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THE ETHICAL ISSUES IN HUMAN STEM CELL RESEARCH REPORT FROM A WORKSHOP 10–11 October, 2000 Organised by the Nordic Committee on Bioethics Nord 2001:21

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THE ETHICAL ISSUES IN HUMAN STEM CELL RESEARCH

REPORT FROM A WORKSHOP

10–11 October, 2000Organised by the Nordic Committee on Bioethics

Nord 2001:21

Nord 2001:21 The Ethical issues in human stem cell research© Nordic Council of Ministers, Copenhagen 2001ISBN 92-893-0653-XISSN 0903-7004Print:AKA-print, Århus 2001Cover and layout: Peter WaldorphCopies: 600Printed on paper approved by the Nordic Environmental Labelling.This publication may be purchased from any of the agents listed on the last page.

The Nordic Committee on Bioetics was established in 1988 to identify and survey ethicalissues related to legislation, research and developments in biotechnology in the Nordic countriesand internationally. The committee has two members from each of the Nordic countries. Itcontributes to the public debate by organising workshops on selected items, publishing reports andpolicy documents, and spreading information to national authorities and national ethicalcommittees.

The Nordic Council of Ministers was established in 1971. It submits proposals on cooperationbetween the governments of the five Nordic countries to the Nordic Council, implements theCouncil's recommendations and reports on results, while directing the work carried out in thetargeted areas. The Prime Minister’s of the five Nordic countries assume overall responsibility forthe cooperation measures, which are co-ordinated by the ministers for cooperation and the NordicCooperation committee. The composition of the Council of Ministers varies, depending on thenature of the issue to be treated.

The Nordic Council was formed in 1952 to promote cooperation between the parliaments andgovernments of Denmark, Iceland, Norway and Sweden. Finland joined in 1955. At the sessions heldby the Council, representatives from the Faroe Islands and Greenland form part of the Danishdelegation, while Åland is represented on the Finnish delegation.The Council consists of 87 electedmembers – all of whom are members of parliament.The Nordic Council takes initiatives, acts in aconsultative capacity and monitors cooperation measures.The Council operates via its institutions:the Plenary Assembly, the Presidium and standing committees.

Nordic Council of Ministers Nordic Council Store Strandstræde 18 P.O. box 3043DK-1255 Copenhagen K DK-1021 Copenhagen KPhone (+45) 33 96 02 00 Phone (+45) 33 96 04 00 Fax (+45) 33 96 02 02 Fax (+45) 33 11 18 70

Homepage: www.ncbio.orgHomepage: www.norden.org

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CONTENTS

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Introduktion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Prospects and problems of human stem cell therapy . . . . . . . . . . . . 9Anne McLaren,Wellcome/CRC Institute,University of Cambridge, UK

Human embryonic stem cells: the Huddinge experience . . . . . . . . . 15Outi Hovatta and Lars Ährlund-Richter, Respectively Department of Clinical Science; Division of Obsterics and Gynaecology,Clinical Research Center; Unit for Embryology and Genetics,Huddinge University Hospital, Karolinska Institute, Sweden

Potential clinical use of human hemopoietic stem cells . . . . . . . . . . 21Ole Didrik Lærum,The Gade Institute, Department of Pathology, University of Bergen, Norway

Report on CNS stem cells and their potential clinical use . . . . . . . . 27Urban Lendahl, Laboratory of Genetics, Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden

European and American ethical debates about stem cells – common underlying themes and some significant differences . . . . 35Søren Holm, Institute of Medicine, Law and Bioethics,University of Manchester and Senter for medisinsk etikk,Oslo University, Norway

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For what purpose can human stem cells be used? A theological view point . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47Jaana Hallamaa, Faculty of Theology, University of Helsinki, Finland

Stem cell research. Philosophical aspects . . . . . . . . . . . . . . . . . . . . . 55Göran Hermerén, Department of Medical Ethics, Lund University, Sweden

Commercial Interest in stem cells . . . . . . . . . . . . . . . . . . . . . . . . . . 79Nils Axelsen, Head, Dept. Clinical Biochemistry, Statens Serum Institut,Copenhagen

Legal problems defining limits for stem cell research . . . . . . . . . . . . 81Linda Nielsen, Institute of Law, University of Copenhagen, Denmark

Using human embryos – the greatest ethical dilemma with stem cell research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89Inger Atterstam, Svenska Dagbladet, Stockholm, Sweden

Opinion from The Nordic Committee on Bioethics based on theWorkshop “Ethical issues in human stem cell research” . . . . . . . . . 10110–11 October, 2000

Udtalelse fra Nordisk Komité for Bioetik baseret på Workshoppen “Ethical issues in human stem cell research”,10–11 Oktober, 2000 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

INTRODUCTION

The research in the field of biotechnology is rapidly developing all over theworld. Biotechnology no doubt produces important and potentially veryuseful knowledge but on the other hand it may challenge ethical values.Within the field of biomedicine, biotechnology has achieved new knowledgeon the human genome during the past decades and thus a potential ofunderstanding the basic steering mechanisms of life. These achievementshave a potential of understanding disease and helping suffering people butthey may also introduce new risks besides a threat of common ethicalvalues due to the potential to manipulate the genome. The NordicCommittee on Bioethics is given the task to analyse and discuss importantethical problems in the field of biotechnology and to try to identify andclarify the Nordic values in dealing with these issues and to produceguidelines for future research and use of this new knowledge.

