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Skepticism About the Convertibility of InducedPluripotent Stem CellsThomas V. Cunningham aa University of PittsburghPublished online: 11 Jan 2013.
To cite this article: Thomas V. Cunningham (2013) Skepticism About the Convertibility of Induced Pluripotent Stem Cells,The American Journal of Bioethics, 13:1, 40-42, DOI: 10.1080/15265161.2012.747027
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Homo sapiens species entitled to legal protection as such.However, should the process lead to the destruction of thepresently existing identity of the original two- to four-cellembryo, then personhood proponents would likely con-sider this cell conversion technique to be impermissible.In conclusion, even if the goal of many personhood pro-ponents is to extend legal protection to each member ofthe Homo sapiens species from the very beginning of itsexistence, we ought to be clear about when such exis-tence begins. Thus, beyond providing a useful critique ofthe potentiality argument in favor of embryo protection,many of the points made by Stier and Schoene-Seifert alsoproblematize the Homo sapiens argument for personhoodthat is very much at the center of the U.S. personhoodmovement.
Cohen, I. G. 2008. Intentional diminishment, the non-identity prob-lem, and legal liability. Hastings Law J. 60: 347375.
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Singer, P. 1975. Animal liberation: A new ethics for our treatment ofanimals. New York, NY: Random House.
Stier, M., and B. Schoene-Seifert. 2013. The argument from poten-tiality in the embryo protection debate: Finally depotentialized?American Journal of Bioethics 13(1): 1927.
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Skepticism About the Convertibilityof Induced Pluripotent Stem Cells
Thomas V. Cunningham, University of Pittsburgh
In this issues target article, Stier and Schoene-Siefert (2013)purport to depotentialize the argument from potentialitybased on their claim that any human cell may be con-verted into a morally significant entity, and consequently,the argument from potentiality finally succumbs to a reduc-tio ad absurdum. I aim to convey two reasons for skepticismabout the innocuousness of the notion of cell convertibility,and hence, the cogency of their argument.
First, some brief remarks about potential. FollowingAristotle, Stier and Schoene-Siefert distinguish two typesof potential, active and passive. This distinction hasbeen captured elsewhere in terms of two senses, producingor becoming (Buckle 1988). An entity is said to have po-tential in the sense of becoming if it maintains its identitythrough a developmental process; it must persist, despitestate changes, while developing new features and quali-ties. What matters is that the entity possesses some causalpower, or potency, such that under suitable conditions it willdevelop into another entity. By contrast, potentiality in thesenseofproductiondoesnot requirepreservationof identitythrough developmental stages or preservation of integrity.If the components of an entity may be used to generate an-other entity, then the former has potential in the productivesense.
Address correspondence to Thomas V. Cunningham, University of Pittsburgh, Department of History and Philosophy of Science, 1017CL, 4200 Fifth Avenue, Pittsburgh, PA 15260, USA. E-mail: email@example.com
Beyond this generic description of potentiality, theconcept takes on particular meaning in the context of themorality of manipulating biological entities. For example,arguments from potentiality aim to persuade that humanembryos have the potential to become morally significantentities, which justifies attributing some (perhaps equiva-lent) moral status and warrant for protection to them.
In their response to this argument, Stier and Schoene-Siefert contend recent biotechnological advancements sug-gest all human cells have the potential to develop intomorally significant entities. Hence, under the assumptionsof the potentiality argument, all cellswarrant protection; theevident absurdity of this conclusion results in a reductio.Their view rests on the contention that through a three-stepprocess, cells lacking moral status may be converted intomorally significant entities. Those steps are (1) conversioninto induced pluripotent stem cells (iPSCs); (2) subsequentconversion into embryos via tetraploid complementation;and (3) introduction into uteruses and development intoneonates.
Stier and Schoene-Siefert acknowledge that no humancells have ever been engineered in this three-step conversionprocess. However, recent work does show that Steps 1 and2 are possible using human cells (Ezashi et al. 2012). We
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focus on these two conversion steps, because they arehow cells are purportedly innocuously converted from onephase to another, concluding with their realizing latentcausal powers to become embryos.
Takahashi and colleagues (2007) describe the first con-version step: Human cells isolated by biotechnology com-panies from knee joints, facial skin, neonatal foreskin, orcarcinomas are infectedwith specially engineered viral vec-tors containing high copies of codes for four proteins.Whenthese proteins are produced by cells nativemachinery, theyundergo changes in gene expression patterns, often referredto as reprogramming. Thereafter, the resultant cellularproteins cause cells to undergo morphological changes andbehave like human embryonic stem cells (hESCs).
Although various biochemical and morphological testsshow that resultant iPSCs behave like hESCs,much remainsunknown about how Conversion Step 1 induces cells to un-dergo these changes. As Takahashi and colleagues note, themechanismsbywhich the fourproteins inducepluripotencyremain elusive (2007, 868). Yet they do know that result-ing cells exhibit more than 20 genomic retroviral integrationsites, suggesting a significant increase in tumorigenesis inthese cells and their derivatives; indeed, they report roughly20% ofmice derived from iPSCs develop tumors.Moreover,for our purposes, they report important limitations to theirresearch. One is that Conversion Step 1 is extremely inef-ficient. Each time they manipulated 500,000 somatic cellsthey were able to generate 10 iPSCs on average. Also, iP-SCs express many genes differently than hESCs, 1,267 tobe exact. So, although the expression profiles of iPSCs andhESCs are much more similar to each other than either is tounconverted somatic cells, they clearly are not identical.
