CMDA Adult vs. Embryonic Stem Cell Research

ADULT VS. EMBRYONIC STEM CELL RESEARCH

1) Human embryonic stem cell lines have proven difficult to develop and maintain.
¹ "The scientists [from South Korea that created the first human clone embryo] used 242 eggs from 16 women donors. Because they started with a huge number of eggs, they could vary the methods they used and the media in which they grew the cells. They derived 30 blastocysts and from these tried 20 times to produce a line of embryo stem cells. The success rate was not high, possibly because of chromosomal abnormalities that appeared in the reprogramming or possibly because of subtle variations in the techniques they used. They ended up with just one line of stem cells, cultivated from a blastocyst that had been cloned from nuclear material taken from cumulus cells belonging to the woman who had donated the egg in the first place." Radford, Tim. "Korean scientists clone 30 human embryos." British Medical Journal 328 (2004). Accessed July 21, 2004 at http://bmj.bmjjournals.com/cgi/content/full/328/7437/421. Original article: Hwang, Woo Suk, et al. "Evidence of a Pluripotent Human Embryonic Stem Cell Line Derived from a Cloned Blastocyst," Science 303 (2004): 1669-1674.

² "Chromosomal abnormalities are commonplace in human embryonal carcinoma cell lines and in mouse embryonic stem-cell lines and have recently been reported in human embryonic stem-cell lines.” C. Cowan et al., “Derivation of Embryonic Stem-Cell Lines from Human Blastocysts,” New England Journal of Medicine 350 (2004): 1353-1356.

³ "The approved [human embryonic stem] cells have all been cultured in the presence of mouse cells--called 'feeder cells'--that apparently supply needed growth factors. It is believed that contamination from mouse viruses or proteins may make such cells unsuitable for introduction into humans for therapeutic purposes." Kennedy, Donald. "Stem Cells: Still Here, Still Waiting." Science 300 (2003): 865. Accessed July 23, 2004 at http://www.sciencemag.org/cgi/content/summary/300/5621/865.

⁴ "The Jones Institute for Reproductive Medicine, located in Norfolk, Virginia, announced in July 2001 that it had created human embryos via IVF for the purpose of deriving human embryonic stem cells. A total of 162 oocytes (eggs) from 12 women were collected and fertilized with sperm donated by two men; 110 fertilized eggs developed, of which 40 developed to the blastocyst stage. The inner cell masses were removed from the blastocysts resulting in three healthy embryonic stem cell lines." Johnson, Judith A. "Report for Congress: Stem Cell Research." Congressional Research Service, July 26, 2004. Accessed at http://www.cnie.org/nle/crsreports/RL31015.pdf on July 21, 2004.

2) Pure embryonic stem cell cultures are difficult to obtain.
⁵ "Scientists are still working on developing proper conditions to differentiate embryonic stem cells into specialized cells. As embryonic stem cells grow very fast, scientists must be very careful in fully differentiating them into specialized cells. Otherwise, any remaining embryonic stem cells can grow uncontrolled and form tumors." "Frequently Asked Questions." International Society for Stem Cell Research. Accessed July 6, 2004 at http://www.isscr.org/science/faq.htm.

⁶ "[W]ithin the [embryonic stem cell] research community, realism has overtaken early euphoria as scientists realize the difficulty of harnessing ESCs safely and effectively for clinical applications. After earlier papers in 2000 and 2001 identified some possibilities, research continued to highlight the tasks that lie ahead in steering cell differentiation and avoiding side effects, such as immune rejection and tumorigenesis.” Hunter, Philip. “Differentiating Hope from Embryonic Stem Cells.” The Scientist 17 (2003): 31. Accessed on July 23, 2004 at www.the-scientist.com/yr2003/dec/hot_031215.html.

3) Embryonic stem cells are unstable and mutate in culture.
⁷ "Within the laboratory from a very few cells you could grow a roomful of [embryonic] cells very easily. But there is an issue we don't know much about, and that is obviously there is a finite probability that at every cell division that a genetic mutation will appear… mutations do occur in these cells, and they are of the nature of making these cells susceptible to formation of tumors." Gearhart, John. "Medical Promise of Embryonic Stem Cell Research (Present and Projected)". President's Council on Bioethics, April 25, 2002. Accessed July 6, 2004 at http://www.bioethics.gov/transcripts/apr02/apr25session1.html.

⁸ "It is not yet known whether any preparation of human ES cells (generally believed to be much longer-lived than adult stem cells) will continue to grow 'indefinitely,' without undergoing genetic changes." "Recent Developments in Stem Cell Research." Monitoring Stem Cell Research. The President's Council on Bioethics, January 2004. Accessed July 6, 2004 at http://www.bioethics.gov/reports/stemcell/chapter4.html.

