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1576 N Engl J Med, Vol. 346, No. 20 May 16, 2002 www.nejm.org

The New England Journal of Medicine

Sounding Board

STEM CELLS SCIENTIFIC, MEDICAL,

AND POLITICAL ISSUES

T is rare that a scientific subject causes controver-sy not only among scientists but also among pol-

iticians and the public. Stem-cell biology is such asubject. The media reports new claims as soon as (orbefore) they appear in the scientific literature or arepresented at scientific meetings. Talk-show hostspresent their views, and both Congress and the ex-ecutive branch follow with policy initiatives. But inits present state, there is little certitude in the scienceof stem cells, and the hard facts are emerging slowly.It is important for the public and policy makers tounderstand the fundamentals of stem-cell biology

and for physicians to recognize that this knowledgewill alter the way we think about the origin and re-generation of tissues and organs and the develop-ment of disease. It has already influenced medical prac-tice and will eventually affect medicine in important

ways. Much will be gained by developing medical in-terventions that are based on these cells and theprocesses that regulate them.

WHAT ARE STEM CELLS?

Stem cells have the unique capacity not only to giverise to more stem cells (self-renewal) but also to gen-erate differentiated progeny.1-3 They are present at allstages of development and probably exist in all multi-cellular organisms. In the blastocyst stage of the em-bryo before implantation, the inner cell mass containscells that will become the fetus. Some of these cellsare pluripotent stem cells that give rise to all types ofsomatic and germ-line cells. When these pluripotentcells are grown in vitro, they become embryonic stem-cell lines.4,5

When mouse embryonic stem cells are transplantedinto mouse blastocysts, the offspring of such blasto-cysts are often somatic and germ-line chimeras thatcarry genes from both the embryonic stem cells andthe original blastocysts. These chimeras are powerfultools for research. One can, for example, repair ormutate a gene in a transplantable embryonic stem celland study the way this action alters the developmentor function of the stem cells daughter cells in themouse recipient. Moreover, the insertion of humandisease genes into mouse embryonic stem cells has

yielded useful animal models of human diseases. Hu-man embryonic stem cells are now available and areat an early stage of validation.6

The developmental stages between pluripotent em-bryonic cells and multipotent tissue-specific stem

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cells, such as hematopoietic stem cells, are still unclear.Pluripotent stem cells generate germ-line stem cellsplus tissue-specific stem cells, perhaps by way of an in-termediate class of multisomatic stem cells, which

would differ from pluripotent cells by contributing to

all somatic lineages, but not the germ line.7 Multipo-tent tissue-specific stem cells can be found from the fe-tal stage onward.3 In adults, they can participate in therenewal and regeneration of tissue, and during fetallife they may be units of tissue generation.

It is likely that there are specific stem cells formost, if not all, tissues, but there is confusion about

when the results of an experiment or a therapeuticintervention can be attributed to stem cells. Verifi-cation of the presence of the critical properties ofstem cells self-renewal and differentiation should be the gold standard for all such studies. Forexample, autologous transplants of mobilized pe-ripheral blood from patients with cancer may con-

tain hematopoietic stem cells, cancer cells, and alltypes of blood cells, yet nearly every group callsthese stem-cell transplants. This practice is incorrectand misleading. The term hematopoietic stem-celltransplantation should be used only when stemcells are the sole cell population in the transplant.

CAN TISSUE-SPECIFIC STEM CELLS

CHANGE THEIR FATES IN ADULTS?

