Clinical Implications of Basic Research

Progress in Human Somatic-Cell Nuclear Transfer

Anthony C.F. Perry, Ph.D.

N Engl J Med 2005; 353:87-88July 7, 2005

Article

In June 2005, Hwang and coworkers at Seoul National University1 reported that pluripotent human embryonic stem cells can efficiently be generated by nuclear transfer from a wide variety of patients (Figure 1Figure 1Derivation of Patient-Specific Therapeutic Cells through Nuclear Transfer.). The authors transferred somatic-cell nuclei from eight male and three female donors, 2 to 56 years of age, into oocytes whose nuclear genomes had been removed. To underscore the clinical relevance of their work, they used donors who had conditions that are potentially amenable to stem-cell therapy: congenital hypogammaglobulinemia, spinal cord injury, and juvenile diabetes.

Cells containing nuclei from nine donors developed to the blastocyst stage, whereas cells containing nuclei from the other two donors failed to do so. Blastocysts from each of the nine patients yielded 1 or 2 embryonic stem cell lines (referred to here by the generic term “nuclear-transfer embryonic stem cells” to denote that they were derived from nuclear-transfer constructs), for a total of 11 embryonic stem cell lines from 31 blastocysts. On average, one cell line was established per 16.8 oocytes, an efficiency of 6.0 percent. This reflects an increase in efficiency by a factor of more than 14 as compared with the report last year by the same group,2 in which a single human nuclear-transfer embryonic stem cell line was derived from 242 oocytes. This improvement is attributed in part to the use of oocytes from younger donors in the present study.

With this improved efficiency, the line has been crossed between viewing the derivation of human nuclear-transfer embryonic stem cells as an experimental system and viewing it as a viable clinical proposition. Scientifically speaking, this is a pedestrian crossing. The derivation of embryonic stem cells from the inner cell mass of blastocyst-stage embryos was first achieved in mice nearly 25 years ago, in primates 10 years ago, and in humans in 1998. Elements of this work showed that in general, it was possible to maintain embryonic stem cells in culture for prolonged periods in an undifferentiated state, although this has yet to be shown for human nuclear-transfer embryonic stem cells. Like the human nuclear-transfer embryonic stem cells described by Hwang et al., undifferentiated embryonic stem cells from a variety of species are pluripotent, in that they can give rise to each of the three founding germ layers of an early embryo.

The next step in assessing the therapeutic potential of human nuclear-transfer embryonic stem cells will be to derive pure populations of clinically relevant cells from them in vitro. It is now possible to induce mouse embryonic stem cells to differentiate into many types of cells (though fewer than 10 percent of the estimated total types of cells), including pancreatic beta cells, cardiomyocytes, and specific subgroups of neurons. There is still only one reported study in which such differentiation has been shown to produce cells that have not been genetically altered and yet are able to correct a deficit after being transplanted — in this case, midbrain dopaminergic neurons in a mouse model of Parkinson's disease.3 Prescriptive differentiation into cells with neuronal specifications has also been shown for human nuclear-transfer embryonic stem cells4 with the first report of the behavior of neuronal precursors derived from such cells after transplantation.5 The derivation of human nuclear-transfer embryonic stem cells is a prelude to the arguably more difficult and time-consuming work ahead and yet brings us closer to the prospect of patient-specific cell therapy.

The importance of the report by Hwang et al. goes beyond this, for it gives the clearest indication yet that the United States has lost the initiative in the human nuclear-transfer debate. In March, the majority of the Asian countries voting on a U.S.-backed, nonbinding statement by the United Nations calling for a ban on all forms of human cloning this past spring rejected it; among them were Cambodia, China, India, North Korea, South Korea, Japan, Singapore, and Thailand. While the United States remains rooted in atavism, Hwang and coworkers have shown that Asia is moving forward.

Source Information

From the Laboratory of Mammalian Molecular Embryology, RIKEN Center for Developmental Biology, Kobe, Japan.

References

References

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   Hwang WS, Roh SI, Lee BC, et al. Patient-specific embryonic stem cells derived from human SCNT blastocysts. Science (in press).
   

2. 2

   Hwang WS, Ryu YJ, Park JH, et al. Evidence of a pluripotent human embryonic stem cell line derived from a cloned blastocyst. Science 2004;303:1669-1674
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   Barberi T, Klivenyi P, Calingasan NY, et al. Neural subtype specification of fertilization and nuclear transfer embryonic stem cells and application in parkinsonian mice. Nat Biotechnol 2003;21:1200-1207
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   Perrier AL, Tabar V, Barberi T, et al. Derivation of midbrain dopamine neurons from human embryonic stem cells. Proc Natl Acad Sci U S A 2004;101:12543-12548
   CrossRef | Web of Science | Medline

5. 5

   Tabar V, Panagiotakos G, Greenberg ED, et al. Migration and differentiation of neural precursors derived from human embryonic stem cells in the rat brain. Nat Biotechnol 2005;23:601-606
   CrossRef | Web of Science | Medline

Citing Articles (3)

Citing Articles

1. 1

   Björn Behr, Sae Hee Ko, Victor W. Wong, Geoffrey C. Gurtner, Michael T. Longaker. (2010) Stem Cells. Plastic and Reconstructive Surgery 126:4, 1163-1171
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2. 2

   R. M. Doerflinger. (2008) The problem of deception in embryonic stem cell research. Cell Proliferation 41, 65-70
   CrossRef

3. 3

   Okie, Susan, . (2005) Stem-Cell Research — Signposts and Roadblocks. New England Journal of Medicine 353:1, 1-5
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