4) Differentiation protocols for many cell types have not been developed.
⁹ This is most likely due to what the National Institutes of Health describes as the "lack of a universally accepted standard for determining what characteristics will predict the ability of such cells to be…differentiated or…useful for the development of therapies." The NIH Update from August 27, 2001 states, "…It is noteworthy that there have been no reported comparative studies on the characteristics of human embryonic stem cells from different derivations." "NIH Update on Embryonic Stem Cell Lines." August 27, 2001. Accessed July 6, 2004 at http://diabetes.about.com/library/blnews/blnstemcellupdateNIH801.htm.

5) Cell types that have been differentiated often act abnormally.
¹⁰ University of Calgary scientists reported that the insulin-producing cells derived from embryonic stem cells are not the "beta cells" needed to reverse diabetes. They failed to function as normal beta cells and to produce the insulin when it was needed. When placed in mice, they did not reverse diabetes but only formed tumors. S. Sipione et al., "Insulin expressing cells from differentiated embryonic stem cells are not beta cells." Diabetologia 47 (2004): 499-508.

¹¹ “Rarely have specific growth factors or culture conditions led to establishment of cultures containing a single cell type…. [T]he possibility arises that transplantation of differentiated human ES cell derivatives into human recipients may result in the formation of ES cell-derived tumors… Irrespective of the persistence of stem cells, the possibility for malignant transformation of the derivatives will also need to be addressed.” Odorico, J.S. et al, “Multilineage differentiation from human embryonic stem cell lines.” Stem Cells 19 (2001): 193-204. Accessed July 23, 2004 at http://stemcells.alphamedpress.org/cgi/reprint/19/3/193.pdf.

¹² “Long-term culture of mouse ES [embryonic stem] cells can lead to a decrease in pluripotency and the gain of distinct chromosomal abnormalities. Here we show that similar chromosomal changes, which resemble those observed in hEC [human embryonal carcinoma] cells from testicular cancer, can occur in hES [human embryonic stem] cells…. The occurrence and potential detrimental effects of such karyotopic changes will need to be considered in the development of hES cell-based transplantation therapies.” Draper, J. et al., “Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem cells.” Nature Biotechnology 22 (2003): 53-54.

6) When embryonic-derived cells have been placed in animals, cancerous tumors have formed.
¹³ “There are still many hurdles to clear before embryonic stem cells can be used therapeutically. For example, because undifferentiated embryonic stem cells can form tumors after transplantation in histocompatible animals, it is important to determine an appropriate state of differentiation before transplantation. Differentiation protocols for many cell types have yet to be established. Targeting the differentiated cells to the appropriate organ and the appropriate part of the organ is also a challenge.” E. Phimister and J. Drazen. “Two Fillips for Human Embryonic Stem Cells.” New England Journal of Medicine 350 (2004): 1351-1352.

¹⁴ Harvard scientists reported in the Proceedings of the National Academy of Sciences that they injected embryonic stem cells into 19 mice with Parkinson's disease. Five out of the 19 mice developed tumors and died. Bjorklund, L. M., R. Sanchez-Pernaute, et al. "Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model." Proceedings of the National Academy of Sciences 99 (2002): 2344-2349.

7) To address the problem of immune rejection, researchers have proposed cloning individual patients to obtain compatible embryonic stem cells.
¹⁵ “ES [embryonic stem] cells and their derivatives carry the same likelihood of immune rejection as a transplanted organ because, like all cells, they carry the surface proteins, or antigens, by which the immune system recognizes invaders. Hundreds of combinations of different types of antigens are possible, meaning that hundreds of thousands of ES cell lines might be needed to establish a bank of cells with immune matches for most potential patients. Creating that many lines could require millions of discarded embryos from IVF clinics… At present, the only sure way to circumvent the problem of immune rejection would be to create an ES cell line using a patient's own genetic material through nuclear transfer or cloning.” R. Lanza and N. Rosenthal. “The Stem Cell Challenge.” Scientific American June (2004): 93-99.

¹⁶ "If [embryonic stem cell] research is to prove successful, many hurdles will have to be surmounted. Scientists will have to learn how to culture stem cells reliably in the laboratory and steer them toward development of the desired tissue types. It will have to be shown that these cells can be safely transplanted into the human body. Even if this is successful, major problems of immunological incompatibility and tissue rejection will remain…Therapeutic cloning promises an 'end run' around all these problems. R. Lanza et al, "The Ethical Validity of Using Nuclear Transfer in Human Transplantation." Journal of the American Medical Association 284 (2000):3175-3179.

