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Induced Pluripotent Stem Cells: Not Yet the Perfect Alternative

They don’t require embryos, yet stem cells derived from adult human cells still face confront ethical and scientific hurdles.

July, 2010- Three years ago, research teams in the United States and Japan reported that they had reprogrammed adult human cells to form pluripotent stem cells—cells capable of differentiating into all cell types. Scientists were elated.

No longer would stem cell researchers need to depend on embryonic tissue; they could now bypass the ethical debate hindering such studies and begin racing ahead to develop stem cell therapies for Alzheimer’s disease, spinal cord injuries, heart disease and a host of other illnesses.

But it turns out that induced pluripotent stem cells (iPS cells) aren’t entirely problem-free. Researchers working with the cells still must countenance certain ethical concerns, and they may also face newly discovered scientific hurdles.

At Hopkins, such issues have prompted a change in the committee that was formerly charged with overseeing human embryonic stem cell research. In March, Hopkins expanded the purview of that committee to include additional types of human pluripotent stem cells, including iPS cells.

The newly named Institutional Stem Cell Research Oversight Committee (ISCRO), whose members include scientists, ethicists, legal scholars, community members and experts in science and transplantation, reviews the ethics of proposed research studies involving these cells and determines whether the proposals meet government regulations and Hopkins policies. One of ISCRO’s first tasks will be to review grants awarded to 31 Hopkins scientists by the Maryland Stem Cell Research Fund. Several of the grants involve iPS cells.

Old Ethical Concerns
Some of the ethical issues aren’t unique to iPS cells. They applied to ES cells, as well, says Debra Matthews, an ISCRO Committee member and bioethicist who runs the Stem Cell Policy and Ethics program at the Johns Hopkins Berman Institute of Bioethics. “But while the debate focused on the embryo problem, these other issues did not receive much attention.”

At the extreme end of such concerns are scenarios evocative of science fiction: Although iPS cells don’t come from embryos, a scientist could conceivably induce the infinitely versatile cells to form sperm and eggs. Going a step further, the scientist might then even cross the gametes in a laboratory dish to study aspects of human genetics. Another what-if scenario that raises ethical questions is the possibility of introducing human iPS cells into an embryo from a mouse or other animal, giving rise to a human-mouse chimera.

“None of this can happen yet,” notes Mathews. “But the possibilities will be very socially contentious. So now is when we need to talk about how to be proactive. It’s good to have the debate now.” There really hasn’t been a significant discourse on these issues, she says.

Furthermore, it’s not likely that scientists would attempt some of these scenarios, says stem cell biologist Elias Zambidis, an ISCRO Committee member. “These ethical dilemmas involving iPS cells are real but theoretical.” Using stem cell technology to clone a person or generate a chimeric person, he says, “is ethically far-out. It would get dinged at the institutional review stage.”

Indeed, Hopkins policies prohibit scientists from introducing pluripotent stem cells into human or nonhuman primate blastocysts, or breeding animals that have had human pluripotent stem cells introduced into their germ cells. These policies parallel those of the National Institutes of Health and National Academy of Sciences.

None of the Hopkins research proposals receiving Maryland Stem Cell funding appear to broach such restrictions. The studies cover a broad range of science, such as using iPS cells from patients as models for studying the genetics and biology of their diseases. In one proposal, neuroscientist Min Li plans to use iPS cells derived from patients who are genetically prone to sudden cardiac arrest to test compounds that may correct the genetic defect.

Reality Check
Neuroscientist Vassilis Koliatsos says that the ethical debate should also separate the “Hollywood rendition” from the reality of what is taking place in the trenches of science.

Several years ago, Koliatsos and colleagues worked on transgenic rats and mice with symptoms of amyotrophic lateral sclerosis, the debilitating nerve disease that impairs muscle strength and coordination. The scientists injected human neural stem cells into the animals’ spinal cords and demonstrated that the injections improved the animals’ movements. Clinical trials based on their research recently began.

Any stem cell therapy for a neurological disease must first be tested in an animal model, says Koliatsos. But unlike the futuristic scenarios that have been imagined, the procedure that he used didn’t give the rats or mice any uniquely human qualities. “You create very circumscribed neural circuits,” says Koliatsos. “Humans are endowed with levels of complexity not present when you put human cells into a rat.”        

But he and several others in the stem cell field say that they do have ethical concerns specific to the use of iPS cells. One involves the issue of informed consent. When ES cells were the focus of research and debate, donors had to complete an extensive informed consent process.

IPS cells can be generated from any adult cell—taken from a blood sample or skin biopsy, for instance. Those cells might then be used for a variety of research projects or as therapies for patients with a broad range of illnesses. In the future, they might even be used for therapies not even yet imagined. But ethically, the patient donor would have to consent to such uses.
Another issue is genetic privacy. The iPS cell would contain the genetic information of the donor. “So we can’t assume that the donor will remain anonymous,” says Mathews. The discourse on iPS cells should include discussion about protecting donors’ privacy.

ISCRO members say those are the sorts of issues that the committee will discuss in deciding whether proposed research is ethically acceptable.

Scientific Hurdles
Ethics aside, of more immediate concern may be the question of whether iPS cells truly are equivalent to ES cells. Zambidis points out that a series of journal articles in the past year have raised the possibility of some significant differences.

For example, stem cell biologist Robert Lanza, of the biotechnology company Advanced Cell Technology, and his colleagues compared differentiated cells derived from a series of iPS cell lines and ES cell lines. While both classes of cells differentiated—to form blood cells, vascular cells or retinal cells—the iPS cells did so at a significantly lower rate and had higher rates of cell death, results they reported in the April 2010 Stem Cells.

Another study raises questions about whether iPS cells can serve as tools for modeling disease. As they reported in the May 7 issue of Cell Stem Cell, researchers at the Dana Farber Cancer Institute and Hebrew University compared ES cells and iPS cells that carried the mutation for the mental impairment disorder fragile X syndrome. They found that while the ES cells expressed the mutation, the iPS cells didn’t.

Some scientists are hoping that such problems arise from the retroviruses that are used to generate iPS cells. Several teams of scientists are now exploring virus-free modes of producing the cells.

Zambidis, for one, is hopeful that science will overcome this technical glitch. He predicts a “tidal wave of papers” exploring such strategies in coming months.

 by Melissa Hendricks

For further information about the ISCRO Committee, visit: http://www.hopkinsmedicine.org/Research/iscro/.

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