. Patient-specific embryonic stem cells derived from human SCNT blastocysts. Science. 2005 Jun 17;308(5729):1777-83. PubMed.

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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.

    image

    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.

  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.

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News

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