrest. Although no brain activity was detected in these individuals, 40 percent of them later showed spontaneous brain activity associated with consciousness during resuscitation efforts, sometimes up to an hour after the heart stopped beating.
Parnia’s team spoke to some of the survivors, as well as other people in the local community who had experienced cardiac arrest, and found that 20 percent of them recalled a conscious experience that occurred when their heart stopped beating.
Although some question Pernia’s findings, his study suggests that something is happening at the point of death. “You can’t talk about the dying brain without thinking about the nature of consciousness,” Pernia says. “And it’s not just the dying brain that challenges our understanding of life, death, and consciousness. The dead brain itself raises questions.”
Optimizing Perfusion
There are good reasons to believe that the brain cannot survive more than ten minutes without oxygen: Attempts to resuscitate a person after this particular time frame are rarely successful, and those who survive often suffer cognitive problems. However, while oxygen deprivation causes cell death, the damage that follows has less to do with the brain not getting oxygen and more to do with what happens when it is resuscitated.
When oxygen-rich blood suddenly flows throughout the body and brain, which has experienced blood stasis or lack of oxygen, this sudden re-entry of blood causes damage known as “reperfusion injury.” “If I break my leg and someone helps me stand up, I’m not told to walk right away because my leg needs treatment,” says Friedrich Beiersdorf of the University of Freiburg. “It’s the same with our organs. When they’re deprived of oxygen, they get damaged.
You can’t just pump blood and expect them to function as before. They have to be treated first.” To prevent reperfusion injury in the pig brain, Versilia and her colleagues developed a combination of drugs that target pathways that typically cause post-ischemic damage. The combination includes molecules that balance the pH of the cell, drugs that prevent an overactive immune response, and antibiotics. They modified a dialysis-like device designed to keep other organs alive outside the body.
Versilia’s team’s device, called BrainEx, can pump the drug compound in a pulsatile manner through the brain’s arterial network at just the right pressure to penetrate the cells and remove waste products. The device worked. Four hours after the heads were severed, the brains were connected to BrainEx and revived, although they did not regain consciousness.
Versilia and his colleagues noted in a 2019 paper that they did not observe any cognitive-related brain activity. In fact, they ensured that this did not happen by ending the experiment after six hours and adding sedatives that inhibit electrical activity to the test compound.
Repeating the experiment on human brains requires a higher level of certainty: If there is evidence of consciousness-like brain functions, the question arises as to whether they are experimenting on a living person and, if so, what rights they should have? “It’s a very complex issue, ethically, legally and scientifically,” Greeley says.
Brain model to test Alzheimer’s drugs and more
Versilia and her colleagues are proceeding with great care, noting that they are being advised by a wide range of bioethicists, legal experts and medical experts. “We had to develop new methods to make sure that there was no organized electrical activity associated with consciousness,” Versilia says.
Currently, researchers are not using resuscitation technology to restore consciousness to a dead person’s brain. Instead, Versilla and his team are keeping the brain cellularly active for up to 24 hours to test treatments for diseases like Alzheimer’s and Parkinson’s.
Making drugs for neurological diseases is difficult, says Versilla, and current methods for testing them are inadequate. “That’s why this field of science is full of unknowns,” he says. “We don’t even know in many cases whether a drug can get into the brain. Now we can get to that. This research will have significant implications for humans.”
Versilia acknowledges that others may try to revive dead brains on a larger scale. “To try to bring the brain back to life, with all its aspects of consciousness, would be nothing less than trying to achieve immortality,” Greeley says. “A living brain in a box is more like hell than life,” he says. “But people are willing to pay a lot of money to have their heads frozen and preserved, when the chances of coming back to life are so slim. I wonder why no one has sold this service before, or I don’t know about it.”
While bringing dead brains back to life is an intriguing but ethically sensitive prospect, Versilia’s research suggests that we may be able to intervene in brains and bodies that are on the verge of death. Although he and his colleagues don’t plan to hook someone up to the BrainEx device at the moment of death, they do want to use their knowledge of resuscitation to save lives.
Saving organs, saving lives
Researchers in 2022 built a similar system called OrganEx to pump a blood-based compound into a whole pig an hour after the pig’s heart stopped beating. They found that the reperfusion treatment reduced cell death in various organs and restored the pig’s brain, heart and kidney function. The heart began to contract, brain metabolism resumed and several genes associated with cell repair were activated. The pig, despite being under anesthesia, showed involuntary movements.
Similar technology is being tested to keep human organs alive for transplant. When a person is declared dead, they are hooked up to a version of OrganEx, and the arteries leading to the brain are closed off to disconnect them from the system. This keeps the organs alive longer, allowing them more time to get to where they are needed. “There are ten times more kidney donors than recipients, but there is still a huge waiting list because we can’t get the organs to where they are needed,” says Versilia. “This development could help save many lives.”
Meanwhile, reperfusion technology is already helping to keep more people alive after injury. Researchers at the University of Freiburg, led by Beiersdorf and the German technology company Resuscitec, spent more than a decade developing “controlled automated whole-body reperfusion,” or CARL, a modified version of the heart-lung bypass technology called ECMO.
While ECMO temporarily takes over the work of the heart and lungs by pumping and cleaning a person’s blood after cardiac arrest, CARL goes further, pumping the body with a mixture of hemoglobin and 13 other components that prevent damage to organs from ischemia (lack of blood and oxygen). The system also has two pumps that simulate the beating motion of the heart, which helps deliver the mixture to all parts of the body and the brain.
Early results from the trials have been promising. Typically, only about 1 in 10 people who go into cardiac arrest survive. But in a trial conducted by Beiersdorf, people whose hearts had stopped beating and had been undergoing cardiopulmonary resuscitation for about an hour were given CARL for about an hour. Of those people, 42 percent survived, and 79 percent had normal cognitive function. Resuscitec will introduce CARL to the European market in 2023, and it is now awaiting approval from the U.S. Food and Drug Administration.
Can death be a treatable condition?
Our better understanding of the moments after cardiac arrest and the possibilities for resuscitation have blurred the line between dead and alive. “It used to be easy to declare a patient dead,” says Becker. “We could say with certainty that their heart had stopped forever, but now we have doubts about whether they were dead or alive.” Perhaps, he says, if the right people and the right devices are available, the heart and brain can be revived in many cases. “With more widespread use of CARL, we will see how long our organs can survive without oxygen, and then we may have to change the definition of death.”
Right now, we are in a state of uncertainty. “It may take some time, but the science of resuscitation will advance to the point where people who are routinely declared dead today will no longer be seen as such,” says Becker. “This is a dramatic shift in the human understanding of life.”