The severe shortage of organs available for human transplant has forced researchers to get creative in generating new ones. Some have pinned their hopes on pigs; others aim to grow organs in a dish — but these efforts have been largely fruitless or plagued by complications.
An approach that’s been simultaneously the most promising and the least successful is developing human organs in animals. But new research from scientists at the Stanford School of Medicine and their collaborators lays the very preliminary groundwork for a technique that might provide scientists with a revived pathway for this type of organ generation.
To show that such an approach is feasible, one would need to demonstrate that human stem cells (which grow into specialized cells and parts of the body, including organs) could survive within the early embryo of an animal, which acts as a sort of biological incubator. But the options for developing those cells are appropriately limited: Laws in the United States — and scientific ethics — carefully prohibit the option of experimenting with chimeras (a mixture of two genetically different cells) between humans and primates, explained Michael Snyder, PhD, professor and chair of genetics.
Instead, the team has turned to the cells of non-human primates to act as a proxy. “We’re using chimpanzee cells in this study because we know they are very close, genetically, to human cells. We show that chimpanzee stem cells can survive in a different animal model — in this case, a rhesus macaque — with the hope that viability will let us further explore organ generation down the line,” said Hiromitsu Nakauchi, MD, PhD, professor of genetics . “This is our long-term goal. And it’s not easy.”
Other research teams have tried this approach, but none had been successful. Only when Stanford veterinary research scientist Morteza Roodgar, DVM, PhD, developed a new method to generate more stable, robust chimpanzee pluripotent stem cells, which possess the capability to grow into any tissue type, did the team find renewed hope for the method.
A paper describing the team’s findings was published in Cell Reports Aug. 30. Snyder, who is the Stanford W. Ascherman, MD, FASC, Professor in Genetics; Nakauchi; and Catherine VandeVoort, PhD, a professor at the UC Davis Primate Research Center, are co-senior authors of the study. Roodgar is the lead author.
A door once closed, now ajar
Scientists have been chasing the prospect of generating human organs in animals for years—many even consider it a holy grail of organ genesis. Using a person’s own stem cells to grow, say, a new liver, would circumvent any possibility of rejection, as the new tissue would reflect their natural biological makeup — and it would remove the often excruciatingly long wait time on transplant lists.
Nakauchi is a pioneer and longtime proponent of interspecies organ generation. In his early work, he has demonstrated that it’s possible to create a rat pancreas in a mouse. His team then showed that the organs generated inside the body of another species can be transplanted back to the original species without rejection. “If this principle were to work between humans and large animals, it would be possible to produce human organs in an animal, such as a pig,” Nakauchi said.
Primate and rodent biology, however, can be worlds apart, so scientists needed to replicate the rodent results in primates. But culturing chimpanzee stem cells proved difficult. They were finicky, wily and otherwise unruly in a dish, dying prematurely and differentiating, or growing into specific cell types, when they weren’t supposed to. (Part of creating good-quality stem cells is ensuring that the cells are stable so they can be programmed to transform into a specific tissue type, Roodgar said.) After many failed experiments, momentum in the field petered out.