Almost every week, the scientific literature and thepublic media announce an experiment showing thatstem cells from one tissue can circulate to anothertissue and adopt the developmental fate of the sec-ond tissue (a process called transdifferentiation). Infact, in only a few studies of transdifferentiation haveauthentic stem cells been prospectively isolated ormarked to ensure the accurate identification of theoriginal cells. In true transdifferentiation, the differ-entiated cells in the second tissue or organ mustarise solely from single cells of the first tissue, andthe transdifferentiated cells must have not only theappearance but also the function of the second tis-sue.8-11 Moreover, it is important to determine wheth-er the original stem cell is a multipotent tissue-restrict-ed stem cell that transdifferentiates or an itinerantstem cell that has traveled through the blood from,say, the heart to the bone marrow and then back tothe heart. (This is a common problem; in mice, morethan 10,000 hematopoietic stem cells pass throughthe bloodstream and tissues every day.)12 It is stillunclear whether true multisomatic stem cells exist inadults, and very few published studies meet the rig-orous criteria essential for the identification of suchcells.8-10 A clear resolution of this question is essentialfor the formulation of a rational public policy con-cerning stem-cell research and medical applications ofstem-cell transplantation.


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HUMAN EMBRYONIC STEM CELLS

IN SCIENCE AND MEDICINE

Several human embryonic stem-cell lines have thecapacity to differentiate into a variety of types of tis-sue.6 The diversity of these lines is limited both by

their number and by the fact that they were derivedfrom patients in fertility clinics. That is, they do notrepresent the full ethnic and genetic diversity of theU.S. population. Nevertheless, much valuable knowl-edge will come from the research use of these cells,

which may make it possible to investigate the gene-expression patterns of all intermediates between plu-ripotent embryonic stem cells and various multipo-tent tissue-specific stem cells, as well as between thesestages and mature tissue cells. Even more might belearned by following the differentiation of single hu-man embryonic stem cells after they have been trans-planted into mouse blastocysts, but in my view, be-fore embarking on such experiments, we must be ableto guarantee that no human gametes could form.

I believe that using the currently available embry-onic stem-cell lines to delineate developmental lin-eages of human cells will be extremely valuable.Knowledge gained from such studies should spawna search for molecules or factors that cause particularcells to follow particular pathways and inhibit themfrom following others. We can expect such researchto affect not only classic pharmaceutical research butalso the development of cell-based therapies.

However, I believe that new lines of human embry-onic stem cells will be needed. We know that the pres-ence of a genetic predilection to a disease does notnecessarily mean that the disease will develop. Germ-line alterations at several loci and somatic mutationsmay also be necessary. For these reasons, it is almostcertain that no line of embryonic stem cells derivedfrom blastocysts produced in fertility clinics will havethe right combination of genes to be useful in studiesof a particular disease. They will not, for example,serve for studies of the many kinds of cancer that re-sult from a succession of somatic mutations. It is self-evident that no available embryonic stem-cell line or,for that matter, any random somatic cell from an af-fected person carries the entire set of genes with rel-evance to the disease under investigation. Only thediseased cells have these genes. By contrast, embryon-

ic stem-cell lines with the appropriate sets of inheritedand acquired genes should prove invaluable for study-ing the cellular basis of many diseases.

How could such stem-cell lines be generated? Oneway is by transferring somatic-cell nuclei into enucle-ated eggs (nuclear transplantation). When stimulatedto divide, the cell can form blastocysts of predefinednuclear genotype (with the mitochondrial DNA com-ing from the egg). Cells from the inner cell mass ofthese blastocysts can be isolated, cultured, and used

to generate embryonic stem-cell lines of predefinedgenotype.13-16 Many groups of investigators plan toderive such stem-cell lines from and for persons whoneed transplants of multipotent stem cells a processcalled therapeutic cloning. The risk of immune rejec-

tion is minimal (there is some risk, however, since pro-teins encoded by mitochondrial genes can stimulatethe immune system).

POLITICAL AND ETHICAL ISSUES

During this congressional session, it is likely thatlegislation will be passed governing research involv-ing human embryonic stem cells, including the prac-tice of deriving embryonic stem-cell lines from em-bryos created in clinics for in vitro fertilization andthe use of nuclear transplantation to produce humanpluripotent cell lines. It is possible that religious andethical considerations will lead to a ban on such re-search. Nearly 25 years ago, similar considerationsled to calls for a ban on research involving recombi-nant DNA, but it is now unquestioned that hun-dreds of thousands of people are alive or healthierbecause of the use of recombinant DNA to produceinsulin, erythropoietin, granulocyte colony-stimulat-ing factor, interferons, and other important therapeu-tic recombinant molecules.

