It was standing room only in the auditorium in the Anlyan Center on April 3, 2003, when actor Christopher Reeve came to speak about stem cells. Famous for playing Superman on the screen, he lost the use of all four limbs after a horseback-riding accident in 1995, and had become an activist supporting human embryonic stem cell (ESC) research. In his talk at Yale, Reeve decried barriers to the ESC research that he believed had the potential to cure his condition.

“It’s morally irresponsible not to allow research to go ahead on all these fronts, with very strict ethical guidelines,” said Reeve. He would not live to see this area of research bear fruit. In October 2004, he died of cardiac arrest.

Not everyone agreed with Reeve, however. Ethical, political, and religious concerns have plagued stem cell research since at least 1998, when researchers in Wisconsin derived the first human ESC line. This area of science may not only involve the destruction of human embryos to harvest or test stem cells, but it also raises concerns about such issues as human-animal chimeras, cloning, and donor payment or consent. Yet stem cells hold promise for treating patients with amyotrophic lateral sclerosis, diabetes, spinal injuries like Reeve’s, or other devastating conditions. The result: years of passionate debate that has reached no consensus, leading to a patchwork ethical and legal status for the cells. In the United States, state stem cell laws range from outright bans to encouragement and funding. Federal law permits the research, yet does not fund experiments that involve embryo creation or destruction. Promising though it is, human embryonic stem cell research in this country has proceeded in fits and starts.

Protecting the embryo & egg donor

The year that Reeve spoke, stem cell research in the United States was sputtering. Two years earlier, President George W. Bush had announced that due to concerns over embryo destruction, federal funds could fund research only on existing lines.

Though the term stem cell includes ESCs as well as other types of stem cells, including adult stem cells found in fully formed organs, concerns about embryo destruction have dominated the ethical conversation since stem cells first appeared in labs, recapitulating arguments about the personhood and moral status of the embryo. Is the common practice of retrieving stem cells from an excess fertility clinic embryo justifiable, though that embryo be destroyed in the process? Some say yes, if the knowledge gained could save lives.

Others, like Daniel Sulmasy, M.D., Ph.D., a University of Chicago ethicist and former Franciscan friar who served on New York State’s stem cell ethics board from 2007 to 2009, say human rights begin at conception. That view makes embryonic destruction unethical and proposes a moral distinction between letting embryos die naturally and destroying them in the lab.

The creation of new embryos—a practice that made headlines in 2014 when Oregon researchers announced that they had created patient-specific ESCs via “therapeutic cloning” with human eggs—also troubles Sulmasy. Anyone who believes human life merits respect from conception to natural death, he says, should oppose the creation of new members of humanity just to use those lives. In this view, he says, “No good end could justify that means.”

Since the 1973 Roe v. Wade decision that legalized abortion, such embryo-centered ideas have influenced federal policy. A two-year moratorium on funding embryo research followed that Supreme Court case; even after the moratorium was lifted, no federal funds were forthcoming. In 1979, an Ethics Advisory Board, born of the newly established congressional National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, approved experimentation on embryos up to 14 days postconception, when the primitive nervous system arises. But despite that recommendation, Congress soon blocked federal funding for such research. The 1995 Dickey-Wicker Amendment banned the use of federal funds for creating or destroying human embryos, a ban that remains in effect today. In August 2000, the Clinton administration published guidelines that would have allowed scientists to use federal funds to buy cells extracted from unused frozen embryos. A year later, before funding was dispersed, President Bush overturned these guidelines with his landmark announcement. It pleased no one.

“Neither side liked Bush’s attempt at a compromise solution,” says Stephen Latham, J.D., Ph.D., director of Yale’s Interdisciplinary Center for Bioethics, who formerly served on Connecticut’s State Stem Cell Research Advisory Committee and who is now a member of Yale’s Embryonic Stem Cell Research Oversight Committtee (ESCRO). Those opposed to embryonic destruction thought the government’s hands were unclean, Latham recalls. Those who supported ESC research pointed out that the existing stem cell lines were of poor quality. Advocates and patients like Reeve seethed, and scientists, urged on by the president’s Council on Bioethics, changed gears and sought non-destructive ways to obtain useful stem cells.

