. Evidence of a pluripotent human embryonic stem cell line derived from a cloned blastocyst. Science. 2004 Mar 12;303(5664):1669-74. PubMed.

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  1. This should be extremely exciting news for the public. In theory, these ES cells isolated from cloned human embryos may not cause immune rejection after transplantation since they carry the nuclear genomic information from the host. It sounds as if we could eventually treat diabetes, osteoarthritis, Alzheimer's, Parkinson's, and other diseases using this technology. In theory, we might not even have to worry about aging because, thanks to this technology, we might be able to generate our own tissues or even organs.

    However, I wonder why the authors used both the egg and the cumulus cells from the same person in this study, if they could have gotten somatic nuclei from other donors. Because of this, the authors cannot rule out the possibility that the cloned embryo developed by means of parthenogenesis rather than nuclear transfer. I would want to see male nuclei transferred to the embryo instead.

    Another question would be whether the cloned ES cell is fully functional as a normal cell. Cloning by nuclear transfer is an inefficient process in which most clones die before birth and survivors often display growth abnormalities (Rideout et al., 2001). This may be due to the tissue-specific DNA methylation pattern from somatic nuclei used in cloning (Humpherys et al., 2001). Although Munsie et al. reported that pluripotent stem cells can be derived from reprogrammed nuclei of terminally differentiated adult somatic cells (Munsie et al., 2000), cloned ES cells may also be modified by tissue-specific epigenesis that has occurred in the somatic cells.

    Finally, I just want to point out that "therapeutic cloning" is "human cloning." I will not discuss the ethical issues, but the reader may want to consider that one of the authors, Dr. Jose B. Cibelli, was Vice President of Research at Advanced Cell Technology Inc. The study was done with more than 200 human eggs, which were donated from 16 women. These women underwent hormone treatment to stimulate their ovaries to overproduce maturing eggs.

    References:

    . Nuclear cloning and epigenetic reprogramming of the genome. Science. 2001 Aug 10;293(5532):1093-8. PubMed.

    . Epigenetic instability in ES cells and cloned mice. Science. 2001 Jul 6;293(5527):95-7. PubMed.

    . Isolation of pluripotent embryonic stem cells from reprogrammed adult mouse somatic cell nuclei. Curr Biol. 2000 Aug 24;10(16):989-92. PubMed.

  2. Normal embryonic development requires fertilization with genomic contributions from both maternal and paternal genomes. During this process genetic rearrangements occur which alter the exact contribution made by each parent to each progeny, and this contributes to every individual’s unique genomic profile. However, the same events that confer genetic diversity also create difficulties for transplant biologists, who have to match donors and recipients to prevent immune rejection of “foreign tissue.” Multiple strategies to bypass the immune intolerance barrier have been developed, though the current strategy reported by Dr. Moon and colleagues is by far the most controversial.

    The idea here is to utilize the known properties of ES cells—which can contribute to, and possibly create, all major tissues and organs—combined with the ability of an oocyte to reprogam somatic nuclei. Individually, each of these technically difficult steps had been shown to be feasible. It had been shown that human ES cells can be derived with efficiencies that approach 30 percent or so, and that somatic nuclear transfer can be used to generate viable cloned offspring in multiple species. During his time at Advanced Cell Technology Inc., Dr. Cibelli had also shown that blastocysts can be derived from enucleated eggs that harbor somatic nuclei, and he had shown that parthenogenetic embryos can generate ES cell lines in primates (as had been shown with other species decades ago).

    The present paper has put all of these technologies together for the first time using human blastocysts, human somatic nuclei, and deriving a viable ES cell line. The results are not entirely unexpected and are in keeping with the cautions echoed by scientists as to efficiency and economic feasibility. A single ES line was obtained from approximately 250 blastocysts and, interestingly, the single line obtained was using somatic nuclei from the same donor. Rather than constituting a novel breakthrough, the success of Moon et al. is likely attributable to their ability to obtain a large number of healthy blastocysts (this helped overcome the low success rates of this procedure), and perhaps to their strategy for removing the oocytes’ genetic material.

    Even if this method can be made routine, efficient, and legal, two issues come to mind when considering its potential use for transplantation. One is time. The entire process of generating, characterizing, and analyzing ES cells takes time. Amplifying enough cells to obtain the numbers needed for an adult is time-consuming, given the slow cycle times of human cells, plus the ability to direct these cells to differentiate in an appropriate manner is still unproven. Add to that the observation that, while cloned mice may appear normal, subtle errors and differences are present (abnormal weight gain, size changes, aberrant shut-off of genes, etc.), and one could perhaps expect that organs generated after therapeutic cloning may suffer from some of the same issues. This will take time to develop, and to detect. People generally need tissue/organs/repair on an emergency basis, and it is not yet clear if the process could be accelerated.

    The second issue is cost, and cost of competing alternatives. The cost of harvesting blastocysts, performing nuclear transfer, generating a line, and subsequent media costs for maintaining such a line can rapidly add up such that, while technically feasible, it may simply not be economically viable. It is useful to note that most companies have not yet figured out a way to make even a garden-variety stem cell therapy economically feasible, let alone customized cell replacement. Of course, if this was the only option, it is possible that there would be a market for it. However, if competing alternatives to such a therapy were available, then it is unlikely to see a great demand. For example, few people are willing to pay to bank and store their own blood, while most are perfectly willing to use a cheaper, competing alternative (matched blood). Similar possibilities/choices exist in this case as well. They include developing a bank of ES cell lines, making universal donor lines by knocking out the immune locus in an existing ES line, strategies of immune tolerization, and development of novel suppressive therapies. While each of these have their own caveats, they represent at least plausible alternatives.

    In any case, it appears to me that this result is a technical tour de force. It illustrates how rapidly progress can be made when tools and techniques (pioneered across different countries) become readily available and information is shared (note authors across continents). I do not, however, expect this to change anything in the short run. In the long run, I believe additional breakthroughs are required before one considers such a strategy the best way to go. Parenthetically, I would suggest that this should not alter the debate on human cloning (in terms of the scientific landscape). This report does not render human cloning more or less feasible.

  3. It is very sad to hear that the data presented in the paper has been fabricated. One can only speculate that the author might have lost his good judgment as a result of extreme competition and expectation by the people and the nation. I hope this incident will not harm the advance of stem cell research.

    When I read this paper, I questioned why the authors used both the egg and the cumulus cells from the same person, and whether the cloned ES cell is fully functional as a normal cell, as I commented before. Unfortunately, my predictions proved real and the human clone did not exist. I believe attempts of making human clones may be continued, and someday it may be accomplished. However, we have to be very careful when we evaluate the outcomes. This distressing incident gave us an important lesson.

    Now may be the time to put more attention to the use of adult stem cells, which is my current main focus. Using this technology, we may be able to isolate stem cells from a patient, modify them, and transplant them back to the patient. The autologous stem cell therapy may eliminate technical and ethical issues associated with ES cells.