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Overview
“Pluripotent” stem cells (i.e. embryonic stem cells = ES cells, and induced pluripotent stem cells = iPS cells) are considered a promising material for cell and tissue replacement therapy. A well-known reason why they receive so much interest is that they possess differentiation potential as well as a proliferation capacity. Whereas this combination of (and the interrelationships between) proliferation and differentiation potential is in the focus of most investigators, these cells show an additional peculiarity which deserves much more attention than it usually receives: pattern formation potential. This latter property bears important implications for safety aspects (tumor formation) as well as for the ethics of stem cell research and application in the human. It has led to confusion in terminology, and we have discussed the use of the terms totipotency/omnipotency/pluripotency and proposed more stringent definitions.
For the embryologist it is no surprise that early embryo-derived (or early embryo-like) cells show pattern formation capacities in connection with their differentiation potential. Stem cell researchers and bioethicists, however, often appear to disregard this. In fact developmental biology tells us that we must expect “pluripotent” cells to have an inclination to initiate processes of pattern formation, i.e. to create a degree of order in any groups of such cells while they differentiate. They may even form rudimentary organ anlagen as seen clearly in teratomas derived from these cells.
This pattern formation potential becomes ethically problematical if it can lead to the creation of a basic body plan (individuation). During in vitro culture and after transplantation of “pluripotent” cells any autonomous development of a basic body plan appears to be a very rare event (apparently due to the unfavourable environmental conditions met in these cases). However, the morphogenetic potential can be fully expressed when tetraploid complementation (TC) is performed: This technique allows to clone viable individuals from ES and iPS cells as has been shown in the mouse. The technique would most probably be applicable in the same way in the human (if ever attempted) which points to an ethical problem that has largely been overlooked so far. This fact definitely needs to be considered when obtaining informed consent but at present it is not being communicated to cell donors. It is also relevant for questions of patentability: Indeed patenting must be regarded non-acceptable in case of human cells possessing this complete “pluripotency”, i.e. cells which would enable direct cloning of identical individuals using TC or any related technologies (including any “pluripotent” cells that have not been tested specifically for this property but must be considered suspect of possessing it).
Logically these considerations should have consequences for research strategies as well as for legislative actions:
- Any use of human cells which are fully totipotent/pluripotent/omnipotent in the sense that they have embryo-forming potential (e.g. when TC is performed) bears these ethical problems and must thus be avoided.
- The goal to abandon sacrificing human embryos (for the derivation of stem cells) is basically laudable. However, in the search for alternative stem cell sources the focus should not be on the induction of “pluripotency” (as in iPS cells) because this creates exactly the ethical problem just described, since it endows these modified cells with properties possibly enabling direct cloning of individuals by TC.
- This asks for a re-focussing of research strategies in the sense that the goal should not be to induce full “pluripotency” (iPS cells) but rather to endow cells with a more limited developmental potential that would exclude early embryonic pattern formation (e.g. gastrulation).
- The state of the art of mammalian developmental biology would now indeed allow for such a re-focussing of research activities. Legislative initiatives should encompass this.
My publications on these topics comprise: (1) ethical considerations with respect to stem cell use in the human; (2) a discussion of the theoretical background provided by developmental biology, specifically with respect to the implications of “pluripotent/omnipotent/totipotent” properties of cells for possessing an individuation potential; (3) some own experimental studies involving (nonhuman) primate embryonic stem cells.
List of Publications
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DENKER, H.-W.:
A quest for redefining stem cell induction strategies: How to deal with ethical objections and patenting problems.
(Lecture) 3rd Disputationes on Native and Induced Pluripotent Stem Cell Standardization, Florence (Italy), March 19–21, 2012.
pdf-download (5.40 MB) Abstract
DENKER, H.-W.:
iPS cells: Ethical problems solved?
(Lecture) 22nd European Students' Conference, Charité Berlin, 23 September 2011.
pdf-download (924 KB) Abstract (4.23 KB)
DENKER, H.-W., HOLM, S.:
Patenting and stem cell pluripotency.
(Comment on: SMITH, A.: 'No' to ban on stem-cell patents. Nature 472, 418, 2011; doi: 10.1038/472418a.)
Nature 472: 418, 2011; Online Comment #22079.
pdf-download (6.56 KB) Nature Website
LITTWIN, T., DENKER, H.-W.:
Segregation during cleavage in the mammalian embryo? A critical comparison of whole-mount/CLSM and section immunohistochemistry casts doubts on segregation of axis-relevant leptin domains in the rabbit.
Histochemistry and Cell Biology 135: 553-570 (2011).