¹⁷ "Human cloning could yield numerous identical embryos, could provide for the study of stem cells derived from individuals known to possess genetic diseases, and might eventually yield transplantable tissues for regenerative medicine that would escape immune rejection." "The Meaning of Human Cloning: An Overview." Human Cloning and Human Dignity: An Ethical Inquiry. President's Council on Bioethics, July 2002. Accessed July 13, 2004 at http://bioethics.gov/reports/cloningreport/overview.html.

8) Besides the ethical inadmissibility of human cloning, some researchers have questioned whether cloning will truly solve the rejection problem. Cells taken from cloned human beings are not normal. Women's groups and others have rightly condemned the commercialization of women required to gain the millions of human eggs needed for such cloning.
¹⁸ "In order to conduct so-called 'therapeutic' cloning on the scale that would yield just a portion of the benefit cloning advocates promise, one would need to harvest a vast number of human eggs from women of child bearing age…The ‘egg dearth' is a mathematic certainty. It is one reason why some researchers say that therapeutic cloning will not be a generally available medical treatment…Recently biotech researchers Jon S. Odorico, Dan S. Kaufman, and James A. Thompson admitted the following in the research journal Stem Cells: ‘The poor availability of human oocytes (eggs), the low efficiency of the nuclear cell procedure, and the long population-doubling time of human ES cells make it difficult to envision this [therapeutic cloning to obtain stem cells] becoming a routine clinical procedure even if ethical considerations were not a significant point of contention.'" Sam Brownback, "Cloning: A Risk to Women?" Senate Commerce Subcommittee on Science, Technology and Space, March 27, 2003.

¹⁹ "With therapeutic cloning, scientists would make an embryo clone of the patient, remove its stem cells and use them to grow needed tissue, which presumably would not be rejected…The Jones Institute for Reproductive Medicine in Norfolk, Va., using in vitro fertilization rather than cloning, started with 162 women's eggs and got three stem cell lines. Advanced Cell Technology, in the first cloning of human embryos, started with 71 eggs and got no stem cells because no embryos developed into proper blastocysts." Pollack, Andrew. “Use of Cloning to Tailor Treatment Has Big Hurdles, Including Cost.” The New York Times, December 18, 2001. http://www.genetics-and-society.org/resources/items/20011218_nytimes_pollack.html

9) Even if each of these problems were somehow solved, at a cost of over $200,000 per patient, only the very wealthy could afford the procedure.
²⁰ "This analysis of the limited body of literature raises concerns about the feasibility and relevance of therapeutic cloning, in its current embodiment, for human clinical practice. A crucial difference is that, although 100 mouse oocytes can be obtained from a few superovulated females at a cost of [approximately] $20, human oocytes must be harvested from superovulated volunteers, who are reimbursed for their participation. Add to this the complexity of the clinical procedure, and the cost of a human oocyte is [approximately] $1,000-2,000 in the U.S. Thus, to generate a set of customized ntES (nuclear transfer embryonic stem) cell lines for an individual, the budget for the human oocyte material alone would be [approximately] $100,000-200,000. This is a prohibitively high sum that will impede the widespread application of this technology in its present form." Mombaerts P. "Therapeutic cloning in the mouse." Proceedings of the National Academy of Science 100 (2003):11924-5.

²¹ "Many scientists now acknowledge that even if "therapeutic cloning" can be perfected--a huge 'if,' despite the South Korean success--it would probably be too impractical and expensive to ever become widely available...Indeed, the potentially high cost of, and intense controversy over, therapeutic cloning have made venture capitalists reluctant to invest in human cloning biotech." Smith, Wesley, J. "On My Mind: Watch out. You may soon be paying for cloning research that the private sector won't." Forbes, March 2, 2004.

1) “Adult” (non-embryonic) stem cells have been found in cord blood, placenta, bone marrow, fat, teeth and other sources.
²² "One extremely interesting finding of the past few years has been the discovery of neuronal stem cells, indicating that cell replenishment was possible within the brain (something previously considered impossible.) Neuronal stem cells have been isolated from various regions of the brain including the more-accessible olfactory bulb as well as the spinal cord, and can even be recovered from cadavers soon after death. Evidence now exists that neuronal stem cells can produce not only neuronal cells but also other tissues, including blood and muscle." Prentice, David. "Adult Stem Cells." Monitoring Stem Cell Research, Appendix K; President's Council on Bioethics. January 2004; Accessed July 12, 2004 at http://www.bioethics.gov/reports/stemcell/appendix_k.html.

