Within minutes of the last heartbeat, a cascade of biochemical events triggered by a lack of blood flow, oxygen and nutrients begins to destroy the body’s cells and organs. But a team of Yale scientists has found 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-protective 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 the journal Nature.
The findings may help prolong 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 longer series of events,” said David Andrijevic, an associate neuroscience researcher at Yale School of Medicine and co-author of the study. “It’s a process that you can intervene in, stop and restore some cellular functions.”
The research builds on an earlier Yale-led project that restored blood circulation and some cellular functions in the brain of a dead pig with a technology called BrainEx. Published in 2019, that study and the new one were led by the lab of Yale’s Nenad Sestan, the Harvey and Kate Cushing Professor of Neurology and Professor of Comparative Medicine, Genetics and Psychiatry.
“If we can restore certain cellular functions in the dead brain, an organ known to be most susceptible 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 included senior author Sestan and colleagues Andrijevic, Zvonimir Vrselja, Taras Lysyy and Shupei Zhang, all of Yale — researchers applied a modified version of BrainEx, called OrganEx, to a 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 pig’s body. Cardiac arrest was induced in anesthetized pigs that were treated with OrganEx one hour after death.
Six hours after treatment with OrganEx, the scientists found that certain key cellular functions were active in many areas of the pigs’ bodies – including the heart, liver and kidneys – and that the function of some organs was restored. For example, they found evidence of electrical activity in the heart that retained its ability to contract.
“We were also able to restore blood circulation throughout the body, which amazed us,” Sestan said.
Normally, when the heart stops beating, organs begin to swell, constricting blood vessels and blocking circulation, he said. However, circulation was restored and the organs in deceased pigs that received OrganEx treatment appeared to be functional at the cellular and tissue level.
“Under the microscope, it was difficult to distinguish between a healthy organ and one that had been treated with OrganEx technology after death,” Vrselja said.
As in the 2019 experiment, the researchers also found that cellular activity in some areas of the brain was restored, although no organized electrical activity indicative of consciousness was detected during any part of the experiment.
The team was particularly surprised to observe involuntary and spontaneous muscle movements in the head and neck region when assessing the treated animals, which remained anesthetized throughout the six-hour experiment. These movements show preservation of some motor functions, Sestan said.
The researchers emphasized that further 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 eventually have several potential applications, the authors said. For example, it can extend the life of organs in patients and expand access to donor organs for transplantation. It may also help treat organs or tissues damaged by ischemia during heart attacks or strokes.
“There are many potential applications for this exciting new technology,” said Stephen Latham, director of Yale’s Interdisciplinary Center for Bioethics. “However, we must maintain close supervision of all future studies, especially any 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.