Within minutes of the final heartbeat, a cascade of biochemical events caused by a lack of blood flow, oxygen and nutrients begins to destroy a body’s cells and organs. But a team of Yale scientists discovered that massive and permanent cell failure doesn’t have to happen so quickly.
Using a new technology developed by the team that delivers a specially designed cell-protecting fluid to organs and tissues, the researchers restored blood circulation and other cellular functions in the pigs a full hour after they died, they report in the Aug. 3 issue of magazine. Nature.
The findings may help extend the health of human organs during surgery and expand the availability of donor organs, the authors said.
“All cells don’t die immediately, there’s a more prolonged series of events,” said David Andrijevic, a research associate in neuroscience at Yale School of Medicine and co-leader of the study. “It’s a process that you can intervene in, stop and restore some cellular function.”
The research builds on an earlier Yale project that restored circulation and some cellular functions in the brain of a dead pig with technology called BrainEx. Published in 2019, this study and the new one were conducted in the laboratory of Yale’s Nenad Sestan, the Harvey and Kate Cushing Professor of Neuroscience and Professor of Comparative Medicine, Genetics and Psychiatry.
“If we could restore certain cellular functions in the dead brain, an organ known to be more sensitive to ischemia [inadequate blood supply]we hypothesized that something similar could be achieved in other vital transplantable organs,” Sestan said.
In the new study — which involved senior author Sestan and collaborators Andrijevic, Zvonimir Vrselja, Taras Lysyy and Shupei Zhang, all from Yale — the researchers applied a modified version of BrainEx called OrganEx to the whole pig. The technology consists of a perfusion device similar to heart-lung machines – which do the work of the heart and lungs during surgery – and an experimental fluid containing compounds that can promote cellular health and suppress inflammation in the whole body of the pig. Cardiac arrest was induced in anesthetized pigs treated with OrganEx one hour after death.
Six hours after treatment with OrganEx, the scientists found that some basic cellular functions were active in many areas of the pigs’ bodies – including the heart, liver and kidneys – and that some organ function had been restored. For example, they found evidence of electrical activity in the heart, which retained the ability to contract.
“We were also able to restore circulation throughout the body, which surprised us,” Sestan said.
Normally, when the heart stops beating, the organs begin to swell, collapsing blood vessels and blocking circulation, he said. However, circulation was restored and the organs in the dead pigs treated with OrganEx appeared functional at the cellular and tissue level.
“Under the microscope, it was difficult to tell the difference between a healthy organ and one that had been treated with OrganEx technology after death,” said Vrselja.
As in the 2019 experiment, the researchers also found that cellular activity in some areas of the brain had been restored, although no organized electrical activity indicative of consciousness was detected in any part of the experiment.
The team was particularly surprised to observe involuntary and spontaneous muscle movements in the head and neck regions when they assessed the treated animals, which remained anesthetized throughout the six-hour experiment. These movements show preservation of some motor functions, Sestan said.
The researchers stressed that additional studies are needed to understand the apparently restored motor functions in animals and that rigorous ethical review by other scientists and bioethicists is needed.
Experimental protocols for the latter study were approved by the Yale Institutional Animal Care and Use Committee and guided by an external advisory and ethics committee.
The OrganEx technology could ultimately have many potential applications, the authors said. For example, it could extend the life of organs in sick people and expand the availability of donor organs for transplantation. It may also be able to help heal organs or tissues damaged by ischemia during heart attacks or strokes.
“There are many potential applications of this exciting new technology,” said Stephen Latham, director of Yale’s Interdisciplinary Center for Bioethics. “However, we must maintain careful oversight of all future studies, particularly those involving brain perfusion.”
The research was funded by the US Department of Health and Human Services, the National Institutes of Health and the National Institute of Mental Health.
This work was supported by NIH BRAIN Initiative grants MH117064, MH117064-01S1, R21DK128662, T32GM136651, F30HD106694, and Schmidt Futures.
The study was conducted at the Yale Translational Research Imaging Center, which is directed by co-author Dr. Albert Sinusas, professor of medicine, radiology and biomedical engineering. The Nature paper provides a full list of authors.