INTRODUCTION
The human body consists of tissues and organs that contain over 200 different cell types.1 these cells carry out all the functions required for viability and reproduction. It was argued long ago, that in some tissues, the differentiated cells have a shorter life span and that they are not able to self -renew.2 This led to the notion that such tissues are maintained by cells that have an extensive renewal capacity, and the ability to differentiate and generate daughter cells. These cells were termed as ‘stem cells”.2 Stem cells generate only the differentiated lineages of the tissues they reside in, therefore the terms ‘multipotent’ or ‘unipotent’.2 Research on stem cells is the focus of public attention for quite some time now; and novel insights and development into cellular therapy have emerged. However, it is not without any ethical implications. It is an ongoing discussion and most of the controversy is surrounding the area of embryo destruction.3
STEM CELL RESEARCH AND ETHICAL IMPLICATIONS
Stem cell research has come a long way now and offered great promise for understanding basic mechanisms of human development. It is also seen to be a hope for new treatments for diseases like myocardial infarction, diabetes, Parkinson’s disease, and spinal cord injury.4 Deriving pluripotent stem cells from oocytes and embryos is a disputed issue with regards to the onset of human personhood and human reproduction.
- Arias, AM. “Drosophila melanogaster and the development of biology in the 20th century.” Methods Mol. Biol. 2008, 420, 1–25.
- Lajtha, LG. “Stem cell concepts.” Nouv. Rev. Fr. Hematol. 1979, 21, 59–65.
- Monroe, KR; Miller, RB; Tobis, J eds. “Fundamentals of the Stem Cell Debate: The Scientific, Religious, Ethical, and Political Issues.” Los Angeles, CA: University of California Press; 2007.
- “Committee on the Biological and Biomedical Applications of Stem Cell Research, Commission on Life Sciences, National Research Council, Board on Neuroscience and Behavioral Health, Institute of Medicine2002 Stem cells and the future of regenerative medicine.” Washington, D.C.: National Academies Press, 2002.
However, other methods of deriving stem cells do not raise that much of ethical concern.
There are different phases of stem cell research and at every step ethical issues arise. In the first phase of donation of biological material, the ethical issue is obtaining informed and voluntary consent. On researching with human embryonic stem cells, the ethical issues are of destruction of embryos and creation of embryos specifically for research purpose.5 Under this, there is further an issue of payment to oocyte donors, medical risks of oocyte retrieval, and protecting reproductive interests of women in infertility treatment. If stem cell lines are derived at different institutions, there is an issue of conflicting legal and ethical standards. If there is a participation in stem cells clinical trials, there are risks and benefits of experimental intervention.5
Cord blood stem cells and adult stem cells are widely used in research and clinical care and do not raise special ethical concerns.5 Overall, embryonic stem cells in human research are particularly ethically and politically controversial because the embryo is destroyed.5 In the US, there always has been a debate on when life actually begins? This topic always crops up whenever there is a talk on abortion.6 Some are of the belief that ‘human life begins at conception’ and therefore embryo should be considered as a person and a person with same moral status as an adult or a live born child.6 Some others, however, have a totally different view. They believe that, in moral sense, an embryo becomes a person at a later stage of development than fertilization. There is also a section of society which believes that embryo is just a bunch of cells that can be used for research purposes without any inhibition or restriction.6
- Lo Bernard, Parham Lindsay. “Ethical Issues in Stem Cell Research.” Endocr Rev. 2009;30(3), 204–213. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726839/; Accessed: 23 April 2013.
