Do animals hold the key to the global shortage of organs? | Science



SThe scientist Wenning Qin holds a petri dish, carefully spills the pink liquid inside and slides it under a microscope. Some identical small bars come into focus. These cells, he explains, are derived from the ear of a pig. And they can contain the future of organ transplantation from animals to humans.

South Korean researchers are expected to transplant pork corneas. in humans within a year. A few groups in the United States are also working to conduct clinical trials of pork organs in the next few years, including a group at Mbadachusetts General Hospital in Boston that is starting a six-person clinical trial that uses skin "blankets". of pork to temporarily protect the skin of burned victims. At the University of Alabama at Birmingham School of Medicine (UAB), researchers plan to transplant pig kidneys in adults and hearts in newborns with difficulties.

And in Cambridge, Mbadachusetts, in a company called eGenesis, scientists like Qin, the company's director of genomic engineering, are genetically preparing pig cells. Their goal, shared by a handful of other biotechnology companies in the United States and Europe that work in genetic engineering, is to create pigs whose organs can be safely transplanted to people.

"I think this is a magic point in the field of [animal transplants]"Says William Westlin, executive vice president of research and development at eGenesis." It's not about it anymore. It's just a matter of when. "





Wenning Qin, Director of Genome Engineering in the cell culture laboratory, studies pig cells designed under the microscope in his eGenesis lab. eGenesis is a biotechnology that genetically manipulates pigs so that their organs can be used for human transplants using CRISPR in Cambridge, Mbadachusetts.



"I think this is a magic point in the field of [animal transplants]"Says William Westlin, executive vice president of research and development at eGenesis Photo: Tony Luong / The Guardian

Futuristic science

Scientists have long pursued the idea of ​​keeping people alive using parts of animals, a process called xenotransplantation. But for a long time it was believed that it was impossible; the first experiments showed that the body takes about five minutes to reject an organ of another species. "No one would dare to speak" about conducting clinical trials for xenotransplantation, says Leo Bühler, president of the International Association of Xenotransplantation.

For a kidney, heart or lung pig to keep a person alive, the human immune system must be tricked into not recognizing that it comes from a different species. That's where the Crispr gene-editing technology comes in, allowing researchers to make targeted changes to a complete set of genes in many places simultaneously. Crispr – abbreviation of short palindromic repeats grouped regularly interspersed – has been used by eGenesis to eliminate from the porcine genome a group of viruses that some concerns could jump to humans after a transplant. Now they are also working to eliminate markers that identify cells as foreign so that the human immune system does not reject them





Wenning Qin, Director of Genome Engineering in her eGenesis lab. eGenesis is a biotechnology that genetically manipulates pigs so that their organs can be used for human transplants using CRISPR in Cambridge, Mbadachusetts.



Wenning Qin in his laboratory at eGenesis. Photography: Tony Luong / The Guardian

Test phase

In unrelated research, other scientists have tested the organs of pigs with bioengineering in nonhuman primates, a crucial step toward a clinical trial in humans. In a recent Nature study, baboons lived for six months with hearts transplanted from pigs that had been genetically modified at some points to reduce rejection, the longest an animal has depended on an organ from another species. In another advance published at the end of 2017, researchers from the National Institutes of Health showed that baboons could live up to three years with a heart of pig beating next to theirs. Improvements in immune suppression medications have also made rejection less likely, says Jay Fishman, a specialist in infectious diseases and immunology at Mbadachusetts General Hospital and Harvard Medical School.

Animal rights activists oppose all research with primates, and such research can be done only in very limited circumstances and in very few facilities. It would be too risky, researchers say, to test such transplants in humans without first testing them in primates. Primates have different immune systems for people, but testing in baboons is a challenge, however.

There are no major scientific obstacles to xenotransplantation, and pig organs will eventually be able to keep people alive and healthy, believes Bruno Reichart, a cardiac surgeon who led the Nature study. Reichart, head of the xenotransplantation collaborative research center at the University Hospital of Munich, says he now needs to extend his experiments with baboons in order to keep 60% or more of life with a pig heart for longer. He would like to try to keep some for a year. But it is not easy to convince a baboon to take immunosuppressant drugs every day. And it's not reasonable to keep an animal tied to an IV for so long, he says.





Immunohistochemical plates of a pig kidney in the molecular biology laboratory in eGenesis. eGenesis, a biotechnology that genetically manipulates pigs so their organs can be used for human transplants using CRISPR in Cambridge, Mbadachusetts.



