The severed pig鈥檚 head had come from the local abattoir. It would have typically been discarded, but , a neuroscientist at Yale School of Medicine, and his colleagues had other ideas. Four hours after this particular animal was decapitated, they removed its brain from its skull. They then connected the dead brain鈥檚 vasculature to tubes that would pump a special cocktail of preserving agents into its blood vessels and turned the perfusion machine on.
That was when . The cortex turned from grey to pink. Brain cells started producing proteins. Neurons juddered back to life, displaying signs of metabolic activity indistinguishable from that of living cells. Basic cellular functions, activities that were supposed to irreversibly cease after blood flow stopped, were restored. The pig鈥檚 brain wasn鈥檛 alive, exactly 鈥� but it certainly wasn鈥檛 dead.
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Now, for the first time, the team is using the technique on human brains.
鈥淲e are trying to be transparent and very careful because there鈥檚 so much value that can come out of this,鈥� says Vrselja. Reanimating 鈥� in a sense 鈥� a dead human brain would have tremendous medical benefits. Researchers could trial drugs on cellularly active human brains, leading to improved treatments. Similar techniques are already being used to better preserve other human organs for transplants, too. And in what is perhaps the most immediately useful application, the resuscitation technology involved raises the possibility of saving people on the cusp of death.
The problem is that it is an ethically complicated undertaking, to put it mildly. And by demonstrating the brain鈥檚 extraordinary resilience, this work forces us to ask, when is a person really dead?
What we thought we knew about death
Vrselja and his colleagues鈥� work on pigs鈥� brains sent shock waves through the medical community five years ago. 鈥淲hen I heard, my first reaction was 鈥榟oly shit!'鈥� recalls , a biomedical legal expert at Stanford University in California. He wasn鈥檛 alone. The idea that a brain cut from a body, deprived of oxygen and kept at room temperature for 4 hours could be revived 鈥済oes against everything we thought we knew about death鈥�, says at the Feinstein Institutes for Medical Research in New York. 鈥淲e鈥檙e at a real paradigm-shifting moment as we redefine what is life and what is death.鈥�
Deciding when someone is dead has never been as easy as you might think. Ancient Greeks used cessation of breathing as a sign of death, holding a candle near the mouth to check. Later physicians confirmed death by trying to shock a presumed dead person into life 鈥� putting their finger to a flame or poking them with needles. In the early 1800s, after several publicised cases of supposed premature burials, mortuaries and hospitals kept corpses for several days ; canny inventors started patenting 鈥渟afety coffins鈥� with air tubes and bells that could be rung from the inside.
We're at a real paradigm-shifting moment as we redefine life and death
These days, people are typically declared dead when their heart stops beating 鈥� known as cardiac arrest 鈥� and cannot be restarted. The UK doesn鈥檛 have a legal definition of death, instead accepting medical opinion. In the US, on the other hand, doctors in most states rely on the to define death, which states that an individual is dead once 鈥渢hey have sustained either irreversible cessation of circulatory and respiratory function or the irreversible cessation of all functions of the entire brain, including the brain stem鈥�.
The key word here is 鈥渋rreversible鈥�. Until recently, we thought we knew two things for sure about death. First, that when your heart stops beating, the electrical activity in the brain ceases within seconds to minutes. Second, that the brain suffers irreparable damage within 5 to 10 minutes of the onset of oxygen deprivation. But recent studies have upended both of these assumptions.
Let鈥檚 start with the notion that electrical activity in the brain diminishes after cardiac arrest. , a neuroscientist at the University of Michigan Medical School in Ann Arbor, and her team before and after the withdrawal of their life support. 鈥淩ather than decreasing in activity, the whole brain appeared to be on fire,鈥� says Borjigin.
In two of the people, brain regions that were silent while the person was on life support suddenly fizzed with activity after it was withdrawn. High-frequency brainwaves called gamma waves, a hallmark of consciousness, also burst into action. Synchronised activity resembling the kind associated with memory and perception lasted for up to 6 minutes. Some brain areas suddenly tried to strike up conversation with the heart. These waves of activity dampened, then intensified three times; in some areas, the activity was 12 times greater than before the individual鈥檚 heart had stopped beating and they were no longer breathing. 鈥淭he dying brain actually starts this massive rescue effort,鈥� says Borjigin. 鈥淚f we can better understand what鈥檚 going on at this point, I believe we could resuscitate it.鈥�
Because the people involved didn鈥檛 survive, it is impossible to know what they experienced in those last moments of frenzied brain activity. But the study confirmed that this boundary between life and death isn鈥檛 black and white 鈥� and it isn鈥檛 the only study to do so.
