20 H A S T I N G S C E N T E R R E P O R T January-February 2008

Recently, research teams led by Shinya Yamanaka andJames Thomson published separate reports that theyhad genetically modified human skin cells to behave

like embryonic stem cells.1 Like their embryonic counterparts,these induced pluripotent stem cells (iPS cells) were capable offorming all three germ layers both in vitro and in immunode-ficient mice, demonstrating their remarkable pluripotentialcharacter. Furthermore, the two teams’ iPS cell colonies weregenetically matched to the human skin cells from which theywere derived, thus enlivening the possibility that one day (per-haps soon) patient- and disease-specific pluripotent stem cellscould be generated for research that could later yield down-stream clinical benefits.

Now that human iPS cells have arrived, many will wonderwhether the thorny ethical challenges surrounding stem cellresearch can be fortuitously bypassed. This is hardly the case.While the scientific possibilities of iPS cells are enormouslyexciting, human iPS cell research raises both new ethical com-plexities and old philosophical problems.

As colleagues and I have noted elsewhere, it would be a se-rious mistake to conclude that iPS cell research averts the needfor human embryonic stem cells.2 Human iPS cell researchmust proceed together with human embryonic stem cell re-search for many important reasons.

Ongoing research on human embryonic stem cells is nec-essary to inform scientists’ growing understanding and analy-ses of human iPS cells. Much more work is needed on bothiPS cells and embryonic stem cells to determine whether thesetwo kinds of stem cells differ in biologically and clinically sig-nificant ways.3 As a matter of fact, we do not know at this

point which of the possible sources of disease-specific pluripo-tent human stem cells—genetically screened IVF embryos,iPS cells, somatic cell nuclear transfer into enucleatedoocytes,4 or somatic cell chromosome transfer into zygotesand blastomeres that have had their own chromosomes re-moved5—will prove to be the best for clinical applications, allother things considered.

Safety is also a major concern for human iPS cells since theretroviruses used to insert the pluripotency-inducing genesmight themselves lead to cancer and other harmful mutations(one of the pluripotency-inducing factors Yamanaka’s groupused was c-Myc, a gene commonly associated with tumor for-mation). In contrast, human embryonic stem cells are theonly pluripotent human cells that are genetically unmodified;they are pluripotent stem cells in their purest, unadulteratedform. Thus, in addition to possessing enormous scientificvalue in their own right, embryonic stem cells will be neededto serve as controls for examining the safety and efficacy ofhuman iPS cells.6

Prudence calls for all research alternatives to be pursued si-multaneously if possible. The idea that iPS cell research can(and should) proceed by itself is not a hope that makes muchscientific sense. Good science is supposed to leave no stoneunturned, subject to rigorous standards of research ethics.

This brings us to my next point. The pursuit of human iPScells raises new challenges for the process of informed consentin biomedical research. That a person must provide voluntaryand informed consent before participating in a scientific studyis a well-known international principle of research ethics. Ac-cording to stem cell research guidelines issued last year by theInternational Society for Stem Cell Research, all body celldonors or their legally authorized guardians must give theircontemporaneous informed consent for the use of the donors’somatic tissues in stem cell research, with a few notable excep-tions.7 These exceptions largely pertain to the use of stored tis-sue samples, which would be a desirable and convenient re-source for iPS cell studies. According to ISSCR guidelines, tis-sue samples may be used for research without contemporane-ous informed consent only if researchers procure somatic cellsfrom a tissue bank whose consent documents specifically des-ignate nuclear reprogramming methods for stem cell researchas one of the possible uses of the donor’s tissues, and if donorshave specifically agreed to this possible use. Only in extreme-ly rare cases may the requirement for specified informed con-sent be waived. In these exceptional cases, there must be noreasonable and adequate alternative source for the uniquecharacteristics of the tissue donor’s somatic cells, such that an-other donor could be found who might offer contemporane-ous informed consent.

The ISSCR guidelines were drafted prior to any publishedwork in iPS cell research, however, and the ISSCR will have torevisit them to determine whether blanket consent formsfrom tissue banks or exception from specified tissue donorconsent is appropriate for iPS cell research. Regardless of howthe ISSCR decides this issue, the concepts of blanket consentand specified donor consent are currently hot issues in the

B Y I N S O O H Y U N

Stem Cellsfrom Skin Cells:The Ethical Questions

Insoo Hyun, “Stem Cells from Skin Cells: The Ethical Questions,” Hastings Cen-ter Report 38, no. 1 (2008): 20-22.