Although the federal government would provide no funding for the research, it did not ban it. Some states, like Arkansas, Indiana, and the Dakotas, did ban the research, while others, like California and Connecticut, established funding and advisory committees. “We had this very sharp debate, but nobody ever said ‘Let’s make this illegal,’ ” Latham says.

Money figures, too, into donor ethics. Sulmasy and others worry that stem cell research or therapy could lead to coercive payments to economically disadvantaged women for their eggs—a concern that becomes more relevant in the wake of the 2014 therapeutic cloning achievement, which could lead to any number of patient-specific ESC therapies. The National Academies of Science disapprove of paying egg donors, though the ethics board in New York State decided (after Sulmasy left) to approve such payment from public research funds.

Stem cells without embryos

In 2007, there came a long-awaited game-changer: stem cells that didn’t require embryo destruction. Scientists in the United States and Japan had walked human adult skin cells back into an embryo-like state, creating induced pluripotent stem cells (iPS cells), a momentous discovery that changed the field. Nine years later, Latham says, researchers are doing more work with iPS cells, which are cheaper and easier to procure than ESCs.

Alas, iPS cells didn’t do away with the ethical issues. For instance, iPS experiments may make use of ESCs as gold-standard comparisons, which means embryo destruction.

Another line of research attempts to derive sperm and eggs from iPS cells. In 2012, a Japanese group achieved this science fiction-like result in mice, announcing that it had created functional sperm from mouse skin cells; the new sperm successfully fertilized an egg, which in turn gave rise to healthy offspring. Needless to say, the prospect of doing such a thing in humans is unsettling.

Then too, iPS researchers soon faced new consent issues. A major regulatory shift came in 2009, when President Barack Obama revoked the Bush ban by executive order, reintroducing federal funding for the study of stem cells derived from excess IVF embryos (though not for their derivation). Stem cell research advocates praised the step. The Obama order, however, included strict criteria relating to informed consent. Were biological parents of donated embryos fully aware of what might become of their donation?

“Some of the lines that Bush’s NIH was willing to fund turned out not to have good consent behind them,” Latham says. New guidelines eventually banned funding for research on older cell lines derived from lab-created embryos, admitting only those derived from fertility clinic extras.

Early iPS cells derived from commercially available cell lines, too, are likely to have been done without donor consent—as with Henrietta Lacks, whose famously immortal cervical cancer cells became a cornerstone of modern biomedical research, though she never consented to their dispersal before her death in 1951.

“There are ethical concerns about derivation of iPS cells,” says Sandra Alfano, Pharm.D., a co-chair of the Yale ESCRO since its founding in 2006. “This idea of review of provenance and whether there was adequate informed consent, that’s probably the biggest part of the job for ESCRO currently.”

Maurice J. Mahoney, M.D., J.D., the other co-chair, adds, “We now insist that people be asked, ‘Is it all right that a cell line that came from your body ends up around the world, in many laboratories, and may be sold, may end up in animal species, which means that animal research is going on with cells from your body?’ … We push those issues now.”

These days, according to Latham, the ESCRO gives extra attention mainly to research proposals that involve mixing human ESCs with animal embryos in such a way that the animal’s nervous tissue or its sex cells could be affected. This addresses unlikely but nonetheless prevalent public concerns that a mouse could be neurologically humanized in a way that could increase its suffering, or that one with altered gametes might escape, reproduce, and cause an unpredictable environmental effect.

No escaping the ethical questions

Yale’s ESCRO observes its 10th anniversary this June, well into the era of stem cell clinical trials. Dozens are now underway, thorny issues notwithstanding. For any discussion of ethical restrictions on stem cell research must also take into account the human cost of such restrictions—something Reeve made clear in his talk at Yale. Millions could die, he said, while scientists look for a way to avoid the ESC moral quandary.

“To say that we should just work on adult stem cells because we’ll get there [eventually], that’s not fair to the people who are suffering from diseases like ALS,” Reeve said. “We’re going to lose valuable time.” /yale medicine