Just minutes after the heart’s last beat, a terrifying cascade of biochemical events caused by a lack of oxygen, nutrients, and blood flow begins to destroy cells. As a consequence, the organs swell and there is a path of no return to death. Or at least that’s what the theory says, because researchers at Yale University have been carrying out experiments for years to reverse, at least partially, this process. In 2019, some brain cells of pigs that had died four hours ago were already ‘resurrected’. Now, as described in a new study in ‘Nature’, they have used this same system to ‘to revive‘ the rest of the organs of pig carcasses that died an hour earlier, even repairing some damaged cells.
The idea arose while the team’s neuroscientists were routinely observing signs of cell viability – that is, some cells still functional – in samples of dead human brain tissue, even hours after death. So, was it possible to take advantage of that ‘lapse’ to ‘bring back to life’ some parts of them? From this premise they developed BrainEx, a mechanism that consists of a series of pumps that inflate a ‘sangre artificial‘ Composed of genetically modified cell-free hemoglobin with anticoagulant properties devised by the researchers themselves. For six hours they attached the pigs’ heads to a machine that kept them at the temperature a live pig would have had, while they inoculated this solution.
Thus, while monitoring the animals, they found signs of molecular activity and signals of basic functions of neuronal, glial and vascular cells. Specifically, and as indicated in their study, also published in ‘Nature’, a reduction in cell death was observed; preservation of anatomical and cellular architecture; restoration of the structure of blood vessels and return of circulation; glial inflammatory responses; signs of active brain metabolism of glucose and oxygen; and in vitro spontaneous neuronal activity at synapses in cells that were removed from BrainEx-treated brains.
“So we thought that if we could restore certain cellular functions in a dead brain, an organ known to be more susceptible to ischemia – the reduction of blood supply – it was possible that something similar could also be achieved in other transplantable organs” , Explain Nenad Sestan, professor of neuroscience, comparative medicine, genetics and psychiatry at Yale, as well as the author of the two studies. Thus, based on BrainEx, they created OrganEx: the same idea but applied to other vital organs such as lungs, liver, kidneys, pancreas or heart, opening the door to keep them ‘alive’ beyond death and a revolutionary step for future human transplants.
The ‘Frankenstein machine’
One hour after their induced death, the pigs were hooked up to a perfusion device similar to cardiopulmonary bypass machines (called ECMOs), which do the work of the heart and lungs during, for example, surgeries or to help to critical patients. An experimental fluid like the BrainEx fluid was also introduced into the circuit, but adapted to the cells of other organs beyond the brain, suppressing the inflammation that occurs after death.
After six hours of OrganEx treatment, the researchers found that key cellular functions — specifically, structural integrity and cellular machinery — were once again active in the heart, lungs, pancreas, liver, kidneys, and even the brain, in which these signals were also monitored (although not as extensive an analysis as in the previous study). In addition, the function of some organs had been restored: for example, they found evidence of electrical activity in the heart, which retained the ability to contract; In addition, they were able to restore circulation throughout the body, which left the researchers “really amazed,” says Sestan. What’s more: under the microscope, the organs that had been treated with this system were difficult to distinguish with the naked eye from a healthy organ.
They also compared the results with the ECMO system: while this treatment did not achieve adequate perfusion of all organs and many blood vessels collapsed, OrganEx achieved full perfusion and stable oxygen consumption. In-depth analyzes of the tissues revealed less cell destruction and more evidence that cell repair was being boosted by the pioneering treatment.
On the left, the circulation of the kidneys after one hour of treatment with ECMO; on the right, the same situation with OrganEx; in black and shaded, the areas where there is traffic (better results on the right, as can be seen)
The experiment went so well that they even observed muscle spasms of the head and neck while treating the animals, which were anesthetized at all times. “These movements indicate that there is also preservation of some motor functions,” explains Sestan. Still, the researchers make it clear that it’s not about a ‘resurrection’ complete set of pigs, which in no case regained full function or come back to life as some kind of ‘zombie’ pig. In fact, as in the previous work, they monitored the brain signals to check that the global electrical activity was not reestablished and, if it did, they could lower the body temperature, administer more anesthesia and stop the experiment.
“Our goal was to restore the functionality of some organs, so further studies are still needed to understand the apparently restored motor functions in animals,” says study co-author Stephen Latham, director of the Yale Interdisciplinary Center for Bioethics. “We must maintain careful oversight of future research, particularly any that involves brain perfusion,” he says of the ethical implications of these types of controversial experiments.
And not just future ones. Both tests passed strict controls by experts in bioethics and medicine, in addition to being planned almost to the millimeter from their origin. “For this reason, only a window of one hour was used from the death of the subject to the application of the treatment, as established. No more,” he says. David Andrijevica neuroscientist at Yale and another of the study’s authors.
Human applications
The logical question after this experiment is whether this system could be used in humans. “It’s a possibility, but it’s still far from practical applications,” explains Latham. “A lot of research is missing to know how we can use it in people and study its consequences.” The researchers do point out that this system can open the door to prolonging the life of human organs and expanding their availability in donors for transplants. Or it could also be used to help treat organs or tissues damaged by ischemia during heart attacks or strokes.
“But it is not that we can improve a heart after having a heart attack, it is not that simple,” says Latham, who indicates that OrganEx does not reverse the death process, nor does it ‘rejuvenate’ the organs after its application. “There are numerous potential applications for this exciting new technology. But, I insist, there is still much research ahead and we are far from being able to apply it to humans.”
For his part, Andrijevic is somewhat more optimistic within the caution: “If we show with future studies that OrganEx is capable of achieving complete and adequate recovery of organs, this approach could increase the pool of organ donors not only by saving organs that would previously be discarded, but also by saving multiple organs at once.