The new question of whether to permit nucleartransplantation for the production of human embry-onic stem-cell lines of defined genotype now facesCongress, state legislatures, and the executive branch,

which is advised by the recently appointed PresidentsCouncil on Bioethics. The debate has been complicat-ed by the fear that nuclear transplantation into enucle-ated eggs might be used to clone a human being. Thispast year, two panels appointed by the National Acad-emies published reports on these questions. One ofthese reports, Stem Cells and the Future of Regener-ative Medicine, includes the deliberations and testi-mony of scientists, physicians, ethicists, and those

who, for religious reasons, moral reasons, or both, op-pose research involving human embryonic stem cells.17

The main recommendations in that report are to allowthe continuation of research on both adult and em-bryonic human stem cells; to permit the expansion ofthe number of embryonic stem-cell lines for researchpurposes; and to encourage research into ways of pre-

venting the immune rejection of stem cells and tissuesderived from them, including those obtained throughtherapeutic cloning.17

The second panel considered the scientific, medi-cal, and ethical aspects of reproductive cloning andnuclear transplantation for the production of pluri-potent human stem-cell lines.18 It did not focus onmoral issues. The intention of the report, Scientificand Medical Aspects of Human Reproductive Clon-ing, was to provide information to broad segments


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The New England Journal of Medicine

of society, including government and private agen-cies. The panel recommended the prohibition of hu-man reproductive cloning and suggested enacting alegally enforceable ban on the procedure and sched-uling a review of this recommendation within five

years. It concluded that the scientific and medicalconsiderations that justify a ban on human reproduc-tive cloning were not applicable to nuclear transplan-tation for the production of stem cells. The legally en-forceable ban would protect against rogue groups thatsought to implant intermediary blastocysts for repro-ductive cloning. The panel also encouraged a broadnational dialogue on the societal, religious, and ethi-cal questions raised by the new technology.18

There may be no middle ground in the debate.For some segments of society, blastocysts producedby nuclear transplantation are embryos to be accord-ed full human rights, and their destruction or biopsyto produce embryonic stem-cell lines constitutes the

taking of lives. But preventing the use of such blasto-cysts would halt all research on embryonic stem-celllines derived from nuclear transplantation, therebyblocking important medical research. I believe suchresearch will be as valuable to medicine as recombi-nant DNA research has proved to be. It is importantthat the ethical and legislative debates proceed withthe understanding that the decision makers are re-sponsible for the lives that would be affected by pre-

venting or delaying research involving embryonicstem cells. The legislative and executive branches offederal and local government that will make decisionsabout research on stem cells should be ready to acceptthis responsibility.

Last summer, the House of Representatives brieflyconsidered and then passed a bill that banned bothhuman reproductive cloning and nuclear transplan-tation for the production of stem cells. The Housepassed the bill without the benefit of any compre-hensive scientific or medical testimony. Since then,reports from the National Academies17,18 and from aCalifornia commission19 have provided extensive and

well-documented scientific, veterinary, and medicaldata, as well as addressing the ethical considerationssurrounding the use of human embryonic stem cells.The issues are now before the Senate. If the Senatepermits nuclear transplantation for the production ofhuman stem cells, it would be prudent for the Houseto use the opportunity of reconsideration to informthemselves by studying these reports, at the very least.

President George W. Bush has appointed a Coun-cil on Bioethics to consider these issues; a minorityof its members are scientists and physicians. Unlikethe panels of the National Academies, whose mem-bers were pledged to maintain objectivity and didnot draft their reports until all the relevant data andinformation had been received and discussed, the

Council on Bioethics contains several members whohave continued to speak and write publicly in oppo-sition to nuclear transplantation for the productionof human pluripotent embryonic stem-cell lines. Inmy view, an objective recommendation cannot be

obtained from that body unless its members layaside their preconceived notions, review the data,and forswear any attempts to sway the public debatebefore they hear all the arguments.