- “Monitoring stem cell research.” Washington, D.C.: The President’s Council on Bioethics. 2004
Amongst all such conflicting views, there are some who hold a middle ground that the early embryo has to be respected as a potential human being, but it should be acceptable to use it for certain types of research, provided the use is justified scientifically; and a voluntary informed consent is sought from the woman who has donated the embryo for the purpose of research.7
Couples and women who undergo treatment for infertility often have remaining frozen embryos after their infertility treatment is complete. How to dispose the frozen embryos is often a question to them.8 Some choose to donate it for research purpose rather than giving it to another couple for reproductive purpose or rather than choosing to destroy it.8 While doing so, some ethical issues crop up like obtaining informed consent from the donating woman or couple, consent from gamete donors, and confidentiality of donor information.5
In a bioethical review on stem cell research and therapy, Hyun argues that the embryo ethics is a thing of the past. At present, new ethical issues are beginning to emerge around deriving and using other human embryonic stem cell – like stem cells, which are cells with a capacity to differentiate into all types of human tissue.9 The main bioethical issue now is how to conduct stem cell research rather than whether it ought to be conducted, which is a thing of the past.9
A recent development in the form of human induced pluripotent stem (iPS) cells has reduced the heat behind the public debate over human embryonic stem cells.9 The iPS cells are nothing but dermal fibroblasts, genetically engineered to behave like human embryonic stem cells.9
- “Report of the Human Embryo Research Panel.” Bethesda, MD: National Institutes of Health. 1994
- Lyerly AD, Faden RR. Embryonic stem cells. “Willingness to donate frozen embryos for stem cell research.” Science, 2007, 317:46–47.
- Hyun Insoo. “The bioethics of stem cell research and therapy.” J Clin Invest. 2010, 120:71–75.
The iPS cell technique pioneered in 2006 in Japan10 showed that human iPS cells can be created, which would behave in the same way as human embryonic stem cells.11-12 However, to advance research on iPS cells, the human embryonic cells must be used as controls. To carry out comparisons on the two, scientists need to expand their knowledge more on human embryonic cells too.9 Safety seems to be a major issue for iPS cell research since the method used to generate iPS cells can lead to harmful mutations in the resulting cells at a later stage.9 In any case, Hyun states that the research and knowledge around iPS cells may be useful to expand overall understanding of stem cell biology, hoping of discoveries of new therapies for patients.9
Use and manipulation of donated human embryos is not required with the iPS cell technology, but it does not mean that there are no ethical concerns associated with it.9 A wide variety of living donors are of help in deriving iPS cells from the somatic tissues. Therefore, the ethical issues that come into play are re-contacting and tracking of the donors, how to deal with incidental findings such as those that may impact the health of a living donor, and the level and scope of donors’ reachthrough rights to the commercial benefits and downstream research uses of their genetically matched iPS cell lines.13-14
- Takahashi K, Yamanaka S. “Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.” Cell, 2006; 126(4):663–676.
- Takahashi K, et al. “Induction of pluripotent stem cells from adult human fibroblasts by defined factors.” Cell. 2007; 131(5):861–872.
- Yu J, et al. “Induced pluripotent stem cell lines derived from human somatic cells.” Science. 2007; 318(5858):1917–1920.
- Aalto-Setälä K, Conklin B, Lo B. “Obtaining consent for future research with induced pluripotent cells: opportunities and challenges.” PLoS Biol. 2009; 7(2), e42.
- Wolf S, et al. “Managing incidental findings in human subjects research: analysis and recommendations.” J Law Med Ethics. 2008, 36(2), 219–248.
So far, stem cell researchers have succeeded in producing a few disease specific human embryonic stem cell lines using those embryos that were unwanted in the fertility clinic and that had tested positive for serious genetic diseases like fragile X syndrome and cystic fibrosis.15-16
However, for complex diseases, there is no genetic screening method. Therefore, researchers had been using the iPS cell technique to create disease –specific stem cell line.17
Bioengineered stem cells are derived using techniques that try to find pluripotency in non-stem cells. Such techniques are classified into two types: pluripotency induced by factor-mediated nuclear programming and somatic cell nuclear transfer (SCNT), better known as cloning.18 SCNT’s first demonstration was done through the creation of a sheep named Dolly.19 The technique is a simple procedure that involves transferring the somatic cell nucleus into an enucleated oocyte.20 This forms a cloned zygote from which embryonic stem cells are derived.20
Altered nuclear transfer is one variation of SCNT. Using lentiviral RNA interference before SCNT, researchers reported inactivation of the Cdx2 gene in murine fibroblasts. This technique resulted in a blastocyte that produced only cells of the inner cell mass.21
- Pickering SJ, et al. “Generation of a human embryonic stem cell line encoding the cystic fibrosis mutation deltaF508, using preimplantation genetic diagnosis.” Reprod Biomed Online. 2005;10(3):390–397.