Acknowledging these aspects of how iPSCs are pro-duced provides one reason for skepticism about Stier andSchoene-Sieferts analysis, because they claim that, muchlike one customizes the options of a software program,nothing substantial is added to the [initial] cell, nothingtaken away (21). However, our epistemic stances towarda software program differ considerably from a developingiPSC or human embryo. Regardless of whether one person-ally knows how software works, many do know; however,no one knows howhuman embryos programswork.Nordo we know for sure whether the 10 iPSCs Takahashi andcolleagues generated out of the initial 500,000 cells wereones they both engineered and selected for, or ones theymerely selected for. Additionally, theirmicroarray data sug-gests something substantial is indeed added to convert theinitial cells to iPSCs: Codes for proteins are added thatchange cells genetic expression profiles, which results intheir having expression profiles unique from either theirprogenitor cells or hESCs. Thus, claims of mere trigger-ing overreach.
Despite Stier and Schoene-Sieferts cogent analysis ofthe importance of identity claims for the argument from po-tentiality, these facts threaten their conclusion. We simplydo not knowwhat it would mean to be identical to an iPSC,because we do not know enough about how iPSCs are cre-ated. Assuming a reductionistic line of reasoning and solelyusing a measure of genetic similarity, it appears iPSCs are
a unique type of cell, being identical to neither their pre-cursors nor hESCs. Hence, we may agree with Stier andSchoene-Siefertto understand the moral status of iPSCs,we will have to make choices about the morality of theirproduction, rather than their identity relations. However,we may disagree that these cells are derived by innocuousmeans, and thus that convertibility is an acceptable premisein a reductio.
This last point relates to the second and most salientpoint for skepticism about the convertibility of iPSCs. InConversion Step 2, it is important to focus on the method oftetraploid complementation. Therein, two two-celled em-bryos are suspended between electrodes and electricallypulsed, causing them to join, which results in the four-celled tetraploid. After a day of culturing, 1015 ESCsor iPSCs may be placed between two tetraploids in a wellon a culture plate. In mice, after another day of culturing,the resulting aggregates may be transferred to pseudo-pregnant females, whowill later bear live pups at extremelylow rates of efficiency (Kang et al. 2009; Nagy et al. 1993).This experimental procedure justifies the claim that any cellhas the potential to be converted into amorally significantentity.
Briefly describing Conversion Step 2 suffices for moti-vating skepticism about its innocuousness because it showsthat to convert iPSCs to embryos requires that one first be-gin with embryos. One must destroy two embryos in order togenerate an embryo from iPSCs. It is not as though innocuouscells are manipulated in morally irrelevant ways in orderto produce embryos by cell conversion. No, one destroystwo embryos in the process. Thus, the moral algebra seemsquite clear. One begins with two entities that have potentialin any meaningful sense of the term. Then one manipulatesthose entities in ways that purportedly destroy that potentialand one uses them to generate potential in a group of cellsthat, prior to that moment, lacked it.
Much remains unknown about early embryogenesis,and hence the development of embryo-like cells, includ-ing iPSCs and hESCs. Our ignorance is important becauseit must be acknowledged when evaluating the cogency ofarguments like Stier and Schoene-Sieferts. We know thatembryos under natural conditions reliably lead to fetusesand neonates. We know that iPSCs do not. We know thatunless they are experimentally manipulated to form de-nuded tetraploids, human embryos are the paradigmaticcells by which the notion of potentiality gains its meaning.But we do not know how they do it. We do not know whatconfers this potential. And yet, despite this ignorance, weare supposed to feel secure in the belief that when amethodof cell conversion strips embryos of their potential, com-bines them with iPSCs, and a new potential emerges, nomorally salient acts have been performed? I am skepticalfor the aforementioned reasons.
In conclusion, although I agree with Stier and Schoene-Sieferts ultimate aims, I believe their argumentoverreaches,further muddying debates over the ethics of hESC-relatedresearch. Elsewhere I describe a central Rawlsian tenetgoverning such important deliberations, where scientificfacts interact subtly with moral intuitions (Cunningham,
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in press). One should meet a criterion of reasonableness. Byglossing over certain facts, including that human embryosare destroyed in the production of iPSC-derived embryos,Stier and Schoene-Siefert fail to meet this threshold. Thus,I suggest skepticism about the notion of convertibility, inpart because the locution suppresses the fact that embryosare destroyed when cells are converted. Hence, convert-ibility poorly serves its function in a reductio against theargument from potentiality.
Buckle, S. 1988. Arguing from potential. Bioethics 2: 227253.
Cunningham, T. In press. What justifies the United States ban onfederal funding for nonreproductive cloning? Medicine, Health Care,and Philosophy.
Ezashi, T., B. Telugu, andR. Roberts. 2012.Model systems for study-ing trophoblast differentiation from human pluripotent stem cells.Cell and Tissue Research 349: 809824.
Kang, L. 2009. iPS cells can support full-term development ofte...