PubMed
MARANCA-HÜWEL, B., DENKER, H.-W.:
Epithelial-mesenchymal transition in rhesus monkey embryonic stem cell colonies: the role of culturing conditions.
In Vitro Cell. Dev. Biol. - Animal 46(6): 516-528 (2010).
PubMed pdf-download (951 KB; Please note the copyright regulations of the SIVBThis material has been published in In Vitro Cell. Dev. Biol. - Animal 46(6): 516-528 (2010), the only accredited archive of the content that has been certified and accepted after peer review. Copyright and all rights therein are retained by the Society for In Vitro Biology. This material may not be copied or e-posted without explicit permission of the copyright owner.
For more information about Reproduction Permission for this article, please visit the SIVB website by clicking on the link above or anywhere on this infobox.!)
DENKER, H.-W.:
Comment on Draft NIH Guidelines for Human Stem Cell Research (2009) (Public Comment ID 16452).
pdf-download (15.1 KB) NIH Website
Unfortunately, NIH has removed this webpage.
However, you are still welcome to download my comment as a PDF (15.1 KB).
DENKER, H.-W.:
Ethical concerns over use of new cloning technique in humans.
Nature 461: 341 (2009). PubMed pdf-download (5.78 KB)
DENKER, H.-W.:
Induced pluripotent stem cells: How to deal with the developmental potential.
Reproductive BioMedicine Online 19 Suppl. 1: 34-37 (2009). PubMed pdf-download (287 KB)
DENKER, H.-W.:
Human embryonic stem cell lines generated without embryo destruction: New strategies, new ethical problems
(Comment on: CHUNG, Y.; KLIMANSKAYA, I.; BECKER, S.; LI, T.; MASERATI, M.; LU, S.-J.; ZDRAVKOVIC, T.; ILIC, D.; GENBACEV, O.; FISHER, S.; KRTOLICA, A.; LANZA, R.: Human embryonic stem cell lines generated without embryo destruction. Cell Stem Cell 2: 113-117, 2008.)
Deutsch (12.2 KB) English (11.3 KB)
DENKER, H.-W.:
Totipotency/pluripotency and patentability.
Stem Cells 26: 1656-1657 (2008). PubMed Stem Cells pdf-download (14.4 KB)
DENKER, H.-W.:
Induzierte pluripotente Stammzellen (iPS) und das Omnipotenz-/Totipotenzproblem.
Leserbrief zu: Richter-Kuhlmann, E.: Stammzellenforschung: Reprogrammierungserfolge entzünden erneut Debatte. Deutsches Ärzteblatt 104: C 2799 - C 2800 (2007). pdf-download (12.5 KB)
Leicht gekürzt veröffentlicht (unter der Überschrift "Stammzellforschung: Ein anderes ethisches Problem") in: Deutsches Ärzteblatt 105 (Heft 11): A 577 - A 578 (2008). to the article
DENKER, H.-W.:
Human embryonic stem cells:
The real challenge for research as well as for bioethics is still ahead of us.
Cells Tissues Organs 187: 250-256 (2008). PubMed pdf-download (155 KB)
DENKER, H.-W., BEHR, R., HENEWEER, C., VIEBAHN, C., THIE, M.:
Epithelial-mesenchymal transition in rhesus monkey embryonic stem cell colonies: a model for processes involved in gastrulation?
Cells Tissues Organs 185: 48-50 (2007). PubMed pdf-download (162 KB)
DENKER, H.-W.:
Heureka!
(Comment on: DEVOLDER, K. and WARD, C. M.: Rescuing human embryonic stem cell research: The possibility of embryo reconstruction after stem cell derivation. Metaphilosophy, Vol. 38, No. 2, 245-263, 2007.)
pdf-download (14.2 KB)
LEI, T., HOHN, H.-P., BEHR, R., DENKER, H.-W.:
Influences of Extracellular Matrix and of Conditioned Media on Differentiation and Invasiveness of Trophoblast Stem Cells.
Placenta 28: 14-21 (2007). PubMed
DENKER, H.-W.:
Comment on:
KLIMANSKAYA, I.; CHUNG, Y.; BECKER, S.; LU, S.-J.; LANZA, R.:
Human embryonic stem cell lines derived from single blastomeres.
Nature 444: 481-485 (2006). pdf-download (7.75 KB)
DENKER, H.-W.:
Potentiality of embryonic stem cells: an ethical problem even with alternative stem cell sources.
Journal of Medical Ethics 32: 665-671 (2006). PubMed pdf-download (131 KB)
DENKER, H.-W.:
Totipotenz – Omnipotenz – Pluripotenz.