- Eiges R, et al. “Developmental study of fragile X syndrome using human embryonic stem cells derived from preimplantation genetically diagnosed embryos.” Cell Stem Cell. 2007, 1(5), 568–577.
- Park IH, et al. “Disease-specific induced pluripotent stem cells.” Cell. 2008, 134(5), 877–886.
- Nelson TJ, Behfar A, Yamada S, Martinez-Fernandez A, Terzic A. “Stem cell platforms for regenerative medicine”. Clin Transl Sci. 2009, 2(3), 222-227.
- Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KH. “Viable offspring derived from fetal and adult mammalian cells”. Nature. 1997, 385 (6619), 810-813.
- Yamanaka S, Blau HM. “Nuclear reprogramming to a pluripotent state by three approaches”. Nature. 2010, 465(7299), 704-712.
- Meissner A, Jaenisch R. “Generation of nuclear transfer-derived pluripotent ES cells from cloned Cdx2-deficient blastocysts”. Nature. 2006, 439 (7073), 212-215.
These cells were studied and found to be pluripotent and functionally similar to embryonic stem cells. This work was based on an old research that showed Cdx2 essential for formation of trophoblast that gives rise to extra embryonic tissues.22
Therefore, this work offered an new and advanced alternative to bioengineered pluripotent stem cells that would not need the viable embryos to be destroyed. However, it needed producing ‘disabled embryos’ that were incapable of implantation, which raised ethical issues, and therefore, this platform, is actively debated.23-24
Despite the limitations of bioengineered stem cells, they still offer unique biological and ethical advantages. One big disadvantage of existing stem cell platforms is the risk of immune rejection.25 Bioengineered stem cells help address this limitation. In the first human embryonic cell phase 1 clinical trial, patients undergoing allogenic cell transplants had to receive immunosuppressive therapy for four months and were monitored for 15 years for evaluation of rejection.26 A major advantage with bioengineered stem cells is that, in regenerative therapy, there is a possibility of autologous transplant avoiding the need for immunosuppressive therapy.27
- Strumpf D, Mao CA, Yamanaka Y, et al. “Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst”. Development. 2005, 132(9), 2093-2102.
- Hipp J, Atala A. “Sources of stem cells for regenerative medicine”. Stem Cell Rev. 2008, 4(1), 3-11.
- Guenin LM. “Wishful thinking will not obviate embryo use”. Stem Cell Rev. 2005, 1(4), 309-315.
- Boyd AS, Fairchild PJ. “Approaches for immunological tolerance induction to stem cell-derived cell replacement therapies”. Expert Rev Clin Immunol. 2010, 6(3), 435-448.
- Geron Corporation. About GRNOPC1 [clinical program]. Geron Web site. http://www.geron.com/GRNOPC1Trial/grnopc1-sec4.html. Accessed May 2, 2011.
- “National Institutes of Health guidelines on human stem cell research.” National Institutes of Health (NIH). http://stemcells.nih.gov/policy/2009guidelines.htm.
Resources for iPS cells can be unlimited because they require only a tissue biopsy for derivation (making it easy for anyone to donate), but human embryonic stem cells have a severe limitation in resource capacity because they must be derived from embryos discarded after IVF.27
Artificial embryo twinning is one less controversial and less technologically complex manner of reproductive cloning in which embryo is created in a petri dish via a procedure, “In Vitro Fertilization (IVF)”.30 To artificially mimic what happens when monozygotic multiples are formed, the embryo is induced to divide into genetic copies of itself. These are then transferred to the womb; and if implantation and further gestation is successful, identical multiples are born.30
- Ramos-Zuniga Rodrigo, Gonzalez –Perez Oscar, Macais –Ornelas Ana, Capilla-Gonzalez Vivian, Quinones-Hinojosa Alfredo. “Ethical Implications in the Use of Embryonic and Adult Neural Stem Cells”. Stem Cells International. 2012. Article ID 470949, 7 pages doi:10.1155/2012/470949
- Y. Mu and F. H. . Gage, “Adult hippocampal neurogenesis and its role in Alzheimer’s disease,” Molecular Neurodegeneration,2011, 6, article 85, 2011.
