Core Concept: Chimeras keep courting controversy

Last autumn, the US National Institutes of Health announced it would not fund any research that entails introducing human pluripotent stem cells into early embryos of another species, including laboratory stalwarts, such as mice, or larger animals like pigs. The agency said it wanted a chance to conduct a formal policy review on these interspecies “chimeras.”

Even as they raise ethical concerns, chimeras like this one—human cells (red) growing inside a blastocyst-stage pig embryo—continue to pique some biomedical researchers’ interest. Image courtesy of Juan Carlos Izpisúa Belmonte.

The backlash from the scientific community was swift. A group of leading stem cell experts wasted no time in condemning the move in Science as “a threat to progress” (1).

“It was a ham-handed approach,” says Christopher Scott, a bioethicist at Baylor College of Medicine in Houston, and one of 11 authors of the Science commentary. “That’s a really terrible way to do science policy because it just creates panic and makes scientists uncertain about their lines of inquiry.”

In August, the NIH reversed course on the ban and proposed allowing funding for studies involving chimeras, with some added provisos. Still, according to Scott, the 10.5-month funding hiatus was long enough to “put at risk some big and important areas of research” in developmental biology, disease modeling, and regenerative medicine.

It’s the latest twist in a decades-long saga for the organismal and cellular contrivances that some consider to be fraught with ethical barriers, and others see as a practical means toward key research insights and disease cures. “There was always controversy,” says Esmail Zanjani, an experimental hematologist at the University of Nevada, who developed the world’s first human–sheep chimeras in the mid-2000s.

Already, since 2009, the NIH has prohibited funding for experiments that put human stem cells into the embryos of our close primate relatives, or studies in which chimeras of any species that have human reproductive cells are allowed to breed. These rules will likely stand with minor tweaks, although the agency is considering an additional layer of scrutiny.

Science, Ethics, Politics

The chimeras of Greek mythology were monstrous creatures possessing parts from multiple animals. In research, the “chimera” label alludes to a variety of approaches. Infectious disease scientists have been making mice with human immune systems for close to 30 years, and cancer biologists have been implanting human tumors into mice for even longer.

The last couple of decades have also seen the development of chimeras in larger farm animals and primates, including pigs with human blood, sheep with part-human livers, and monkeys with human neural tissue. Through it all, there's been opposition.

Twenty years ago, Stuart Newman, a developmental biologist at New York Medical College, and activist Jeremy Rifkin sought to patent the process of creating chimeras from the embryonic cells of humans and animals. If they won the patent, Newman and Rifkin planned to prevent others from commercializing human–animal combinations. If they lost—which they eventually did—it would set legal precedent that these hybrids were not patentable and thereby prevent others from profiting on a technique that they found morally objectionable. “Either way,” says Newman, “there was something to be gained.”

Chimera research would continue to court controversy as it entered the political fray. President Bill Clinton spoke out after the Massachusetts biotechnology company Advanced Cell Technology claimed in 1998 to have created hybrid cow–human embryos. “I am deeply troubled by this news of experiments involving the mingling of human and nonhuman species,” Clinton wrote to the National Bioethics Advisory Commission in a request for an inquiry (2).

President George W. Bush later urged the passage of a bill to ban outright the creation of all human–animal chimeras, something he described in his 2006 State of the Union address as one of “the most egregious abuses of medical research” (3). (Republican Kansas Senator Sam Brownback introduced the “Human Chimera Prohibition Act” in 2005, but it went nowhere.)

Chimeric Menagerie

For the most part, all of the chimeric creations of recent decades have involved injecting human cells into already-born or fetal animals. The reason: the types of human stem cells available to researchers just didn’t comingle or engraft well to early animal embryos.

That started to change last year with the discovery of a new type of human pluripotent stem cell that can efficiently cross the species barrier in mouse embryos that are about a week old (4). According to Juan Carlos Izpisúa Belmonte, the developmental biologist at the Salk Institute for Biological Studies who discovered those cells, his team has since generated even newer types of stem cells that can mix with earlier-stage embryos of livestock.

The latest advances in genome-editing tools, such as CRISPR-Cas9, have also empowered scientists to enrich the human contribution of particular tissues in the resulting creatures. That confluence of cutting-edge technologies has given chimeras “more of a plausible route to widespread clinical use,” says Hank Greely, director of the Center for Law and the Biosciences at Stanford Law School.

Several research teams around the world are now actively trying to grow human hearts, livers, pancreases, and other organs inside pigs and sheep. By knocking out certain genes in the animals’ DNA, scientists can make embryos that are incapable of forming a specific tissue. The researchers can then insert human pluripotent stem cells that should fill in the missing organ. By gestating the embryo in a surrogate sow or ewe, they hope to harvest the organs for human transplantation.

“It’s still very early-stage work: proof-of-principle that this could even be possible,” says Izpisúa Belmonte, one of the pioneers of this line of research (which has been supported to date with non-NIH funds).

Izpisúa Belmonte is quick to point out that his team, which includes collaborators at the University of California, Davis, and in Spain, currently destroys their human–pig chimeras after just 28 days, well short of a pig’s 114-day gestation. And the researchers make sure to check that no human cells are contributing to brain or reproductive tissues. “It is a cautious, thoughtful, and stepwise approach,” Izpisúa Belmonte says.

But critics of the research still worry about the ways that new technologies are blurring the lines between species. “Anything where you mix tissues of different organisms you can call a chimera, but these embryo chimeras are something different,” says Newman. “You’re really making the chimera when the species identity of the organism is being formed.”

Additional Scrutiny

Under a proposal outlined in August, an internal NIH committee will review any and all applications to make human chimeras from early embryos of any mammalian species (up through and including the gastrulation stage when the three fundamental tissue layers start to appear). The panel will also oversee any studies, excluding those with rodents, in which human cells might alter the brain in some way, regardless of when the cells are introduced.

Carrie Wolinetz, associate director for science policy at NIH, says the agency was not responding to any specific project proposal or grant application to work with early embryos or to create large-animal models with human brains. “But we did see investigators saying this was their plan for the future—the kind of ‘next step’—and we wanted to make sure we got out ahead of that.”

Wolinetz rejects the notion that any politics are at play. The NIH’s policy, she says, is simply getting out ahead of the research as the science evolves. “It allowed us to not be disruptive, and then really talk to the scientists and really think about what policy makes sense given where the science is,” Wolinetz says, “and we don’t usually have the luxury to do that.”

Many researchers, however, see the additional regulations put forward by the NIH as superfluous. As first proposed in a 2005 National Academies report (5), institutional oversight committees in the United States now routinely review any research involving human pluripotent stem cells that could be ethically problematic (a review of most in vitro induced pluripotent stem cells work, for example, was not deemed necessary). And there’s nothing in the work of Izpisúa Belmonte or others that is pushing any new ethical boundaries, asserts Greely.

“The concerns are not about growing a human gall bladder or pancreas in a pig. Very few people care about that,” he says. “It’s about brains, it’s about gametes… And I think the existing mechanisms were fine to take care of the concerns that people have.”

For many, chimeras provoke disgust, crossing a sacrosanct ethical line. But decades after these human–animal hybrids first sparked controversy in the research realm, scientists still see the potential for life-saving, tailor-made tissues and organs. “There’s this huge unmet medical need for transplants,” says Scott, “and what might be done in animals [with chimeras] could really help with this critical crisis.”