What if nuclear transplantation for the productionof stem cells is banned in the United States but al-lowed in other countries (for example, China, Swe-den, and the United Kingdom)? Biomedical research-ers in the United States will have to learn of newadvances by reading about them, rather than partici-pating in them, or they will have to leave the UnitedStates in order to participate in research. New biomed-ical companies that translate these discoveries intotherapies will be created in other countries, not here.

And what if these companies succeed? Their productscould not be imported to treat our patients (accordingto provisions of the Weldon bill [H.R.2505] and theBrownback bill [S.790, the Human Cloning Prohi-bition Act of 2001]), and only the wealthy wouldgain access to such treatments abroad. Even if thesetherapies could be imported, it is possible that physi-cians might withhold them from their patients for re-ligious reasons.

Unfortunately, there are few in Congress or thePresidents council who can evaluate the scientificand medical issues in order to make an appropriatelyinformed decision. Too often in recent Senate hear-ings, the views expressed by senators have been based

on articles in newspapers and popular magazinesrather than reports of the National Academies or ar-ticles in peer-reviewed journals. Some journalists arefailing the public trust by publicizing findings thathave not been published in the scientific literature orindependently replicated.

In summary, experiments in animals have shownthat nuclear transplantation for the production ofembryonic stem-cell lines can be accomplished withmature cell nuclei, including nuclei containing medi-cally important genetic defects and mutations. Thereis already evidence that these embryonic stem-celllines can help unlock secrets of developmental andpathogenic events that might not be revealed other-

wise. The technology is ready for the production ofhuman embryonic stem-cell lines from diverse mem-bers of our society, from somatic cells of patients

with heritable diseases, and from diseased cells (forexample, all cancers) whose nuclei are a repositoryof the history of inherited and somatic mutationsthat caused these diseases. The method has the po-tential for producing cells for the treatment of a va-riety of diseases. Congress, the President, and the


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medical community now face a difficult decision: toprevent the production of blastocysts by nuclear trans-plantation, or to pursue paths of medical researchand therapies that, in my view, will affect hundredsof thousands of lives.

IRVING L. WEISSMAN, M.D.

Stanford University School of MedicineStanford, CA 94305-5323

Dr. Weissman was cofounder of two companies that perform researchwith adult stem cells, SyStemix, Inc., and StemCells, Inc., and has held orholds significant equity in these companies. He was also the chairman ofthe National Academies panel cited in reference 17. The opinions expressedin this article are those of the author and not necessarily those of that panelor the National Academies.

REFERENCES

1. Becker AJ, McCulloch EA, Till JE. Cytological demonstration of theclonal nature of spleen colonies derived from transplanted mouse marrowcells. Nature 1963;197:452-4.2.