²³ "These results indicate that adult skeletal muscle contains a rich source of hematopoietic progenitors for both myeloid and lymphoid lineages... these data document that satellite cells and muscle-derived stem cells represent distinct populations and demonstrate that muscle-derived stem cells have the potential to give rise to myogenic cells via a myocyte-mediated inductive interaction." Asakura A et al., “Myogenic specification of side population cells in skeletal muscle.” Journal of Cell Biology 159 (2002): 123–134.

²⁴ "In this study, we characterized the self-renewal capability, multi-lineage differentiation capacity, and clonogenic efficiency of human dental pulp stem cells (DPSCs). DPSCs were capable of forming ectopic dentin and associated pulp tissue in vivo. Stromal-like cells were reestablished in culture from primary DPSC transplants and re-transplanted into immunocompromised mice to generate a dentin-pulp-like tissue, demonstrating their self-renewal capability…These results demonstrate that human dental pulp stem cells possess stem-cell-like qualities, including self-renewal capability and multi-lineage differentiation." Gronthos S et al., "Stem cell properties of human dental pulp stem cells." Journal of Dental Research 81 (2002): 531-535.

²⁵ "In this study, we determined if a population of stem cells could be isolated from human adipose tissue. Human adipose tissue, obtained by suction-assisted lipectomy (i.e., liposuction), was processed to obtain a fibroblast-like population of cells or a processed lipoaspirate (PLA). In conclusion, the data support the hypothesis that a human lipoaspirate contains multipotent cells and may represent an alternative stem cell source to bone marrow-derived MSCs." Zuk PA et al, “Multilineage cells from human adipose tissue: implications for cell-based therapies.” Tissue Engineering 7 (2001): 211-228.

²⁶ "We investigated the potential use of rat amniotic epithelial (RAE) cells as donor cells for transplantation-based therapy in brain ischemia. These results suggest that intracerebral transplantation of amniotic epithelial cells may have therapeutic potential for the treatment of ischemic damage in neuronal disorders." Okawa H et al., “Amniotic epithelial cells transform into neuron-like cells in the ischemic brain.” NeuroReport 12 (2001): 4003-4007.

²⁷ "We describe here the isolation of stem cells from juvenile and adult rodent skin. Because these cells (termed SKPs for skin-derived precursors) generate both neural and mesodermal progeny, we propose that they represent a novel multipotent adult stem cell and suggest that skin may provide an accessible, autologous source of stem cells for transplantation." Toma JG et al, “Isolation of multipotent adult stem cells from the dermis of mammalian skin.” Nature Cell Biology 3 (2002): 778-784.

2) Adult stem cells found in one type of tissue can repair damage in another tissue type. Multipotent adult progenitor cells (MAPC) found in bone marrow can develop into all of the 210 different types of tissue in the human body.
²⁸ "MAPC appear to have pluripotent potential both in vitro and in vivo. Furthermore, they appear to proliferate without obvious senescence when maintained under very stringently controlled culture conditions. Because of these reasons, some have argued that they might be a viable alternative to ES cells." Verfaillie, Catherine. "Multipotent Adult Progenitor Cells: An Update." Monitoring Stem Cell Research, President's Council on Bioethics. January 2004; Appendix J. Accessed July 6, 2004 at http://www.bioethics.gov/reports/stemcell/appendix_j.html

²⁹ "Analysis of serial contrast-enhanced MRI suggests that intracoronary infusion of adult progenitor cells in patients with AMI beneficially affects postinfarction remodeling processes. The migratory capacity of the infused cells is a major determinant of infarct remodeling, disclosing a causal effect of progenitor cell therapy on regeneration enhancement. These data indicate that cell therapy may beneficially modify the healing process of myocardial infarction." Britten MB et al., "Infarct remodeling after intracoronary progenitor cell treatment in patients with acute myocardial infarction." Circulation 108 (2003): 2212-2218.

3) Adult stem cells can be harvested from each patient, multiplied in culture and transplanted back into the patient. They genetically match and therefore are not subject to immune rejection.
³⁰ "Researchers in the U.S. and Taiwan used corneal adult stem cells to grow new corneas for patients with previously untreatable eye damage. Adult stem cells were taken from the patients themselves in 16 cases, or a family member for 4 other patients. The cells were then grown in culture before transplantation onto the damaged eyes. Sixteen of the 20 patients had improved vision." Schwab IR et al. “Successful transplantation of bioengineered tissue replacements in patients with ocular surface disease.” Cornea 19 (2000): 421-426.

