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How scientists revived the organs of dead pigs and what this feat means for transplants

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Using a special machine that pumps blood and other fluids around the body, researchers regenerated cells and organs from pigs an hour after the animals died of cardiac arrest. This feat could one day increase the number of human organs available for transplant.

The team connected the circulatory system of the animals OrganEx, a system that pumps a mixture of blood and fluid-borne nutrients “perfusate” around the body. Cells from all major organs of pigs that had been anesthetized and euthanized not only survived but also showed signs of cellular regeneration, the team wrote last week in Nature.

The system was adapted from an earlier model called BrainEx. In 2019, researchers demonstrated that the latter can be used restore blood circulation in the brain of pigs after the death of animals. The latest version, OrganEx, perfused organs more effectively than a heart-lung bypass machine known as an ECMO (extracorporeal membrane oxygenation) machine that had been tested in other pigs, the team wrote. In the new study, experimental pigs were compared with three control groups of animals that were measured at different time points after death.

OrganEx technology reverses some of the deleterious effects of prolonged ischemia. Representative images of cardiac electrocardiogram (top), albumin immunostaining in liver (middle), and actin in kidney (bottom). Images on the left represent organs perfused with control, while images on the right represent organs perfused with OrganEx technology. Tissue integrity and certain cellular functions were restored with OrganEx technology within an hour of circulatory arrest. credit: David Andrievich, Zvonimir Vrsela, Taras Lysii, Shupei Zhang; Sestan laboratory; Yale School of Medicine

Once the system was up and running, none of the animals showed any coordinated brain activity indicative of consciousness. However, the experiments raise ethical questions about the definition and meaning of death.

Scientific American spoke with study co-authors Zvonimir Vrsela and David Andrijevic, MDs and neurologists at Yale School of Medicine, about how OrganEx works, challenges in its development, and ethical considerations.

[An edited transcript of the interview follows.]

Why did you develop the OrganEx system and how does it build on your earlier BrainEx system?

VRSELYA: When our first study came out in 2019, the main conclusion was that things aren’t dying as fast as we thought. After that, we had a lot of communication with our colleagues. The idea was this: if it works in the brain, which is the most complex and receptive organ [circulatory death], then he should work in all other bodies as well. So we decided to try it on the whole body, one hour after ischemia [after blood flow stops], and we can basically replicate the results of the original cell preservation study. It is still in its infancy, but now at least there is an idea that these organs can be saved and used for transplants.

So, is there an idea that it would ever be possible to preserve the living organs of a person who has recently died by preserving them for a longer period of time before transplanting?

VRSELYA: Just think about the shortage of organs. There is a long waiting list. Kidneys, for example, are the most necessary organ. And now, when this system is optimized and advanced to the point where you can take people who have been dead for an hour and whose organs are not suitable for transplant, ideally we [can] maybe start using those organs. After all, it’s not science for science’s sake. You want to do things because it’s important.

ANDRIEVICH: You want to help save people’s lives.

Can you explain how OrganEx works?

ANDRIEVICH: Essentially, the whole technology consists of two important components: one is a perfusion device, similar to clinical heart-lung machines and very similar to ECMO machines. We like to call it “ECMO on steroids” because there are lots of different pumps and sensors, there’s an artificial kidney inside the system, and so on.

Another important part of the technology is the perfusate [the liquid that is pumped throughout the body], which is based on the first BrainEx perfusate. But now it is compatible with the whole body and optimized to work with other vital organs, as we have shown in our work, such as the kidneys, heart and liver. In addition, this whole body tune-up activates your immune system, blood clotting system, and autonomic nervous system. So this perfusate was optimized to control those things as well. We connect the animal’s vasculature to our system and monitor organ perfusion with our machine. The fluid circulating inside is actually a mixture of the animal’s endogenous blood and our perfusate.

Why didn’t you just use animal blood instead of mixing it with the perfusate?

VRSELYA: It doesn’t work.

ANDRIEVICH: Exactly. One of our control groups was just the clinical standard, ECMO, in which we just tried to restore circulation with the animal’s own blood. And it was terrible.

Blood is living tissue. If you wait an hour, that living tissue—those cells inside—starts to die. You just can’t get circulation going with that dead stuff inside the blood. Our perfusate is completely acellular – there are no cells in it.

Your system pumps a mixture of blood and perfusate. At this point, the animal’s heart does not work?

ANDRIEVICH: As reported in the article, we observed the recovery of the electrical ventricular activity of the heart. We also noticed with our eyes that the heart is really contracting. But the quality of these heartbeats is debatable and we have not evaluated it properly.

How did your system keep the pig cells from dying after the animals were electrocuted?

VRSELJA: When cells are shocked [such as when blood stops pumping]they try to die first.

ANDRIEVICH: Then, once you restore circulation, you can actually reach those organs with our perfusate, a specially formulated drug cocktail that affects the cells and tells them, “Don’t die; there is hope.”

Do you see your system being used in the future for people with life-threatening organ failure?

VRSELYA: This is a difficult question to answer because we are now focused on organ recovery.

ANDRIEVICH: It’s going to take a lot of animal studies to confirm that it works and to what extent and so on before we even think about translating this technology.

How did you handle some of the ethical considerations in the OrganEx experiments?

ANDRIEVICH: We were very careful. All of our experiments were planned and supervised by Yale University [Institutional Animal Care and Use] Committee and external consultants [and ethics] committees. Throughout the experiment, we cooled the animals to reduce their brain activity, and we added neuron blockers to our perfusate to reduce [brain activity]. In addition, we added anesthesia throughout the experiment.

Do you foresee a moment when you can say that these experiments have gone too far?

VRSELYA: We work on cell recovery, and we’ve always had a thorough approach. And for these things to happen, the cells must be alive. But with all the work that has been done in recent years in terms of bioethics and the development of guidelines and approaches, it is clear that there is public involvement and interest in this. I think it’s up to the wider community of scientists and ethicists to guide it to the point where it’s reasonable to do something.

You just want to make sure that at the end of the day you’re addressing the underlying problem, which is the organ shortage, and you want to do it in the best possible way.

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