H A S T I N G S C E N T E R R E P O R T 21January-February 2008

ethics of genetic research on stored human tissues. Thus,human iPS cell researchers may find themselves getting sweptinto this ongoing debate if they decide to use stored somaticcells.

On the other hand, obtaining contemporaneous informedconsent from tissue donors is not a simple proposition either.A chief aim of iPS cell research is to produce patient- and dis-ease-specific stem cells for study and for the eventual develop-ment of clinical applications. As a result, iPS cell researcherswill be especially interested in collecting skin biopsies frompeople who suffer from a range of seriously debilitating dis-eases and injuries for which we have not yet found cures. Re-searchers must be extremelycareful not to take unfair advan-tage of these patients and theirfamilies. Unlike stem cell studiesthat use IVF embryos, humaniPS cell research would leave asurvivor behind who is the ge-netic source of an iPS cell line.Moreover, these individuals arelikely to suffer from grave med-ical conditions. Those who vol-unteer to donate their own ortheir ill children’s somatic cellsfor iPS cell research may do soin the hopes of directly or indi-rectly benefiting themselves ortheir loved ones through down-stream therapeutic applicationsof these genetically-matchedstem cell lines.8 Given these pos-sible motivations and the direcircumstances in which manypatients and their families mayfind themselves, it is crucial thatresearchers not inadvertently ex-ploit their donors’ hopes and aspirations.

To guard against this danger, due care must be taken dur-ing the informed consent process to protect the liberty inter-ests of patients providing tissue samples for iPS cell research.As with all human materials donors in stem cell research, so-matic cell donors must be adequately informed of the aspectsof the research that reasonable people would typically find rel-evant to their decision to participate.9 Especially pertinentmay be the fact that iPS cell lines would be geneticallymatched to their original tissue donors and that they will like-ly be shared with researchers at different institutions for acad-emic and commercial purposes, most of which are unknownat this time. Donors should also be aware that their resultingiPS cells will likely be transplanted into laboratory animals forhuman-to-animal chimera experiments, first to assess thecells’ developmental capabilities and later to conduct preclini-cal proof of concept studies in animal models. Because sometissue donors may be uneasy with the idea that their geneti-cally-matched iPS cells could be used to develop human bio-

logical characteristics in laboratory animals, they should begiven an opportunity early in the consent process to refuse todonate their tissues for iPS cell research.

These are just a few examples of the factors that must beaddressed during the informed consent process. My mainpoint here is that, given the unique nature of iPS cell research,the ethical challenges of ensuring rigorous informed consentand of preventing the excessive lure of “therapeutic hope”10

may be especially acute.Another ethical factor to consider involves the welfare in-

terests of patients who in the foreseeable future may seek outclinical research involving human iPS cells or their direct de-

rivatives. These human studiescould include first-time researchvolunteers or original donors forautologous transplantationstudies. In either case, the po-tential for abuse is great. Unlikeattempting to generate patient-specific pluripotent stem cellsvia somatic cell nuclear transfer(cloning), iPS cell research is rel-atively easy. There are no scarcehuman eggs to procure or mi-cromanipulation techniques tomaster, as in human researchcloning. Almost any competentcell biologist or geneticist can at-tempt to produce human iPScells. This fact alone may com-pound the ever-present and veryreal threat that some researchersor clinicians could move tooquickly to human clinical trialsor offer unproven “treatments”using human stem cells. Again,the keen exploitability of des-

perate patients and their families should not be casuallyshrugged off. Presently the ISSCR is in the process of orga-nizing a multinational, multidisciplinary task force to draftinternational guidelines for the clinical translation of stemcells. Undoubtedly, the implications of these recent break-throughs in iPS cell research will be a major issue for this newtask force.

Admittedly, some observers will argue that the majority ofthe concerns I have raised here are manageable as long as rig-orous standards of informed consent are upheld and strictguidelines for translational research are followed. Some mayeven find reassurance in the belief that human iPS cell re-search should be capable of producing valuable patient- anddisease-specific stem cell lines without resorting to human re-search cloning and ushering in all its perceived social conse-quences. Others may applaud the apparent ability of iPS cellsto preserve some people’s conceptions of the sanctity of po-tential or nascent human life. From certain moral and theo-

Now that induced pluripotent stem cells arehere, many will wonder

whether ethical challengessurrounding stem cell

research can be fortuitously bypassed.