³¹ R. Galli, et al. transformed neural stem cells into muscle cells, not only in culture, but after injection into mice. “With adult stem cells there would also be the possibility of auto-transplantation, eliminating all the problems of immunological compatibility and rejection.” Transplant rejection would be a significant problem if using embryonic stem cells. Galli, R. et al. “Skeletal myogenic potential of human and mouse neural stem cells.” Nature Neuroscience 3 (2000): 986-991.

4) Adult stem cells work in multiple ways to repair damaged tissue. They fuse with cells in damaged organs and initiate repair. They take cues from tissue that has been damaged and begin to directly produce cells. Sometimes they secrete substances that cause undamaged cells to divide and replace damaged or dead cells.
³² "Because hematopoietic (blood forming) stem cells (HSCs) can restore and maintain blood formation following transplantation into immune deficient hosts, growth of HSCs in culture is important for many clinical applications…These adult stem cells efficiently rescued immune-compromised mice and generated all blood cells." Ó. P. do Pinto, et al. “Hematopoietic Progenitor/Stem Cells Immortalized by Lhx2 Generate Functional Hematopoietic Cells in vivo." Blood (2002): 3939-3946.

³³ A team of researchers in Tampa, Florida reported that "cord blood stem cells are beneficial in reversing the behavioral effects of spinal cord injury, even when infused 5 days after injury." Garbuzova-Davis, Svitlana, et al. "Intravenous Administration of Human Umbilical Cord Blood Cells in a Mouse Model of Amyotrophic Lateral Sclerosis: Distribution, Migration, and Differentiation." Journal of Hematotherapy and Stem Cell Research 12 (2003): 255–270.

³⁴ "[Adult stem cells] appear to be able to respond at least in some respects to cues that are present in certain organs to differentiate into the cell type that is specific for that organ…You can take a single [adult stem] cell, and give it to a mouse that was lethally irradiated so it has no blood, and this cell can recreate the red cells, the white cells, platelets, lymphocytes, for the lifetime of that animal…It has been shown for bone marrow cells…that if you transplant these into an animal that was irradiated, and you look in tissues outside of the blood, that you can actually find, for instance, skeletal-muscle cells, heart muscle cells, or endothelial cells, that are now derived from this donor hematopoietic cell." Verfaillie, Catherine. "Medical Promise of Adult Stem Cell Research (Present and Projected)." President's Council on Bioethics, April 25, 2002. Accessed July 13, 2004 at http://bioethics.gov/transcripts/apr02/apr25session2.html.

5) Since adult stem cells require limited, if any, manipulation, and are readily available from a number of sources, the cost for their clinical application will be far more reasonable than any application from embryonic stem cells.

6) There are no ethical concerns in their use, making them acceptable to virtually all patients and healthcare providers and a bipartisan point of agreement for federal funding.

7) Adult stem cells are already providing cures in animals and clinical human trials.
³⁵ Science News reported in April of 2001 that stem cells were transplanted into the spinal cords of rats after nine days of paralysis. They were able to stand and walk, though not perfectly, within two weeks. Seppa, N. “Stem cells repair rat spinal cord damage.” Science News, April 12, 2001.

³⁶ David Prentice, PhD, wrote in "Adult Stem Cells" that many groups have used bone marrow derived stem cells in treatment of patients with damaged cardiac tissue. "Results from these clinical trials indicate that bone marrow derived stem cells, including cells from the patients themselves, can regenerate damaged cardiac tissue and improve cardiac performance in humans," Dr. Prentice said. Prentice, David. "Adult Stem Cells." Do No Harm, July 2003. Accessed July 6, 2004 at http://www.stemcellresearch.org/facts/prentice.htm.

³⁷ The Lancet reported that patients' bone marrow improved blood circulation in gangrenous limbs so well that amputation was avoided. Tateishi-Yuyama E et al.; “Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial.” Lancet 360 (2002): 427-435.

³⁸ "Here we present the results of the first human autologous transplantation of neural stem cells and stem cell-derived dopaminergic neurons. These results strongly suggest that autologous transplantation of neural stem cell-derived dopamine-producing cells may be an effective restorative therapy for Parkinson's Disease. At one year post-transplantation, total clinical scores improved by 83%. Motor scores improved by 88%." Levesque, M and Neuman, T. "Autologous transplantation of adult human neural stem cells and differentiated dopaminergic neurons for Parkinson's disease: one-year post-operative clinical and functional metabolic results." American Association of Neurological Surgeons, April 2002. http://www.aans.org/Library/Article.aspx?ArticleId=12096

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