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Chimeras keep courting controversy Elie Dolgin, Science Writer

Last autumn, the US National Institutes of Health announced it would not fund any research that entails introducing human pluripotent stem cells into early of another species, including laboratory stal- warts, 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.” The backlash from the scientific community was swift. A group of leading stem 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 commen- tary. “That’s a really terrible way to do science policy because it just creates panic and makes scientists uncer- — ” Even as they raise ethical concerns, chimeras like this one tain about their lines of inquiry. human cells (red) growing inside a -stage pig In August, the NIH reversed course on the ban and —continue to pique some biomedical researchers’ proposed allowing funding for studies involving chi- interest. Image courtesy of Juan Carlos Izpisua ´ Belmonte. meras, with some added provisos. Still, according to Scott, the 10.5-month funding hiatus was long enough The last couple of decades have also seen the “ to put at risk some big and important areas of re- development of chimeras in larger farm animals and ” search in developmental biology, disease modeling, primates, including pigs with human blood, with and regenerative medicine. part-human , and monkeys with human neural ’ It s the latest twist in a decades-long saga for the tissue. Through it all, there’s been opposition. organismal and cellular contrivances that some con- Twenty years ago, , a developmental sider to be fraught with ethical barriers, and others see biologist at New York Medical College, and activist as a practical means toward key research insights and Jeremy Rifkin sought to patent the process of creating “ ” disease cures. There was always controversy, says chimeras from the embryonic cells of humans and Esmail Zanjani, an experimental hematologist at the animals. If they won the patent, Newman and Rifkin ’ University of Nevada, who developed the world s first planned to prevent others from commercializing hu- – human sheep chimeras in the mid-2000s. man–animal combinations. If they lost—which they Already, since 2009, the NIH has prohibited fund- eventually did—it would set legal precedent that these ing for experiments that put human stem cells into the hybrids were not patentable and thereby prevent embryos of our close primate relatives, or studies in which others from profiting on a technique that they found chimeras of any species that have human reproductive morally objectionable. “Either way,” says Newman, cells are allowed to breed. These rules will likely stand “there was something to be gained.” with minor tweaks, although the agency is considering an research would continue to court contro- additional layer of scrutiny. versy as it entered the political fray. President Bill ClintonspokeoutaftertheMassachusetts biotechnology Science, Ethics, Politics company Advanced Cell Technology claimed in 1998 to The chimeras of Greek mythology were monstrous have created cow–human embryos. “I am deeply creatures possessing parts from multiple animals. In troubled by this news of experiments involving the research, the “chimera” label alludes to a variety of mingling of human and nonhuman species,” Clinton approaches. Infectious disease scientists have been wrote to the National Advisory Commission in making mice with human immune systems for close to a request for an inquiry (2). 30 years, and cancer biologists have been implanting President George W. Bush later urged the passage of human tumors into mice for even longer. a bill to ban outright the creation of all human–animal

