Updated 21 January 2005: Science magazine has formally retracted this paper because its data were fabricated; see ARF related news story.

In February 2004, researchers at Seoul National University in Korea surprised the world when they reported that they had isolated the first human clone by somatic cell nuclear transfer (see ARF related news story). That technique, commonly called therapeutic cloning, led to the development of a human blastocyst from which Woo Suk Hwang and colleagues were able to extract human embryonic stem cells. The paper was a milestone, but it also raised an interesting question. To get the blastocyst, Hwang and colleagues had taken nuclei from somatic cells, the cumulus cells that surround oocytes in the ovary, and injected them into enucleated oocytes from the same donor. Could the embryo actually have been derived by parthenogenesis, the rare but documented development of an unfertilized egg into an embryo (see ARF related news story on primate parthenogenesis). In today’s Sciencexpress, Hwang, Gerald Schatten, and colleagues in Korea and at the University of Pittsburgh School of Medicine, Pennsylvania, would seem to put such questions to rest. They report that they have repeated the procedure—11 times—using nuclei and oocytes from different donors.

Today’s paper is sure to be another milestone for many reasons. Not only does it confirm that therapeutic cloning is possible in humans, but it also suggests that the procedure is a relatively easy way to develop patient-specific embryonic stem cells. What’s more, the researchers devised a way to grow those embryonic stem cells on human feeder cells; most human embryonic cell lines isolated to date have been grown on mouse feeder cells, making them unsuitable for use in human experiments.

Hwang and colleagues used somatic cell nuclear transfer (SCNT) to plant skin nuclei from patients suffering from injury or disease into enucleated oocytes isolated from healthy female donors. In most cases, the nuclei and oocytes were from unrelated volunteers. The authors successfully fused nuclei in 129 out of 185 attempts. Thirty-one (24 percent) went on to form blastocysts and from these Hwang and colleagues generated 11 embryonic stem cell lines. The nuclei donors (10) ranged from 2 to 56 years old, and were suffering from spinal cord injury, juvenile diabetes, or congenital hypogamma-globulinemia, an immunodeficiency disorder.

The stem cells had the chromosomal karyotype of the donor (male for male donors, female for female) and the authors used DNA fingerprinting to confirm that the cell lines were derived from the correct nuclei donor. The stem cells expressed markers common to pluripotent stem cells and each was capable of generating into cells of all three germ layers: ectoderm, mesoderm, and endoderm.

As the authors write, “these cells are still likely to be defective and cannot be used directly in cell transplantation to patients.” But they can be used to study disease progression and assist in drug development. The study also opens up the possibility of generating patient-specific stem cells to generate tissue for repair in the case of a traumatic injury, such as spinal cord damage.

“This is a landmark paper that establishes the feasibility of generating embryonic stem cell lines from individuals with devastating diseases, including Alzheimer’s,” said David Scadden, professor of medicine at Harvard Medical School and co-director of the Harvard Stem Cell Institute. “The impact of this on developing therapies is still unknown, but at least now we can envision generating neurons in the laboratory that are genetically identical to those that are defective in people with the disease. That should mean we can study patients in great detail, evaluating them for why and how they are susceptible to disease, and whether specific modifications can alter their susceptibility to disease and screen compounds in hopes that some will become drugs to combat the disease. The much improved efficiency of successful nuclear transfer demonstrated by this paper also greatly reduces concerns about whether this process will ever be useful scientifically and mitigates concerns about needing so many donors that exploitation might become prevalent,” he added.

Federal funding cannot be used to conduct such research in the United States under current administration guidelines, prompting many US research institutions and states to seek private funding for stem cell research. But stem cell technology is shrouded in broader ethical debates, not only about whether therapeutic cloning should be legal or illegal, but also about how such research should be conducted. For example, ovarian hyperstimulation, which is necessary to harvest the oocytes needed for these experiments, is not without risk and can, in rare cases, leave donors infertile. In another article in today’s Sciencexpress, David Magnus and Mildred Cho, of the Stanford Center for Biomedical Ethics address this and other ethical issues that are sure to be increasingly relevant to all members of the research community now that the technical barriers to therapeutic cloning are falling.—Tom Fagan

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  1. See 23 January 2006 Update to Rao's comment on stem cell research by this research group. Designer Cells
    The use of stem cells for therapy faces a number of hurdles including the issues of immune suppression. The body has a surveillance program to differentiate self from non-self that recognizes transplanted cells as foreign and rejects them. Clinicians and scientists have succeeded in transplanting organs or performing bone marrow transplants by matching donor tissue to the recipient and thus bypassing or suppressing the immune response. Such strategies have been successful as evidenced by the large number of organ and bone marrow transplants performed each year, although it often necessitates lifetime immunosuppressive therapy.

