Juan Carlos Izpisúa Belmonte’s mission is provocatively ambitious: End the shortage of organs that causes nearly two dozen Americans — and many others around the world — to die each day while awaiting a transplant.
The Salk Institute scientist’s strategy for fulfilling that mission is bold: Inject targeted human cells into designated animals’ embryos, then spurring those embryos to grow the desired human organs. The ultimate result would be pigs or other mammals born with human kidneys, livers, hearts or lungs — organs that can be transplanted into ailing people.
Izpisúa Belmonte is a global pioneer in trying to cultivate these cross-species chimeras. After years of experiments, in 2015 his team reported success in coaxing a newly identified type of human stem cell to not only live in mouse embryos, but also integrate into the embryos’ structure. Those embryos weren’t allowed to develop further because of U.S. regulations.
Last week, the National Institutes of Health gave Izpisúa Belmonte $2.5 million to advance his research with monkey cells implanted into pig embryos. Since monkeys are biologically similar to humans, analysis of pig-monkey chimeras should yield insights that can be applied to eventual production of human organs, he said. And unlike mice, pigs are large enough to grow usable human organs.
However, the agency didn’t fund Izpisúa Belmonte’s bid to create human-pig chimeras. He calls the new grant a compromise that postpones having to deal with questions about the moral implications of making human-animal life in this groundbreaking way.
Izpisúa Belmonte, who has said he takes great care with his science because he’s mindful of those concerns, is forging ahead in his native Spain — where the government funds his human-pig chimera research. He hopes U.S. officials will change policy to underwrite the same work here. The NIH is considering whether to lift its moratorium while adding more ethical review to this field of science.
“We have to be positive,” Izpisúa Belmonte said in a phone interview Thursday from Spain, where he oversees a lab in addition to the one at the Salk Institute for Biological Studies in La Jolla. “Monkey cells will allow us to explore the barriers (of development) between the monkey and the pig. That will illuminate what we need to do for human cells.”
For many years, animal-human chimeras have been created for medical research. This includes producing rodents that bear human tumors and mice with brains injected with the kind of human brain cells destroyed in Parkinson’s disease.
The difference with the Izpisúa Belmonte approach is the use of the newly identified kind of stem cells. His team named them region-selective pluripotent stem cells because they preferentially develop in specific regions of an embryo.
Pluripotent stem cells can differentiate to become nearly any type of adult cell in the body — red blood cells, brain cells, liver cells and so on. Region-selective pluripotent stem cells have the advantage of integrating into the developing embryo, merging into the correct tissues as they form. They are also less likely to form tumors than other kinds of pluripotent stem cells.
However, these are still pluripotent stem cells, which means they have the potential to migrate throughout the animal’s body, including to the brain. The possibility of creating an animal with a partly human consciousness, however remote, has generated controversy in scientific and broader circles.
Those concerns aside, a number of bioethicists have accepted the concept of growing human organs in animals, including geneticist Laura Rivard at the University of San Diego and the Rev. Tad Pacholczyk, director of education at The National Catholic Bioethics Center in Philadelphia.
Their reasoning: If it’s permissible to raise and kill animals for food, it should be permissible to use them to save lives — as long as they’re treated humanely in the process.
Human brain structures or reproductive tissue such as ovaries and testicles shouldn’t be grown, and embryonic stem cells shouldn’t be used, Pacholczyk said, conforming with Catholic teaching.
There are also safety questions, said Pacholczyk, whose scientific training includes a Ph.D. in neuroscience from Yale University. Pigs and other animals may contain viruses and other pathogens that could be transferred to transplant patients.
Those safety issues apply as well to attempts to produce genetically modified pig organs that can be transplanted into humans. The company, Synthetic Genomics in La Jolla, is collaborating with a subsidiary of United Therapeutics to advance this technology.
Izpisúa Belmonte said he and colleagues would like to begin with a patient’s own cells, so the final organ is genetically matched to that patient. This would reduce the risk of the person’s immune system rejecting the transplanted organ.
Izpisúa Belmonte’s team would convert the cells into artificial embryonic stem cells called induced pluripotent stem cells, also known as IPS cells. These IPS cells could then be nurtured into other kinds of desired cells and injected into the animal embryo.
Because IPS cells can develop into hundreds of types of cells in the adult body, getting them to turn into the targeted kind of cells is complicated. Performing this research with monkey cells could guide scientists on how to work with human cells, Izpisúa Belmonte said.
From there, the research could take two paths, he said. Currently, it’s unclear which one would turn out to be better.
One route is to put the region-specific pluripotent stem cells into an animal embryo very early in that embryo’s development process. This strategy carries the risk of the pluripotent cells migrating elsewhere — because scientists haven’t fully charted the embryo’s development path.
“So you want to generate a pancreas, but the cells could migrate to the liver,” Izpisúa Belmonte said.
The other path would be to convert the pluripotent stem cells into more mature “progenitor” cells that have partly differentiated. These progenitor cells can only become one organ.
His team has recently made progress toward that goal. It has produced progenitor cells for human as well as mouse kidneys, the researchers announced in a study published Oct. 6 in the journal Cell Stem Cell.
“The idea is that these cells can become only kidneys,” Izpisúa Belmonte said. This would eliminate the worry that the chimeras would develop some kind of humanlike consciousness.
Long road ahead
Pursuing both paths increases the chance of successfully creating usable human organs, he said. But an additional obstacle needs to be solved: Pigs gestate much faster than humans, taking three months and three weeks. So a human organ would be only partially formed by the time a pig-human chimera is born.
While Izpisúa Belmonte imagines a future in which there’s no shortage of organs for transplant, he’s also scientifically realistic. It will take many years to realize this vision, and numerous technical obstacles must be solved first.
“To create an organ, we will need much more understanding of the biological processes of embryonic development,” Izpisúa Belmonte said.
But even before then, the research holds promise for other benefits. For example, he said, drug toxicology screening could be performed in human tissue grown and sustained in animals. Drugs often have to be abandoned because of toxicity when tested in humans. This adds to the already high cost of drug development, he said.
“If we were to have human cells growing in an animal, we could do the tests in earlier stages of development of the drug,” Izpisúa Belmonte said. “If it’s toxic, they stop development and they don’t have to waste millions.”
Article Credit: The San Diego Union-Tribune