- Illmensee, Karl et al. “Human Embryo Twinning with Applications in Reproductive Medicine.” Fertility and Sterility, 2009, 93.2: 423-427.
If it is not successful, the procedure is repeated. This provides an infertile couple an increased chance of successful reproduction.31 Some embryos can be saved and implanted at a later date. Therefore, it is possible to create identical multiples that are not born at the same time. One advantage in this technique is that the one child can serve as a bone marrow or blood donor for the other sibling, anytime if there is a need, since they are genetically identical. Thus, the existence of cloned person is mutually beneficial. However, this too holds some concerns. There is as debate and controversy that artificially dividing the embryo constitutes an immoral manipulation of the embryo. As much as possible, a unique embryo should be allowed to develop without interference.32 in his paper, McCormick has also stated another worry over the child’s individuality.32 Naturally occurring twins are valued as individuals, but the worry in embryos created through artificial twinning is that the children may not be valued precisely because of synthetic nature of their genesis.32
It was necessary to have ethical support in view of the response from society to scientific and technological advances applied to medicine. Here is where the field of bioethics was applied in association with life science and survival.
An ongoing debate according to Zacharias et al is if we have sufficient human embryonic cell lines to innovate better techniques or whether it is essential to continue deriving more lines by embryonic destruction? 33
- Robertson John. “The Question of Human Cloning.” Hastings Center Report, 1994, 24.2: 6-14.
- McCormick, Richard. “Blastomere Separation: Some Concerns.” Hastings Center Report, 1994, 24.2: 14- 16.
- Zacharias David. Nelson Timothy, Mueller Paul, Hook Christopher. “The Science and Ethics of Induced Pluripotency: What Will Become of Embryonic Stem Cells?” Mayo Clin Proc. 2011;86(7):634-640.
Since past two years, the availability of human embryonic cell lines has been increasing dramatically and has almost doubled now, compared to previous 15 years. There are still many more cell lines under review by the NIH. 33 Legally, there may be a conclusion and what should be prohibited and what should be permitted, but ethical and social disagreement will always remain. Whatever the prohibitions and agreements are, it should be in favor or be beneficial to human beings that are the main beneficiaries.33
In conclusion, even after so many years of research and innovations, constant and extensive discussion is required about the role of stem cells and their ethical implications. If there is a balance, scientists are able to work more efficiently on a technology that seems to have a great potential to solve health problems in different stages of life.
References:
Arias, AM. “Drosophila melanogaster and the development of biology in the 20th century.” Methods Mol. Biol. 2008, 420, 1–25.
Aalto-Setälä K, Conklin B, Lo B. “Obtaining consent for future research with induced pluripotent cells: opportunities and challenges.” PLoS Biol. 2009; 7(2), e42.
Boyd AS, Fairchild PJ. “Approaches for immunological tolerance induction to stem cell-derived cell replacement therapies”. Expert Rev Clin Immunol. 2010, 6(3), 435-448.
“Committee on the Biological and Biomedical Applications of Stem Cell Research, Commission on Life Sciences, National Research Council, Board on Neuroscience and Behavioral Health, Institute of Medicine2002 Stem cells and the future of regenerative medicine.” Washington, D.C.: National Academies Press, 2002.
Eiges R, et al. “Developmental study of fragile X syndrome using human embryonic stem cells derived from preimplantation genetically diagnosed embryos.” Cell Stem Cell. 2007, 1(5), 568–577.
Geron Corporation. About GRNOPC1 [clinical program]. Geron Web site. http://www.geron.com/GRNOPC1Trial/grnopc1-sec4.html. Accessed May 2, 2011.
Guenin LM. “Wishful thinking will not obviate embryo use”. Stem Cell Rev. 2005, 1(4), 309-315.
Hipp J, Atala A. “Sources of stem cells for regenerative medicine”. Stem Cell Rev. 2008, 4(1), 3-11.