    A second hurdle that hinders the wider application of cell therapy is the lack of an abundant and reliable source of cells. Both adult stem cell (SC) and embryonic stem cell (ESC) proponents have argued that stem cells can solve this source issue by providing a reliable, potentially unlimited source of cells. Adult SC proponents have suggested that using stem cells from adults may be better, in part, because personalized stem cells could be utilized bypassing the immune issues altogether. ESC proponents had argued that if a sufficient number of lines were available, one could match, much as we do with blood transfusion, organ banks, or cord blood, or generate personalized ESC lines by SCNT using techniques that are currently available (though not applicable for federal funding in the US and banned in others).

    The group in Korea led by Woo Suk-Hwang showed that this is indeed possible. In an elegant series of experiments, they derived a series of personalized ESC lines that were pluripotent, karyotypically normal, and matched the DNA profile of the donor. Equally important, they derived these lines on human feeders that were derived from the same patients whose donor nuclei were used to develop these lines, limiting exposure to xenoproducts. Though no efficiency numbers were reported, these must be reasonably good for this group to have derived the number of cell lines they did and suggests that this could indeed become relatively routine.

    The blastocysts used in this experiment were not matched in any way to the donors, and it is reasonable to assume that mitochondria were not donor-derived, and as such, these cells contain genetic information from more than one individual. It will be important to determine if cells with mismatched mitochondria behave differently from other cells in transplant procedures, and this group is uniquely placed in testing this important biological question.

    While no doubt their results are of importance for the transplant field, I believe it is also an unprecedented advance for basic biologists. We will be able to study for the first time issues such as aging and its reversal. By allowing one to examine the process of epigenetic remodeling in a dish (over a short time period), one can begin to understand factors that regulate reactivation and suppression of genes in different tissues and organs, and by allowing homologous recombination in ESC that are patient-specific, one can begin to probe pathways that are disease-specific and evaluate methods to cure specific genetic defects. By allowing one to create patient-specific cell lines, one can imagine developing/identifying specific drugs that are ideal for treatment. It is heartening to see that this group identified such fundamental questions as an important reason why such research needs to progress.

    It is these fundamental issues that are of importance to the Alzheimer community (at least initially), and I fully expect that one could and will develop a battery of ESC lines from people who have an unambiguous diagnosis of Alzheimer's to begin to evaluate pathways and mechanisms that lead to this progressive disease.

    It is important to note that this research is not illegal in the United States (although efforts are underway to make it so). It is not, however, eligible for federal funding, and one cannot use the infrastructure of tools and techniques developed over the past 20 years in the United States with the aid of the NIH/DOD/NSF funding to study the newly developed lines. This inability to use the cutting-edge strategies on SNP mapping, whole genome analysis, methylation, and epigenetic analysis pioneered in the States will no doubt slow down efforts in this country. It is perhaps coincidental that these results appeared just as the Senate and Congress begin debating expanding the availability of cell lines. One can hope that the US Government will take into account all recent advances to determine what would be the best policy for the NIH to follow.

    View all comments by Mahendra Rao
  2. I had reviewed the potential of both this paper and this group's 2004 Science paper to affect how stem cell science was done. It reflected in my mind a possible solution to the issues of immune rejection and efficiency that had limited the potential use of these cells. The reported results suggested that both problems could be solved and, indeed, had been solved.

    It was with great disappointment that I learned that the published data that we relied on was almost totally fabricated. These papers have now been withdrawn, and while the potential of these solutions remains, clearly we are some way off from having reduced it to practice.

    I am saddened that the field had to suffer this agony of embarrassment, but am heartened by the courage of the young investigators who pushed for an investigation, and by the robustness of the investigative process that helped uncover the misdeeds.

    View all comments by Mahendra Rao

References

News Citations

  1. Science Retracts Stem Cell Papers, Fallout Continues
  2. Not Quite a Dolly, But It's a Human Clone
  3. Primate Stem Cells by Parthenogenesis

Further Reading

No Available Further Reading

Primary Papers

  1. . Ethics. Issues in oocyte donation for stem cell research. Science. 2005 Jun 17;308(5729):1747-8. PubMed.
  2. . Patient-specific embryonic stem cells derived from human SCNT blastocysts. Science. 2005 Jun 17;308(5729):1777-83. PubMed.