Minutes after 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 researchers 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-protecting fluid to organs and tissues, researchers restored blood flow and other cellular functions in pigs a full hour after they died, the journal reported on Aug. 3. Nature.
The findings could help improve the health of human organs during surgery and expand the availability of donor organs, the authors said.
“All cells don’t die at once, there’s a longer series of events,” said David Andrijevic, an associate scientist in neuroscience at Yale School of Medicine and one of the study’s authors. “It’s a process where you can intervene, stop and restore some of the cell’s functions.
The research builds on an earlier Yale-led project that restored blood flow and certain cellular functions in the brain of a dead pig using a technology called BrainEx. Published in 2019, that and the new study were led by the laboratory of Yale researcher 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, the organ known to be most susceptible to ischemia [inadequate blood supply]we hypothesized that something similar can be achieved in other vital transplantable organs as well,” said Sestan.
In the new study, which involved senior author Sestan and colleagues 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 the heart-lung machines that do the work of the heart and lungs during surgery, and an experimental fluid containing compounds that can promote cell health and suppress inflammation throughout the pig’s body. Cardiac arrest was induced in anesthetized pigs treated with OrganEx one hour after death.
Six hours after treatment with OrganEx, the researchers found that some basic cellular functions were active in many parts of the pigs’ bodies, including the heart, liver and kidneys, and that some organ functions were restored. For example, they found evidence of electrical activity in a heart that retained the ability to contract.
“We were also able to restore blood flow throughout the body, which surprised us,” said Sestan.
Normally, when the heart stops beating, organs begin to swell, constricting blood vessels and blocking blood flow, he said. However, blood flow was restored and the organs of dead pigs treated with OrganEx appeared to be functional at the cellular and tissue level.
“Looking under the microscope, it was difficult to distinguish a healthy organ from an organ that had been processed with OrganEx technology after death,” said Vrselja.
As in 2019 during the 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 when they evaluated the treated animals, who were anesthetized throughout the six-hour experiment, by observing involuntary and spontaneous muscle movements in the head and neck regions. These movements indicate preservation of some motor functions, Sestan said.
The researchers emphasized that further research is needed to understand the apparently restored motor functions of the animals and that rigorous ethical review by other scientists and bioethicists is needed.
Experimental protocols for the latest study were approved by the Yale Institutional Animal Care and Use Committee and guided by an external advisory and ethics committee.
The authors said the OrganEx technology could ultimately have several potential applications. For example, it could extend the life of patients’ organs and expand the availability of donor organs for transplantation. It can also help heal 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 the Yale Interdisciplinary Center for Bioethics. “However, we need to carefully monitor all future studies, especially those involving brain perfusion.”
The study 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.