Hyun Insoo. “The bioethics of stem cell research and therapy.” J Clin Invest. 2010, 120:71–75.
Illmensee, Karl et al. “Human Embryo Twinning with Applications in Reproductive Medicine.” Fertility and Sterility, 2009, 93.2: 423-427.
Lajtha, LG. “Stem cell concepts.” Nouv. Rev. Fr. Hematol. 1979, 21, 59–65.
Lo Bernard, Parham Lindsay. “Ethical Issues in Stem Cell Research.” Endocr Rev. 2009;30(3), 204–213. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726839/; Accessed: 23 April 2013.
Lyerly AD, Faden RR. Embryonic stem cells. “Willingness to donate frozen embryos for stem cell research.” Science, 2007, 317:46–47.
Meissner A, Jaenisch R. “Generation of nuclear transfer-derived pluripotent ES cells from cloned Cdx2-deficient blastocysts”. Nature. 2006, 439 (7073), 212-215.
Monroe, KR; Miller, RB; Tobis, J eds. “Fundamentals of the Stem Cell Debate: The Scientific, Religious, Ethical, and Political Issues.” Los Angeles, CA: University of California Press; 2007.
McCormick, Richard. “Blastomere Separation: Some Concerns.” Hastings Center Report , 1994, 24.2: 14- 16.
“Monitoring stem cell research.” Washington, D.C.: The President’s Council on Bioethics. 2004
“National Institutes of Health guidelines on human stem cell research.” National Institutes of Health (NIH). http://stemcells.nih.gov/policy/2009guidelines.htm.
Nelson TJ, Behfar A, Yamada S, Martinez-Fernandez A, Terzic A. “Stem cell platforms for regenerative medicine”. Clin Transl Sci. 2009, 2(3), 222-227.
Park IH, et al. “Disease-specific induced pluripotent stem cells.” Cell. 2008, 134(5), 877–886.
Pickering SJ, et al. “Generation of a human embryonic stem cell line encoding the cystic fibrosis mutation deltaF508, using preimplantation genetic diagnosis.” Reprod Biomed Online. 2005;10(3):390–397.
Ramos-Zuniga Rodrigo, Gonzalez –Perez Oscar, Macais –Ornelas Ana, Capilla-Gonzalez Vivian, Quinones-Hinojosa Alfredo. “Ethical Implications in the Use of Embryonic and Adult Neural Stem Cells”. Stem Cells International. 2012. Article ID 470949, 7 pages doi:10.1155/2012/470949
“Report of the Human Embryo Research Panel.” Bethesda, MD: National Institutes of Health. 1994
Robertson John. “The Question of Human Cloning.” Hastings Center Report , 1994, 24.2: 6-14.
Strumpf D, Mao CA, Yamanaka Y, et al. “Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst”. Development. 2005, 132(9), 2093-2102.
Takahashi K, Yamanaka S. “Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.” Cell, 2006; 126(4):663–676.
Takahashi K, et al. “Induction of pluripotent stem cells from adult human fibroblasts by defined factors.” Cell. 2007; 131(5):861–872.
Wolf S, et al. “Managing incidental findings in human subjects research: analysis and recommendations.” J Law Med Ethics. 2008, 36(2), 219–248.
Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KH. “Viable offspring derived from fetal and adult mammalian cells”. Nature. 1997, 385 (6619), 810-813.
Yu J, et al. “Induced pluripotent stem cell lines derived from human somatic cells.” Science. 2007; 318(5858):1917–1920.
Yamanaka S, Blau HM. “Nuclear reprogramming to a pluripotent state by three approaches”. Nature. 2010, 465(7299), 704-712.
Y. Mu and F. H. . Gage, “Adult hippocampal neurogenesis and its role in Alzheimer’s disease,” Molecular Neurodegeneration,2011, 6, article 85, 2011.
Zacharias David. Nelson Timothy, Mueller Paul, Hook Christopher. “The Science and Ethics of Induced Pluripotency: What Will Become of Embryonic Stem Cells?” Mayo Clin Proc. 2011;86(7):634-640.