Ausblendungsphänomene in der Stammzelldebatte: Indikatoren für den Konflikt zwischen Norm- und Nutzenkultur?
In: Th. S. Hoffmann, W. Schweidler (Eds.): Normkultur versus Nutzenkultur. Über kulturelle Kontexte von Bioethik und Biorecht. Walter de Gruyter, Berlin/New York, 2006, pp. 249-272. pdf-download (9.81 MB)
DENKER, U., DENKER, H.-W.:
Embryonale Stammzellforschung: Aufklärung notwendig.
Problematik der informierten Zustimmung der Spender.
Dtsch. Ärzteblatt 102 (Heft 13): A892-A893 (2005). pdf-download (56.7 KB)
BEHR, R., HENEWEER, C., VIEBAHN, C., DENKER, H.-W., THIE, M.:
Epithelial-mesenchymal transition in colonies of rhesus monkey embryonic stem cells: a model for processes involved in gastrulation.
StemCells 23: 805-816 (2005). PubMed pdf-download (559 KB)
BEHR, R., HENEWEER, C., VIEBAHN, C., DENKER, H.-W., THIE, M.:
Epithelial-mesenchymal transition in colonies of rhesus monkey embryonic stem cells: a model for processes involved in gastrulation?
(Abstr.) Verh. Anat. Ges. 100 (Anat. Anz./Ann. Anat. Suppl. 187): 203, 2005.
DENKER, H.-W.:
Early human development: New data raise important embryological and ethical questions relevant for stem cell research.
Naturwissenschaften 91: 1-21 (2004). PubMed pdf-download (853 KB)
DENKER, H.-W.:
Die Potenz von menschlichen ES-Zellen als Argument gegen ihre Patentierbarkeit.
Jahrbuch für Wissenschaft und Ethik, Bd. 9 (L. Honnefelder u. C. Streffer, Eds.). Walter de Gruyter, Berlin/New York, 2004, pp. 367-371. pdf-download (8.75 MB)
english abstract (0.99 MB): The developmental potential of human embryonic stem cells argues against their patentability
BEHR, R., DENKER, H.-W., HENEWEER, C., HOHN, H.-P., VIEBAHN, C., von RECKLINGHAUSEN, I., THIE, M.:
Epithelial-mesenchymal transition in colonies of rhesus monkey embryonic stem cells: a model for processes involved in gastrulation?
(Abstr.) Interne Klausurtagung des Kompetenznetzwerks Stammzellforschung NRW, Herne (Germany), November 19th-20th, 2004, Abstracts, p.&nsbp;56.
KRUSE, L.H., HENEWEER, C., DENKER, H.-W. and THIE, M.:
Ko-Kultur von embryonalen Stammzellen (ES-Zellen) und Trophoblast: Expression von Stammzell- und Keimblattmarkern in ES-Zellen.
(Abstr.) Verh. Anat. Ges. 99 (Ann. Anat./Anat. Anz. 186), 249 (2004).
BEHR, R., HENEWEER, C., DENKER, H.-W., THIE, M.:
Epithelial-mesenchymal transition in colonies of rhesus monkey embryonic stem cells: a model for gastrulation?
(Abstr.) 2nd Internatl. Meet. Stem Cell Network North Rhine Westphalia, April 1st-2nd, 2004, Abstr. ID 005 (p. 24).
download poster (1.28 MB)
DENKER, H.-W.:
Experten-Stellungnahme zum Thema „Neue Entwicklungen in der Stammzellforschung“ vor der Enquete-Kommission „Ethik und Recht der modernen Medizin“ des Deutschen Bundestags.
Nichtöffentliche Anhörung am 8.12.2003. Text der schriftl. Stellungnahme: Kom.-Drs. 15-92:
Statement Denker (in the Web Archive of the German Bundestag, 26.5 KB)
All documents of the hearing (in the Web Archive of the German Bundestag)
pdf-download (26.5 KB)
DENKER, H.-W.:
Totipotenz oder Pluripotenz? Embryonale Stammzellen, die Alleskönner.
Editorial in: Dtsch. Ärzteblatt 100 (Heft 42): A 2728-2730 (2003). pdf-download (57.0 KB)
DENKER, H.-W.:
Embryonale Stammzellen als entwicklungsbiologisches Modell: Frühembryonale Musterbildung und Totipotenz.
