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Surgeons announced this week they had performed the first transplant of a pig heart to a human. The 7 January surgery was a milestone for research on transplants between species, known as xenotransplantation. It’s still unclear how well or how long the heart will function, but researchers hope the technique can someday make up for a shortage in human organs for ailing patients.

The procedure, done by a team at the University of Maryland School of Medicine (UMSOM), was a major test for several experimental innovations designed to keep the pig heart functioning in a human chest, including 10 genetic changes in the pigs, a novel immunosuppressant given to the recipient, and a cocaine-laced solution used to incubate the heart. Here’s how science and ethical considerations informed the complex procedure.

Why did this patient get a pig heart?
The transplant recipient, 57-year-old David Bennett, had advanced heart failure and a type of arrhythmia called ventricular fibrillation. Because he had not taken steps to control his high blood pressure and other health problems, physicians at the University of Maryland Medical Center and nearby institutions deemed him ineligible for a human heart transplant, says Muhammad Mohiuddin, director of the cardiac xenotransplantation program at UMSOM. “A human organ is considered a very precious thing,” he says. “The main concern was whether to give the heart to a person who may not be able to take care of it.”

Instead, with Bennett’s consent, the UMSOM team sought a “compassionate use” authorization from the U.S. Food and Drug Administration (FDA) to give him a heart from a genetically modified pig created by Revivicor, a biotech company. Mohiuddin and colleagues have worked with pig organs provided by Revivicor for years. In 2016, they reported that pig hearts could remain healthy for more than 2 years when transplanted into a baboon's abdomen, and have since done transplants into baboons’ chests, where the hearts sustain life. In recent experiments, baboons relying on Revivicor’s pig hearts survived up to 9 months, Mohiuddin says. (Those primates died with functioning hearts after contracting lung infections unrelated to the transplant, he says.)

What genes were changed in the donor pig, and why?
Xenotransplantation risks provoking rejection, an immune response in the recipient that can cause the organ from another species to fail. A key problem is that antibodies produced by people recognize certain sugars on the surface of pig cells as foreign. “You really need to get rid of as much antibody binding as you can upfront to get the graft to survive longer,” says Joseph Tector, a transplant surgeon at the University of Miami who was not involved with the new surgery.

So, in one of its lines of engineered pigs, Revivicor knocked out three genes for enzymes that enable pig cells to synthesize those sugars.

Six tweaks were additions of human genes: two anti-inflammatory genes, two genes that promote normal blood coagulation and prevent blood vessel damage, and two other regulatory proteins that help tamp down antibody response.

A final modification removed the gene for a growth hormone receptor to reduce the chance that a pig organ, roughly matched in size to the patient’s chest, will outgrow it once implanted. In September 2021, Mohiuddin and colleagues reported that this modification reduced the growth of pig hearts transplanted into baboons—a change they expect will help prevent heart failure in people.

Were all 10 genetic changes necessary?
That’s not clear, xenotransplantation researchers say. In collaboration with Revivicor, the UMSOM team has studied baboons with progressively more genetic modifications and seen increasing longevity in the hearts. But baboon experiments are costly, and limits on the number of animals in a study make it difficult to test the effects of each modification independently. “We don’t know how much each of those genes is helping,” Mohiuddin says.

https://www.science.org/content/article/here-s-how-scientists-pulled-first-pig-human-heart-transplant" target="_blank">Source and See More : Science