This is hardly the case.

22 H A S T I N G S C E N T E R R E P O R T January-February 2008

logical points of view, isn’t human iPS cell research superior toall other methods for deriving pluripotent stem cells?

Perhaps not—at least not according to the very same valuesuppositions of the public that I just described. It is worthnoting that human iPS cell research carries the familiar ring ofold philosophical questions about reproduction, life, andwhat it means to be human. The Yamanaka and Thomson re-search teams have shown that ordinary skin cells can be drivenback to a primitive, embryonic state of pluripotency. But noone knows yet exactly where the limits of this reprogrammingtechnique lie. Perhaps iPS cell researchers will discover thatskin cells can be driven back even further in development to atotipotent state—that is, to a single zygote-like cell capable ofgenerating not only all three germ layers but also all the sup-porting extra-embryonic tissues. If this were to happen, thenone could argue that any cell in a person’s body has the bio-logical potential to give rise to another complete human beingunder the right circumstances, regardless of whether the orig-inal person is alive or recently deceased. Such a circumstancewould be truly equivalent to human cloning in the original,horticultural sense of the Greek word klon—that is, “twig.”

Even if this bizarre scenario is deemed scientifically impos-sible, there is still another, perhaps more realistic possibilityworth considering. Human iPS cells, if they are truly pluripo-tent, should be capable of generating human sex cells. Butthen this would entail that ordinary skin cells could be trans-formed into human sperm and eggs. This fact could radicallyalter our commonsense notions of human fertility and infer-tility. New biological categories and entities could result, andthese have historically disrupted some of society’s longstand-ing philosophical assumptions.

Without doubt, these recent breakthroughs in human iPScell research are of monumental importance for both science

and society, but the ethical issues corresponding to iPS cell re-search are much more complex than many might initially be-lieve and should not be glossed over. Some may wonderwhether we will soon enter a “Brave New World” withunimaginable scientific possibilities. I believe we are alreadystanding in that world, and that researchers, patient advocacygroups, and the public should be both happy and cautiousabout it.

1. K. Takahashi, K. Tanabe, M. Ohnuki, et al., “Induction of Pluripo-tent Stem Cells from Adult Human Fibroblasts by Defined Factors,”Cell 131 (2007): 861-72; J. Yu, M.A. Vodyanik, K. Smuga-Otto, et al.,“Induced Pluripotent Stem Cell Lines Derived from Human SomaticCells,” Science, published online November 20, 2007.

2. I. Hyun, K. Hochedlinger, R. Jaenisch, and S. Yamanaka, “NewAdvances in iPS Cell Research Do Not Obviate the Need for HumanEmbryonic Stem Cells,” Cell Stem Cell 1 (2007): 367-68.

3. Takahashi et al., “Induction of Pluripotent Stem Cells from AdultHuman Fibroblasts by Defined Factors”; Yu et al., “Induced PluripotentStem Cell Lines Derived from Human Somatic Cells.”

4. J.A. Byrne, D.A. Pedersen, L.L. Clepper, et al., “Producing PrimateEmbryonic Stem Cells by Somatic Cell Nuclear Transfer,” Nature 450(2007): 497-502.

5. D. Egli, J. Rosains, G. Birkhoff, and K. Eggan, “DevelopmentalReprogramming after Chromosome Transfer into Mitotic Mouse Zy-gotes,” Nature 447 (2007): 679-85.

6. Hyun, Hochedlinger, Jaenisch, and Yamanaka, “New Advances iniPS Cell Research.”

7. International Society for Stem Cell Research, “Guidelines for theConduct of Human Embryonic Stem Cell Research,” http://www.isscr.org/guidelines/ISSCRhESCguidelines2006.pdf (2006).

8. I. Hyun, “Magic Eggs and the Frontier of Stem Cell Science,”Hasting Center Report 36, no. 2 (2006): 16-19.

9. International Society for Stem Cell Research, “Guidelines for theConduct of Human Embryonic Stem Cell Research.”

10. Hyun, “Magic Eggs.”