In: Die Frühphase der Entwicklung des Menschen. (G. Rager /A. Holderegger, Eds.); Reihe: Herausforderung und Besinnung, Band 19; Universitätsverlag Freiburg/Schweiz, 2003: 23-71. pdf-download (104 MB)
THIE, M., BEHR, R., BRUCKMANN, E., HOHN, H.-P., DENKER, H.-W.:
Markerprofile und Musterbildungseigenschaften von embryonalen Stammzellen: Zell- und molekularbiologische Befunde zum Selbststrukturierungs-Potential.
(Abstr.) Klausurtagung des Kompetenznetzwerks Stammzellforschung NRW, Hagen 14.-15.7.2003 (Abstractband) (www.stammzellen.nrw.de).
BEHR, R., THIE, M., BRUCKMANN, E., KROMBERG, I., DENKER, H.-W.:
Rhesus embryonic stem cell colonies express marker genes for early embryonic patterning.
(Abstr.) Verh. Anat Ges. 98; Anat. Anz./Ann. Anat. 185 (Suppl.): 224, 2003.
BRUCKMANN, E., BEHR, R., THIE, M., DENKER, H.-W.:
Rhesus embryonic stem cell culture on feeder cells vs. cell-free laminin.
(Abstr.) Verh. Anat Ges. 98; Anat. Anz./Ann. Anat. 185 (Suppl.): 231, 2003.
DENKER; H.-W.:
Forschung an embryonalen Stammzellen: Eine Diskussion der Begriffe Totipotenz und Pluripotenz.
In: Stammzellenforschung und therapeutisches Klonen. (F. S. Oduncu, U. Schroth und W. Vossenkuhl, Eds.) Vandenhoeck und Ruprecht, Göttingen; 2002, pp. 19-35. pdf-download (35.1 MB)
THIE, M., BEHR, R., BRUCKMANN, E., HOHN, H.-P., DENKER, H.-W.:
Gene profiling and pattern formation of embryonic stem cells: culture of Rhesus embryonic stem cells on feeder cells vs. cell-free laminin.
(Abstr.) First Internatl. Meet. of the Stem Cell Network North Rhine Westphalia, Düsseldorf, November 27th, 2002, pp. 30-31.
THIE, M., BRUCKMANN, E., BEHR, R., DENKER, H.-W.:
Culture of rhesus embryonic stem cells (rESC) on feeder cells vs. cell-free laminin: effects on the expression of stem cell markers.
(Abstr.) 2nd Symposium on Therapeutic Applications of Human Stem and Precursor Cells. Hannover, Nov. 6 - 8, 2002, P16/p.80.
DENKER, H.-W.:
Embryonale Stammzellen und ihre ethische Wertigkeit: Aspekte des Totipotenz-Problems.
In: Jahrbuch für Wissenschaft und Ethik, Band 5 (L. Honnefelder und C. Streffer, Eds.). Walter de Gruyter, Berlin/New York, 2000, pp. 291-304. pdf-download (16.6 MB)
DENKER, H.-W.:
Stellungnahme zur Leitfrage „Kann, unter Berücksichtigung der verschiedenen naturwissenschaftlich verwendeten Definitionen von ‚Pluripotenz‘ bzw. ‚Totipotenz‘, gegenwärtig zuverlässig ausgeschlossen werden, dass die Biopsie an Zellen durchgeführt wird, aus denen sich ein lebensfähiger Embryo entwickeln könnte?“.
In: Deutscher Bundestag, 14. Wahlperiode, 11. Sitzung der Enquete-Kommission Recht und Ethik der modernen Medizin, 13. November 2000. Öffentliche Anhörung von Sachverständigen zum Thema Präimplantationsdiagnostik, Statements der Sachverständigen, S. 9-10.
Statement Denker (in the Web Archive of the German Bundestag, 14.8 KB)
All documents of the hearing (in the Web Archive of the German Bundestag)
pdf-download (14.8 KB)
DENKER, H.-W.:
Zur Thematik „Embryonale Stammzellen“.
In: Marburger Bund – Ärztliche Nachrichten Nr. 8 vom 4.6.1999, S. 2. pdf-download (9.63 MB)
DENKER, H.-W.:
Embryonic stem cells: An exciting field for basic research and tissue engineering, but also an ethical dilemma?
Cells Tissues Organs 165: 246-249 (1999). pdf-download (188 KB)
DENKER, H.-W.:
Lecture, Third German-Israeli Symposium “Human Dignity and Sanctity of Life”, Ramat-Gan (Israel), 20./21. Mai 1997.
Report in: Institut für Wissenschaft und Ethik (Bonn): Veranstaltungsarchiv, Abgeschlossene Fachtagungen. to the article pdf-download (31.6 KB)