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Friday, July 12, 2024

Scientists Just Tried Growing Human Kidneys in Pigs

In a first, researchers in China have used pigs to grow early-stage kidneys made up of mostly human cells. The advance is a step closer to producing organs in animals that could one day be transplanted to people.

More than 100,000 people in the United States are on the national transplant waiting list, and 17 people across the country die each day waiting for a donor organ, according to the Organ Procurement and Transplantation Network. Kidneys are the most in demand, with nearly 89,000 Americans needing one as of September.

“The ability to generate human organs in pigs would make a significant impact in reducing the number of patients on a waiting list in the United States and around the world,” says Mary Garry, a professor of medicine at the University of Minnesota who studies chimeric organisms—those that contain cells from different species—but wasn’t involved in the research. Garry’s team showed in 2020 and 2021 that it was possible to grow humanized blood vessels and skeletal muscle in pigs.

Attempts at making animal chimeras in the lab began decades earlier. In 1984, researchers at the Institute of Animal Physiology in Cambridge, England, reported that they had created goat-sheep chimeras by mixing embryos from the two species. More recently, news leaked in 2019 that scientists had made the first embryos that were part human and part monkey. (They subsequently destroyed them.) The work was eventually published in 2021. Led by Juan Carlos Izpisúa Belmonte, then a professor at the Salk Institute for Biological Studies in California, the team carried out their experiments in China, where they said monkey embryos were cheaper and easier to obtain.

In the current study, a team led by scientists at Guangzhou Institutes of Biomedicine and Health injected more than 1,800 pig embryos with human stem cells and then transferred them into the wombs of 13 female pigs. They allowed the chimeric embryos to grow for up to 28 days, then stopped the pregnancies to remove and examine the embryos. They collected five, which all had kidneys that were developing normally and contained up to 65 percent human cells. The research was published September 7 in the journal Cell Stem Cell. (The study authors didn’t respond to WIRED’s request for an interview.)

“It is remarkable to see that about 60 percent of the primordial pig kidney contained human cells,” says Jun Wu, a stem cell biologist at the University of Texas Southwestern Medical Center, who wasn’t involved in the new study. Wu, Belmonte, and their colleagues were the first to grow embryos with mixed human and pig tissues, a feat they reported in a 2017 study. In that paper, Wu and his team also described growing a rat pancreas, heart, and eyes in a developing mouse.

Integrating cells from pigs and humans, however, has proven more difficult than combining cells from rats and mice, which are much closer genetic relatives. Pig cells tend to outcompete human cells when transplanted into animal tissue, causing the human cells to quickly die off. As a result, the contribution of human cells in the chimeric embryos Wu’s group produced was low. This study, he says, is a big improvement.

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There’s another challenge with growing a humanized organ inside an animal: Organs need room to develop, and if there’s already an existing organ, it’s hard to grow a new version. “There’s no place for it,” says Paul Knoepfler, a stem cell biologist at UC Davis, who wasn’t involved in the current study. “So what these researchers tried to do was make space for a human organ to grow inside of an animal.”

To do this, the researchers used the gene editing tool Crispr to knock out two genes in the pig embryos needed for kidney development. This stopped the embryos from forming pig kidneys and created a “niche,” or microenvironment, where the humanized kidneys could take root instead.

They then turned a batch of regular human cells into pluripotent stem cells—which have the ability to turn into any cell type in the body. In these cells, they turned up the expression of two genes to prevent them from dying and to improve their chances of integrating with the pig cells. The chimeric embryos were made by injecting the human stem cells into the pig embryos. Before transferring them to the pig wombs, the researchers gave the embryos a special cocktail of nutrients to help both the human and pig cells stay alive, since these cells usually have different needs.

When the embryos were removed, the kidneys had formed structures typical of that stage of development: the fine tubes needed to remove waste and the buds of cells that later turn into ducts that connect the kidney to the bladder. But since the pregnancies were stopped early, it’s unknown whether the kidneys would have continued developing normally and become functioning organs that could be used in transplants.

Knoepfler says the results are exciting, but he raised concerns about the two genes the researchers edited to make the human cells more likely to survive when transplanted: MYCN and BCL2. When these genes are overexpressed, they can cause cancer. He says there would need to be extensive animal testing to determine whether organs grown from these edits could cause cancer if they were transplanted into humans.

For now, scientists are still a long way from growing a fully human organ inside a pig. “Humans diverged from pigs about 80 million years ago, so growing human cells in a pig embryo is a significant—and, at the moment, inefficient—task,” Garry says.

Why pigs then, when they differ so much from humans? Scientists think they’d make ideal donor animals for people because of their similar anatomies and organ size. And right now, transplant centers can’t keep up with the demand for organs. The average wait time for a kidney transplant is three to five years at most centers in the US but can be longer in certain parts of the country.

Pig organs can’t simply be transferred into human recipients, though. Pig tissue is swiftly rejected by the human immune system, and pigs also harbor innate viruses that could be passed on to transplant patients.

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To avoid these scenarios, researchers elsewhere are trying to genetically engineer pigs so that their organs won’t be rejected if they are transplanted into people. In January 2022, David Bennett became the first person to receive a genetically engineered pig heart. He survived two months with the organ before dying of heart failure. Researchers are now testing engineered pig kidneys in brain-dead donors.

Other groups are trying to grow human organs from stem cells in the lab. So far, scientists have only been able to produce tiny balls of tissue the size of peas. Known as organoids, these 3D blobs have some of the same cells and structures as the organs they’re meant to mimic but are still far from the real thing.

Even if scientists manage to grow full-fledged humanized organs inside pigs, there’s no guarantee they’d be compatible with the human immune system. “Even if you get 90 percent human cells, 10 percent pig, there's a high likelihood that the recipient would have to stay on immunosuppression in the same way that a typical organ-transplant recipient would,” Knoepfler says.

And that’s the big question facing any technique that aims to generate transplant organs for patients: “Will an organ, regardless of how you make it, be accepted by the recipient?” Knoepfler asks.

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