Siminovitch L, McCulloch EA, Till JE. The distribution of colony-forming cells among spleen colonies. J Cell Comp Physiol 1963;62:327-36.3. Weissman IL. Translating stem and progenitor cell biology to the clinic:barriers and opportunities. Science 2000;287:1442-6.4. Evans MJ, Kaufman MH. Establishment in culture of pluripotent cellsfrom mouse embryos. Nature 1981;292:154-6.5. Martin GR. Isolation of a pluripotent cell line from early mouse em-bryos cultured in medium conditioned by teratocarcinoma stem cells. ProcNatl Acad Sci U S A 1981;78:7634-8.6. Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem celllines derived from human blastocysts. Science 1998;282:1145-7. [Erratum,Science 1998;282:1827.]7. Weissman IL. Stem cells: units of development, units of recognition,and units in evolution. Cell 2000;100:157-68.8. Anderson DJ, Gage FH, Weissman IL. Can stem cells cross lineageboundaries? Nat Med 2001;7:393-5.9. Weissman IL, Anderson DJ, Gage F. Stem and progenitor cells: origins,phenotypes, lineage commitments, and transdifferentiation. Annu Rev CellDev Biol 2001;17:387-403.10. Morrison SJ. Stem cell potential: can anything make anything? CurrBiol 2001;11:R7-R9.11. Blau HM, Brazelton TR, Weimann JM. The evolving concept of astem cell: entity or function? Cell 2001;105:829-41.12. Wright DE, Wagers AJ, Gulati AP, Johnson FL, Weissman IL. Physio-logical migration of hematopoietic stem and progenitor cells. Science2001;294:1933-6.13. Wakayama T, Tabar V, Rodriguez I, Perry AC, Studer L, MombaertsP. Differentiation of embryonic stem cell lines generated from adult somat-ic cells by nuclear transfer. Science 2001;292:740-3.14. Munsie MJ, Michalska AE, OBrien CM, Trounson AO, Pera MF,Mountford PS. Isolation of pluripotent embryonic stem cells from repro-grammed adult mouse somatic cell nuclei. Curr Biol 2000;10:989-92.15. Hochedlinger K, Jaenisch R. Monoclonal mice generated by nucleartransfer from mature B and T donor cells. Nature 2002;415:1035-8.16. Kawase E, Yamazaki Y, Yagi T, Yanagimachi R, Pedersen RA. Mouseembryonic stem (ES) cell lines established from neuronal cell-derivedcloned blastocysts. Genesis 2000;28:156-63.17. Committee on the Biological and Biomedical Applications of StemCell Research. Stem cells and the future of regenerative medicine. Wash-ington, D.C.: National Academy Press, 2002.18. Panel on Scientific and Medical Aspects of Human ReproductiveCloning. Scientific and medical aspects of human reproductive cloning.

Washington, D.C.: National Academy Press, 2002.19. California Advisory Committee on Human Cloning. Final report ofthe California Advisory Committee on Human Cloning. Sacramento: Cal-ifornia Department of Health Serv ices, 2002. (Accessed April 23, 2002, athttp://www.law.stanford.edu/features/greely/.)

Copyright 2002 Massachusetts Medical Society.

EUROPEAN PERSPECTIVESON THERAPEUTIC CLONING

LTHOUGH recent advances in stem-cell re-

search hold promise for therapeutic use, thispromise has been accompanied by social, political,economic, legal, religious, and ethical questions. Thesequestions have touched a raw nerve, and numerouslaws and regulations have been implemented or arebeing considered in order to control the use andspread of this new technology. The legal situation isparticularly complex in Europe, where each countryis governed through both national legislation andthe international European legislation passed by theEuropean Union. Since there are deep social and po-litical disparities among countries within the unionthat stem in part from cultural and religious differ-ences, it is not surprising that a patchwork of legis-

lation and regulation is emerging. These legislativeand regulatory initiatives address two main ethicalquestions. First, does the production or use of humanembryos in research threaten human dignity? Andsecond, might therapeutic cloning lead to a commer-cialization of human eggs or embryos? In this article,I will discuss the ways in which these questions arebeing addressed in Europe.

PRODUCTION AND USE OF EMBRYOS

IN RESEARCH AND THERAPY

The debate over the production or use of embryosin research can be reframed to highlight the ethical is-sues if it is posed in the following form: to what extent

do human embryos and fetuses in their early stageshave the right to protection? It is a fundamental tenetin many European cultures that humans shall not betreated merely as the means to an end but also as endsin themselves. If the rights accorded to humans afterbirth are also valid for unborn humans, from whatstage of development are these rights accorded?

The vigor with which this problem is debated var-ies from country to country. In countries in whichreligion has a strong influence on political decisionmaking, such as Italy, Germany, Norway, Argentina,and the United States, the moral status of the humansperm, egg, or fetus is at the center of the debate. Ifa fertilized egg is conceded moral status, conductingexperiments on this egg becomes more morally prob-lematic than if it were not conceded any such statusin its own right. A focus on human dignity reveals abasic conflict: the mothers dignity (especially herright to ultimate authority over her own body) standsopposed to that of the fertilized egg (in terms of itsright to develop into a person). The dignity of theadult human (male or female) also conflicts with whatis alleged in some countries to be the right of the

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