South Korean team makes patient-specific stem cells

American researchers talk ethics

Last year, South Korean researcherWoo Suk Hwang and colleagues at Seoul National University stunned the world with news first published in Science on-line that they had developed stem cells from a cloned human embryo, using somatic-cell nuclear transfer.

In those studies, the scientists created 30 cloned embryos, using 242 eggs from 16 healthy women. The scientists were able to actually derive an embryonic stem cell line from only one of those 30 embryos, but proof of principle nevertheless was achieved. The news made Science’s top 10 list of breakthroughs for 2004.

In news published in May, again in Science on-line, Hwang might have assured his place on that list for 2005, as well. He and colleagues at Seoul National University, MizMedi Hospital, Hanna Women’s Clinic, and Hanyang University (all located in Seoul), and the University of Pittsburgh School of Medicine, report that with improvement in their techniques, they have gone from proof of principle to deriving stem cell lines with what may be near-optimum efficiency; they now can consistently get a stem cell line in fewer than 20 tries. Furthermore, while last year’s experiments involved using both skin cells and eggs from the same donor, here, skin cells from a patient were fused with an egg from a healthy volunteer donor.

Gerald Schatten, PhD, professor of obstetrics, gynecology and reproductive sciences and cell biology and physiology at University of Pittsburgh School of Medicine and senior author of the paper, told reporters at a press conference that the technology "is a way of deriving cells that grow in two dimensions and that may be nature’s very best immune-matched repair kit." He added that Hwang’s group is doing "some of the most important scientific work of our generation."

Hwang himself attributed the increased efficiency to several methodological improvements; among other things, improved micromanipulation and the use of human feeder cells, which originated with the patients themselves, rather than animal-based feeder cell lines.

The researchers generated disease-bearing stem cell lines from three separate populations: Nine of the 11 stem cell lines generated came from spinal cord injury patients, and one each from a juvenile diabetes patient and from a patient with a variant of so-called "bubble boy disease," a genetic immune deficiency. When asked about the specific patient groups they chose, Schatten said, "Dr. Hwang has a deep professional and personal commitment" to the study of spinal cord injuries, and that while the diseases differ with respect to whether they are genetic or environmental in origin, all three of them theoretically are curable by the transplantation of just one cell type (though in the case of genetic diseases, the genetic defect would first need to be treated for such transplantation to do any good). He also noted that each of the three cell types comes from one of the three basic body lineages. Beta-islet cells are derived from endoderm, blood-forming stem cells from mesoderm, and motor neurons from ectoderm.

The stem cells immunologically matched the donors of the skin cells, and spontaneously differentiated into major cell types. But transplantation is just one of the uses for the lines, and probably the one that is furthest in the future. Schatten stressed that spontaneous differentiation is a very different animal from directed differentiation — i.e., getting the specific cell type you want. To him, the major near-term implication is that "it is now possible to make disease-bearing stem cells to analyze the root causes of diseases."

Could it have happened in U.S.?

In the United States, the regulatory climate for stem cells has changed significantly since Hwang and his group made their February 2004 announcement. At the time, Advanced Cell Technology CEO Robert Lanza told BioWorld Today that there is "virtually no funding [in the U.S.]" for ESC work.

In the meantime, California has passed a $3 billion funding initiative for stem cell research, Proposition 71, and a number of other states appear ready to follow suit. The Stem Cell Research Enhancement Act also is being considered on Capitol Hill; it would provide federal funding that would circumvent President Bush’s restrictions on such grants.

Indeed, when asked at the press briefing whether the research could have been conducted in the United States, David Magnus, a bioethicist at Stanford University and co-author of a policy forum that accompanies the research paper, answered, "It’s a moving target; and in the U.S., it also depends on which state you’re in. My guess is that if this had happened in California, there would have been a mandatory IRB review and there would have been some tweaks."

Ethical concerns also were addressed in an accompanying editorial by Magnus and his colleague and co-author Mildred Cho, also a bioethicist at Stanford University. While the lay public’s greatest concern probably is whether the technology represents another step toward the feasibility of cloned embryos, neither the scientists nor the ethicists seemed to feel that that is the most pressing concern.

Both Hwang and Schatten strongly reiterated their opposition to reproductive cloning, which Hwang called "unsafe and unethical." He added, "I also feel that it may be biologically impossible."

Schatten elaborated that the methods used in the paper were derived from pig cloning and "ethics aside, it is completely unfeasible ever to have that amount of oocytes to work with" in humans.

Both Hwang and Schatten stressed that they work with "nuclear transfer constructs" rather than embryos. Magnus echoed the scientists’ opinion and added that the new methods are actually preferable from an ethical standpoint to deriving stem cells from IVF eggs: "It’s impossible, given what was done to these cells and where the science is, that they could have developed into an embryo. So even for the people who believe that potentiality is the key to personhood, these things, whatever they are, are not people. That’s why I believe somatic-cell nuclear transfer is a better way to derive these cells than IVF eggs."

For the experts, both scientists and ethicists, the bigger ethical problem lies in informed consent by donors, and assuring that donors understand both the risks and the remoteness of benefits, which possibly still are decades away. Magnus also said that "the risks to oocyte donors are not well captured by the current frameworks of informed consent," adding that they "are not research subjects, nor are they patients." He likened them most closely to live organ donors.

On the side of the somatic-cell donors, the bigger issue is making sure that donors understand that they personally should not expect to benefit from the discoveries made with their donated cells, since practical applications are most likely still decades away. "It is important that [donors] not be misled about how close we are to success," Cho said.

Both Magnus and Cho pointed out that unrealistic donor hopes are not unique to stem cell research, and that the guidelines for informed consent forms contribute to the problem: The ethical guidelines of the National Academy of Sciences require that "all future uses" be mentioned in an informed consent form. And therein lies the rub, Magnus said: "Putting in all future uses without making it sound like we are very close to therapies is very difficult."