鈥淲e鈥檙e all conditioned to think of death as this binary thing,鈥� says Sam Parnia, a cardiopulmonary researcher at New York University. 鈥淵ou鈥檙e alive and then you鈥檙e dead. Most people aren鈥檛 willing to accept that biology doesn鈥檛 work that way.鈥� , his team recorded brain activity in 53 people who were being resuscitated after a cardiac arrest. Despite almost all of the patients flatlining 鈥� meaning their brain activity was silent 鈥� associated with consciousness during resuscitation attempts, sometimes up to an hour after their heart had stopped. Parnia鈥檚 team spoke to some of the people who survived, as well as others in the local community who had experienced a cardiac arrest, and found that 20 per cent recalled a conscious experience that occurred during the time in which their heart had stopped.
Although some question Parnia鈥檚 findings, the study nevertheless demonstrates that something is happening at the point of death. 鈥淵ou can鈥檛 talk about the dying brain without thinking about the nature of consciousness,鈥� says Parnia. And it isn鈥檛 just the dying brain that is making us question our understanding of life, death and consciousness. The dead brain is raising questions, too.
Perfecting perfusion
We had good reason to believe that the brain couldn鈥檛 survive more than 10 minutes without oxygen: trying to revive a person after that deadline is rarely successful and those that survive often experience cognitive problems. However, though oxygen deprivation does initiate cell death, the damage that follows has less to do with the brain not receiving oxygen and more to do with what happens when it is restored. When oxygen-rich blood suddenly starts pumping around a body and brain that have experienced ischaemia, or lack of oxygen, this sudden reintroduction causes what are known as reperfusion injuries.
Friedhelm Beyersdorf at the University of Freiburg, Germany, likens it to a broken leg. 鈥淚f I break my leg and someone helps me to stand, they don鈥檛 tell me to walk immediately, because my leg needs treatment,鈥� he says. 鈥淚t鈥檚 the same with our organs. Once they go without oxygen, they are damaged. You can鈥檛 just pump blood back in and expect them to work as before 鈥� they need to be treated first.鈥�
To prevent reperfusion injuries in his pig brains, Vrselja and his colleagues developed a cocktail of drugs that target the pathways that typically lead to damage after ischaemia. This included molecules that balance cell pH, drugs that prevent an excessive immune response and antibiotics. They modified a dialysis-type machine designed to keep other organs alive outside of the body. Their device, called BrainEx, could perfuse this cocktail through the brain鈥檚 arterial network in a pulsating fashion, at just the right pressure to penetrate cells, while also clearing waste products.
It worked. Four hours after decapitation, the brains were plugged into BrainEx and revived 鈥� albeit not to the point of consciousness. In paper, Vrselja and his co-authors were quick to note that they didn鈥檛 observe brain activity associated with perception. Indeed, they had made sure this didn鈥檛 happen by ending the experiment after 6 hours and including sedatives in their cocktail that inhibited electrical activity.
Repeating the experiment on a donated human brain, however, requires a greater level of assurance: if there were any evidence of consciousness-like brain function, that would raise the question of whether you are experimenting on a live person, and what rights they then deserve. 鈥淭hat鈥檚 very tricky ethically, legally and scientifically,鈥� says Greely.
Model brains for Alzheimer鈥檚 drugs testing and more
Vrselja and his colleagues are treading extremely carefully, noting that they have a broad group of bioethicists and legal and medical experts advising them. 鈥淲e had to develop new methods to make sure no electrical activity is occurring in an organised way that might reflect any kind of consciousness,鈥� says Vrselja.