Immunohistochemical plates of a pig kidney in the molecular biology laboratory in eGenesis. Photography: Tony Luong / The Guardian

Endless supplication

The potential for such technology is enormous. At this time, 75,000 people in the US UU They wait for an organ transplant, and about 20 die each day because they could not receive one. Another 6,000 are waiting for organs in the United Kingdom. Unlike human organs, where patients have to wait for someone else to die, the supply of organs and pig cells would be virtually unlimited. Devin Eckhoff, a liver transplant surgeon at the University of Alabama School of Medicine in Birmingham, says that if he receives the green light today, he could be producing 50 pigs for transplants within nine months. (Animals that are genetically engineered for transplantation would not be allowed to enter the food supply, so they do not pose a risk to the public, Eckhoff noted). He says it's frustrating to see his patients become seriously ill and then die from lack of replacement organs. "I've dedicated my life to transplants," he says. With the available organs of the pigs, "think of how many more lives we could save".

Pigs ready for transplantation could do much more than simply provide organs. Eventually, they could be used to produce the islet cells, groups of pancreatic hormone-producing cells that people with diabetes need. Pork blood could be used to administer transfusions to traumatized patients and people with chronic diseases such as sickle cell anemia, who often develop antibodies against human blood cells because they have received so many transfusions. Even pigs could produce dopamine-producing cells, and transplant them to patients with Parkinson's disease, says David Cooper, who co-directs the xenotransplantation program at the UAB.





Immunohistochemical plates of a pig kidney in the molecular biology laboratory in eGenesis. eGenesis, a biotechnology that genetically manipulates pigs so their organs can be used for human transplants using CRISPR in Cambridge, Mbadachusetts.



Immunohistochemical plates of a pig kidney in the molecular biology laboratory in eGenesis. Photography: Tony Luong / The Guardian

"It will revolutionize medicine when it arrives," says Cooper. "You would have these organs available when you want them … If someone has had a heart attack, you could take out their heart and put a pig heart in the place, there is great potential here."

Even if a pig organ can not last forever in a person, it should be able to buy someone's time. At this time, newborns can wait on the organ transplant list for more than three months to get a new heart, which often faces a mortality rate of more than 50%, says David Cleveland, cardiac surgeon at the UAB. Cleveland wants to use xenotransplantation to save babies born with conbad heart defects. "There is a great need," he says. Artificial hearts can keep adults alive while waiting for a transplant, but there is no such device for babies. Clearly, there are difficulties in using a pig heart permanently for a baby, but at least the pig's heart could be used as a bridge, says Cleveland, keeping the baby healthy until a human heart is available. He also hopes that babies' immature immune systems will facilitate acceptance of pig hearts.

Pigskin may also help burn patients, says Jeremy Goverman, the principal investigator of the Mbadachusetts General Skin Study. Now, he often can not find human skin samples large enough to cover large wounds. He believes that a skin patch from a pig would be more profitable than one from a corpse. For countries that can not maintain human tissue banks, pigskin could be an alternative to save lives, he says.





eGenesis, a biotechnology that genetically manipulates pigs so their organs can be used for human transplants using CRISPR in Cambridge, Mbadachusetts.



eGenesis, a biotechnology that genetically manipulates pigs so that their organs can be used for human transplants using Crispr in Cambridge, Mbadachusetts. Photography: Tony Luong / The Guardian

The road ahead

The UAB researchers aim to increase reproduction in their sterile facilities this year. They plan to raise enough 150 lb. animals for a pilot trial and a small clinical trial on people. But money is, as always, a problem. Researchers are also concerned about how the public will perceive xenotransplantation, although initial surveys suggest that people are open to the concept. Of course, some will reject the idea of ​​sacrificing animals for experiments and organs, even if they are used to save human lives.





Pig cells manipulated under the microscope in eGenesis. eGenesis, a biotechnology that genetically manipulates pigs so their organs can be used for human transplants using CRISPR in Cambridge, Mbadachusetts.



Pig cells manipulated under the microscope in eGenesis. Photography: Tony Luong / The Guardian

Researchers will not identify the locations of their animal research laboratories for fear of animal welfare activists. But Americans already eat about 120 million pigs a year, and no one has to accept a pig organ, says Cooper, and donation of human organs continues for the foreseeable future. He thinks that his seriously ill patients would be happy to get a pig organ as long as it works, just as he has seen that people's ideas about how to become an organ donor evolve when they need it. "When it hits you personally and you're going to die, I think your attitude changes," says Cooper.

The final obstacle, the only way to really know if the xenotransplant will work, will be to try it with people, says Fishman. "I think we're all waiting for the first clinical trial."


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