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Researchers connect gene-edited pig livers to bodies of brain-dead people

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Researchers connect gene-edited pig livers to bodies of brain-dead people

Researchers connect gene-edited pig livers to bodies of brain-dead people

Surgeon Abraham Shaked estimates that he has performed more than 2,500 liver transplants in his working life. But what he did last December was completely new to him: Together with a team from the University of Pennsylvania (UPenn) in Philadelphia, he connected the veins of a brain-dead man to a refrigerator-sized machine containing an intact pig liver. For three days, the man’s blood flowed into the machine, through the pig’s liver and back into his body.


This “extracorporeal,” or outside the body, liver could help people survive acute liver failure, which can be caused by infection, poisoning or (the most common cause) too much alcohol. UPenn conducted the trial together with the biotech company eGenesis. A damaged liver can no longer do its job of filtering toxins from the body, processing nutrients and producing proteins. Connection to an external liver could give those affected time. “You want to give the liver time to recover – or at least treat it with care until a transplant is possible,” explains Shaked.

The Philadelphia liver experiment is just the latest research project to experiment with organs from pigs that have previously been genetically modified to make their tissue more compatible with that of humans. In previous studies at the University of Maryland, the hearts of two men with end-stage heart disease were replaced with pig hearts developed by another company, United Therapeutics. Remarkably, both were able to live with the animal heart, but only for a short time; both died within two months of the transplant. Scientists continue to investigate why the hearts failed. At least the second patient’s heart showed signs of rejection.

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Now some doctors say using a pig organ that lies outside the body might be easier because it only has to survive for a limited time. “If what we’re doing works the way we think it does, then I think this technology could be the first pig organ to be truly used clinically,” says Shaked. The big goal of the “pig engineering” companies, which include eGenesis, United and Makana Therapeutics, is to produce customized hearts, kidneys or lungs that can keep a person alive for years. To do this, they have all made genetic changes so that the animal tissue is protected from the human immune system, which would otherwise attack the organs.

For three days, the man’s blood flowed into OrganOx’s machine, through the pig’s liver and back into his body.

(Image: eGenesis / OrganOx)

Using a liver outside the body largely avoids the problem of long-term rejection of the organ because it only needs to remain functional for a few days rather than years. The genetic changes made to the pigs also appear to protect the organs from severe rejection reactions in the short term. “There is no complex immunology here,” says Shaked. “We eliminate the issue of rejection because we don’t use the organ for long. It acts more like a machine.”

The idea would be to use the external organ to support people with liver failure until a human liver transplant is available for them – or at least until their liver has recovered somewhat, which is entirely possible given the organ’s ability to regenerate. Patients who could benefit include those who have overdosed on strong painkillers or consumed too much alcohol over time and then develop acute liver failure.

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Mike Curtis, CEO of eGenesis, explains that his biotech company is also testing pig kidneys and hearts that his employees have already transplanted into baboons. eGenesis hopes to test these organs on humans in the foreseeable future. A little over a year ago, however, he realized that an “extracorporeal” liver could lead to a product more quickly. The transplant is of course the goal. “But we first have to prove that we have something to invest in. There is an acute need for livers with few competing products,” says Curtis.

It is crucial for biotech companies to get a product into human trials as quickly as possible, because then the partners of the big pharmaceutical companies come knocking. And pig organ transplants have always had a reputation as a speculative technology that never really caught on. “The curiosity is still there and people are knocking,” says Curtis. “They see technology as the future. The question is: next year or in 100?” When it comes to heart transplantation, for example, people are really on the wrong track, believes the eGenesis CEO. “With extracorporeal therapy, however, it is a bit like developing other products. You can strive for constant improvements.”

This is the first time an organ from one of the eGenesis gene-edited pigs has been tested on a human. The company is prepared to seek approval to begin a formal study of the liver system later this year – and not just an experiment, Curtis said. If given the green light, it could be the first clinical trial using such organs. (The heart transplants came with a special permit that allows novel forms of therapy for terminal patients.)

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The pig kidney experiment began Dec. 22 after the family of an elderly man who suffered a brain hemorrhage agreed to allow his body to be used for research. He was brain dead, but his heart was still beating. During the experiment, the pig liver was installed in a device made by OrganOx, which is normally used to keep donated human organs warm and supplied with blood so they stay fresh longer for transplants. In this case, tubes connected to the subject’s veins were inserted into the device – and both sides remained connected for 72 hours.

The idea of ​​an extracorporeal organ has been tried before. In the 1990s, researchers connected several patients to pig livers, but the organs quickly died. According to eGenesis, the liver in this experiment, which came from a genetically modified Yucatan mini-pig, was still healthy even after three days.

The question is practical use: Unlike hearts and kidneys, pig livers are probably not plausible candidates for direct transplantation into humans. One of the organ’s jobs is to mass produce proteins, fats and glucose – and the pig versions of these molecules would likely provoke a strong immune response even against a genetically engineered liver. Adam Griesemer, surgical director of the NYU Langone Transplant Institute, says extracorporeal use is “probably the only use” for pig livers.


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