For now, they aren鈥檛 using this technology to attempt to restore consciousness to a dead human brain. Instead, Vrselja and his team are keeping brains cellularly active for up to 24 hours to test treatments for conditions such as Alzheimer鈥檚 and Parkinson鈥檚. It is hard to develop drugs for neurological conditions, says Vrselja, because current methods for testing them are insufficient. 鈥淭hat鈥檚 why the field is riddled with mystery 鈥� often we don鈥檛 even know if a drug can get into the brain,鈥� he says. 鈥淣ow we can address that. It鈥檚 research that鈥檚 going to make a real difference to humans.鈥�
Vrselja acknowledged, however, that others may attempt to resurrect dead brains in a greater capacity. Trying to bring a brain back to life, consciousness and all, would be nothing less than an attempt at immortality, says Greely. 鈥淎 living brain in a box seems to me like hell rather than life, but people pay a lot of money to have their heads cryogenically frozen with highly implausible chances of reanimation. I鈥檓 a little surprised no quack has tried selling this service yet 鈥� as far as I know.鈥�
If bringing back an already dead brain is a tantalising if ethically sensitive prospect, Vrselja鈥檚 research also suggests we could intervene in brains and bodies on the brink of death. Though he and his colleagues have no intention of plugging anyone at the point of death into their BrainEx machine, they want to use their new knowledge about resuscitation to help save human lives.
Saving organs, saving lives
In 2022, they developed a similar system, , to perfuse a blood-based cocktail through a whole pig 1 hour after its heart had stopped beating. They found that the reperfusion therapy reduced cell death in various organs and restored function in the pig鈥檚 brain, heart and kidneys. The heart began to contract, the brain resumed metabolising and several genes associated with cellular repair were switched on. The pig even started to make involuntary movements, despite being anaesthetised.
Similar technology is now being trialled to keep human organs alive for transplant. When a person is pronounced dead, they are attached to a version of OrganEx, with the arteries leading to the brain clamped so that it is shut off from the system. In doing so, organs stay alive for much longer, giving them more time to get where they are needed. 鈥淭here is a tenfold number more donors than kidney recipients, yet there is a huge waiting list because we can鈥檛 get the organs to where they need to be,鈥� says Vrselja. 鈥淭his can really help save a lot of lives.鈥�
Meanwhile, reperfusion technology is already helping keep more people alive after injury. Researchers at the University of Freiburg, led by Beyersdorf, and German technology company Resuscitec spent more than a decade developing , which is a modified version of a heart-lung bypass technology called extracorporeal membrane oxygenation, or ECMO. While ECMO temporarily takes over heart and lung function by circulating and cleaning a person鈥檚 blood after cardiac arrest, CARL goes further, perfusing the body with a cocktail of haemoglobin 鈥� the oxygen-carrying protein in blood 鈥� and 13 other components that protect organs from ischaemic damage. It also features two pumps that replicate the pulsing motion of the heart, helping the cocktail reach all areas of the body and brain.
Early trial results are promising. Typically, only about 1 in 10 people who experience a cardiac arrest survive. But in a trial run by Beyersdorf, CARL was given to people whose hearts had stopped and who had received CPR for around an hour; of these, 42 per cent survived and 79 per cent of those had normal cognitive function. Early results from another trial of CARL in Germany, in people whose hearts stopped outside of a hospital, showed that it revived five of the first 10 people treated. Resuscitec brought CARL to market in Europe in 2023 and is awaiting FDA approval in the US.
Could death be a treatable condition?
Our greater understanding of the moments after cardiac arrest and the possibilities of restoring life is blurring the line between dead and not dead. 鈥淚t used to be straightforward to pronounce a patient dead,鈥� says Becker. 鈥淚 could safely say with confidence that their heart had irreversibly stopped. Now, it鈥檚 more 鈥榯hey鈥檙e dead, nudge nudge, wink wink鈥�.鈥� By that, he means that while they are dead because the treatments available at that moment can鈥檛 save them, he can鈥檛 be sure that they are irreversibly dead. 鈥淚f we had the right people in the room, the right machines, I know that the heart and brain might be revived,鈥� he says. 鈥淪o are they really dead?鈥�
At the moment, that question remains unresolved. 鈥淎s CARL is used more widely, we鈥檒l see how long our organs can survive without oxygen,鈥� says Beyersdorf. 鈥淎nd then perhaps we鈥檒l have to change our definition of death.鈥�
For now, we are in a grey zone. 鈥淚t will take a while, but the field of resuscitation is going to advance so that people who are routinely diagnosed as dead today are not viewed that way any longer,鈥� says Becker. 鈥淭hat鈥檚 a pretty remarkable rewriting of human existence.鈥�
