Over the years that scientists have been inserting human cells into the embryos of mice, causing the furry creatures to grow Mini Me versions of human tissues and even brain structures, none of the animals have ever looked up in a panic and screamed, “What am I doing in this body?!” But the prospect of something going sci-fi-ishly wrong in experiments that create “chimeras” — creatures containing cells and even organs from another species — has long made scientists and bioethicists uneasy, enough so that in September the National Institutes of Health announced that it would no longer fund some chimera research.
Now comes the backlash.
In an emphatic letter published today in Science, 11 researchers argue that NIH should reverse its decision against funding studies in which scientists implant human stem cells into early, nonhuman embryos. By bailing on such experiments, the letter argues, NIH “poses a threat to progress,” strangling research that “has tremendous promise” for developmental biology (understanding how embryos develop) and regenerative medicine (providing cells, tissues, or organs to treat diseases).
NIH’s decision was “sudden, unexpected, and Draconian,” said Dr. Sean Wu of Stanford University School of Medicine — something NIH is likely to hear more of on Friday during a daylong workshop on the science and ethics of part-human chimeras.
‘Geeps’ to AIDS
Research with chimeras (named for the lion-goat-serpent mashup of Greek mythology) is not new. In 1984 scientists melded cells from goat and sheep embryos, producing a “geep.” A human-mouse chimera called SCID-hu (human thymus, liver, or lymph nodes; mouse everything else) has been a workhorse of studies in AIDS, cancer, and other diseases for nearly 30 years. Few objected. Then scientists turned to brain cells.
“There’s been concern that transplanting human brain tissue into mice would make them think like us,” said Wu. But in hundreds of studies doing that, “there’s been nothing like a mouse with human thoughts.”
To which some bioethicists add: “Yet.”
“It’s partly a queasiness thing,” said legal scholar Josephine Johnston of the Hastings Center, a bioethics research institute. “Most people consider the brain to be what gives rise to everything human.”
No one knows how many human cells would make a mouse brain think human thoughts — let alone how you’d measure that. But one glimpse came in 2013, when scientists transplanted human neural stem cells into the brains of mice which had damage in regions responsible for learning and memory. The creatures performed better on standard tests of those skills, including swimming a water maze, researchers at the University of Wisconsin reported.
And scientists got a surprise last year when researchers led by Dr. Steven Goldman of the University of Rochester Medical Center transplanted brain cells from human fetuses into the brains of newborn mice. Although the human cells became glial cells (the brain’s scaffolding) and not neurons, the mice unexpectedly became four times as smart as regular mice, as measured by how well they ran mazes and other tests.
Since 2009 NIH guidelines have prohibited funding experiments in which human stem cells are injected into primate embryos or in which human-animal chimeras breed. (If a mouse producing human sperm mated with a mouse producing human eggs, the result might be human embryo gestating in a mouse womb, though it would presumably quickly be miscarried.) NIH continues to support studies where human cells go into newborn, not embryonic, mice. But its September decision bars experiments in which human stem cells are injected into very early embryos. The younger the embryo, the more likely it is to integrate any human cells.
In a statement to STAT, NIH said its funding moratorium “was not initiated by any particular study” and “to the best of our knowledge, there are no existing grants that would be affected” by it. Instead, NIH had seen “indications” that “scientists are considering exploring the use of human pluripotent cells in early stage animal embryos,” including to grow human tissues or organs.
One such study is the brainchild of developmental biologist Juan Carlos Izpisúa Belmonte of the Salk Institute for Biological Studies in San Diego. In an application for a prestigious “Pioneer Award” from NIH this year, he proposed injecting human pluripotent stem cells into pig embryos whose genes for specific organs had been knocked out. The combination, he said, should allow a human pancreas or liver to grow in the pig, developing along with the embryo. He has a grant from a private foundation for the research, but the NIH award would have let him move more quickly toward the ultimate goal: growing human organs in pigs for transplantation.
Belmonte’s proposal received glowing reviews from the Pioneer panel this year. “At no point did anyone say there is an ethical problem and this shouldn’t go forward,” he said. “So we were a little bit down when we got a call from NIH two weeks later, out of the blue, saying the guidelines are going to change and this experiment can’t be done anymore” with NIH funding.
Belmonte uses very early-stage pig embryos, whose biological signals are capable of turning human stem cells into the “perfect human organs” he’s after. Neither older embryos nor newborns can do that, he said.
The chimera research that NIH proposes to abandon is being done in Europe, Israel, and elsewhere. “It’s a little bit difficult to understand how we would pass this opportunity and this leadership to other countries,” Belmonte said.