11984–11985 | PNAS | October 25, 2016 | vol. 113 | no. 43 www.pnas.org/cgi/doi/10.1073/pnas.1615787113 Downloaded by guest on September 24, 2021 chimeras, something he described in his 2006 State species. “Anything where you mix tissues of different of the Union address as one of “the most egregious you can call a chimera, but these embryo abuses of medical research” (3). (Republican Kansas chimeras are something different,” says Newman. Senator introduced the “Human “You’re really making the chimera when the species Chimera Prohibition Act” in 2005, but it went identity of the is being formed.” nowhere.) Additional Scrutiny Chimeric Menagerie Under a proposal outlined in August, an internal NIH For the most part, all of the chimeric creations of re- committee will review any and all applications to make cent decades have involved injecting human cells into human chimeras from early embryos of any mammalian already-born or fetal animals. The reason: the types of species (up through and including the gastrulation stage human stem cells available to researchers just didn’t when the three fundamental tissue layers start to appear). comingle or engraft well to early animal embryos. The panel will also oversee any studies, excluding those That started to change last year with the discovery with rodents, in which human cells might alter the brain of a new type of human pluripotent that can in some way, regardless of when the cells are introduced. efficiently cross the species barrier in mouse embryos Carrie Wolinetz, associate director for science policy that are about a week old (4). According to Juan at NIH, says the agency was not responding to any Carlos Izpis ´uaBelmonte, the developmental biologist specific project proposal or grant application to work at the Salk Institute for Biological Studies who dis- with early embryos or to create large-animal models with covered those cells, his team has since generated human brains. “But we did see investigators saying this even newer types of stem cells that can mix with ear- was their plan for the future—the kind of ‘next step’— lier-stage embryos of livestock. andwewantedtomakesurewegotoutaheadofthat.” The latest advances in -editing tools, such Wolinetz rejects the notion that any politics are at as CRISPR-, have also empowered scientists to play. The NIH’s policy, she says, is simply getting enrich the human contribution of particular tissues in out ahead of the research as the science evolves. “It the resulting creatures. That confluence of cutting- allowed us to not be disruptive, and then really talk to edge technologies has given chimeras “more of a the scientists and really think about what policy makes plausible route to widespread clinical use,” says Hank sense given where the science is,” Wolinetz says, “and Greely, director of the Center for Law and the Bio- we don’t usually have the luxury to do that.” sciences at Stanford Law School. Many researchers, however, see the additional regu- Several research teams around the world are now lations put forward by the NIH as superfluous. As actively trying to grow human hearts, livers, pancreases, first proposed in a 2005 National Academies report and other organs inside pigs and sheep. By knocking (5), institutional oversight committees in the United out certain genes in the animals’ DNA, scientists can States now routinely review any research involving make embryos that are incapable of forming a specific human pluripotent stem cells that could be ethically tissue. The researchers can then insert human pluripo- problematic (a review of most in vitro induced plurip- tent stem cells that should fill in the missing . By otent stem cells work, for example, was not deemed gestating the embryo in a surrogate sow or ewe, they necessary). And there’s nothing in the work of Izpisua ´ hope to harvest the organs for human transplantation. Belmonte or others that is pushing any new ethical “It’s still very early-stage work: proof-of-principle boundaries, asserts Greely. that this could even be possible,” says Izpisua ´ Belmonte, “The concerns are not about growing a human gall one of the pioneers of this line of research (which has bladder or pancreas in a pig. Very few people care been supported to date with non-NIH funds). about that,” he says. “It’s about brains, it’s about Izpis ´ua Belmonte is quick to point out that his gametes...And I think the existing mechanisms were team, which includes collaborators at the University of fine to take care of the concerns that people have.” California, Davis, and in Spain, currently destroys their For many, chimeras provoke disgust, crossing a human–pig chimeras after just 28 days, well short of a sacrosanct ethical line. But decades after these hu- pig’s 114-day gestation. And the researchers make man–animal hybrids first sparked controversy in the sure to check that no human cells are contributing to research realm, scientists still see the potential for life- brain or reproductive tissues. “It is a cautious, thoughtful, saving, tailor-made tissues and organs. “There’s this and stepwise approach,” Izpisua ´ Belmonte says. huge unmet medical need for transplants,” says Scott, But critics of the research still worry about the ways “and what might be done in animals [with chimeras] that new technologies are blurring the lines between could really help with this critical crisis.”

1 Sharma A, et al. (2015) Lift NIH restrictions on chimera research. Science 350(6261):640. 2 Clinton B (1998) President Clinton’s Request Re: Embryonic Stem Cells. Available at https://bioethicsarchive.georgetown.edu/nbac/ transcripts/nov98/day1_stemcell.htm. Accessed September 29, 2016. 3 Bush GW (2006) State of the Union Address. Available at https://georgewbush-whitehouse.archives.gov/stateoftheunion/2006/. Accessed Spetember 29, 2016. 4 Wu J, et al. (2015) An alternative pluripotent state confers interspecies chimaeric competency. Nature 521(7552):316–321. 5 Committee on Guidelines for Human Research, et al. (2005) Guidelines for Human Embryonic Stem Cell Research (The National Academies Press, Washington, DC).

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