In 1998, for the first time, human stem cells were cultured in an Americanlaboratory and hopes arose for the potential of this research to enable newtherapies for several presently incurable diseases.This research is, however,based on collecting and growing stem cells from different sources amongwhich early embryonal tissue and aborted fetuses are thought to be themost efficient.The use of human embryos for research, especially if creatingnew embryos for research purposes only, has been the focus of aninternational debate and the new stem cell research poses new importantethical questions necessary to illuminate from different angels.

To this background The Nordic Committee on Bioethics arranged aworkshop “The Ethical issues in human stem cell research” 10–11 October,2000. Prominent researchers in the field were invited besides philosophers,

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theologians, journalists and politicians to discuss the following items:• What is the present status of human stem cell research? Which are the

techniques, sources and different types of stem cells presently used?• Can we use human embryos and aborted foetal tissues for research?

If so, under which premises? • Can we allow manipulation of human tissues for the production of new

cells/tissues for transplantation purposes?• Can these techniques be combined with the somatic cell nuclear transfer

techniques?• Can human cells be patented and commercialised?• Which are the common Nordic values relevant to these issues and do

we need guidelines and legislation to control stem cell research andfuture applications?

This report includes the introductory talks given by the invited speakersand also a summary of the general discussion.The Nordic Committee onBioethics also gives an opinion at the end of this booklet based on thepresentations and discussions in the workshop.Although this opinion mightbe premature we found it important to summarise and conclude thepresent impressions of a Nordic opinion. Such opinions are not leastimportant as a basis for further debate, which we are looking forward to.

December, 2000

Gisela DahlquistChairperson for the Nordic Committee on BioethicsUmeå UniversitySweden

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INTRODUKTION

Forskningen på det bioteknologiske område er i hurtig udvikling over heleverden. Bioteknologi giver uden tvivl en vigtig og potentielt brugbar viden,men på den anden side kan den udfordre etiske værdier. På biomedicinområdet har bioteknologien, gennem de sidste årtier, opnået ny viden ommenneskelige gener og derigennem en mulighed for at forstå de grund-læggende styrende mekanismer for liv. Disse bedrifter giver en mulighed forat forstå sygdom og for at hjælpe lidende mennesker, men muligheden forat manipulere med menneskets gener bringer måske også nye risici med sigudover truslen mod almene etiske værdier. Nordisk Komité for Bioetik hartil opgave at analysere og diskutere vigtige etiske problemer på detbioteknologiske område og at forsøge at identificere og præcisere denordiske værdier i disse spørgsmål og producere retningslinier for denfremtidige forskning og brugen af denne nye viden.

I 1998 blev der i et amerikansk laboratorium dyrket stamceller for førstegang, og der blev skabt håb om, at denne forskning kunne muliggøre nyeformer for behandling mod flere sygdomme, der hidtil har væretuhelbredelige. Denne forskning er imidlertid baseret på at indsamle ogudvikle stamceller fra forskellige kilder, hvor imellem tidligt fostervæv ogaborterede fostre regnes for de mest anvendelige. Brugen af fosteranlæg framennesker til forskning, især hvis de skabes i forskningsøjemed, har væretfokus for international debat, og den nye stamcelleforskning stiller nye vigtigeetiske spørgsmål, som det er nødvendigt at belyse fra forskellige vinkler.

På den baggrund, arrangerede Nordisk Komité for Bioetik en workshop medtitlen ”The Ethical issues in human stem cell research” 10 og 11 oktober,2000.

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Prominente forskere på området var inviteret sammen med både filosoffer,teologer, journalister og politikere for at diskutere følgende punkter:

• Hvordan er den nuværende situation indenfor stamcelleforskning? Hvilketeknikker, materialer og forskellige typer stamceller bruger man pånuværende tidspunkt?

• Kan vi bruge menneskelige fosteranlæg og aborteret fostervæv tilforskning? Hvis vi kan, under hvilke præmisser må det bruges?

• Kan vi tillade manipulation af menneskeligt væv til produktion af nyeceller/nyt væv til transplantationsformål?

• Kan disse teknikker kombineres med somatiske cellekerne overførsels-teknikker?

• Kan menneskelige celler blive patenteret og kommercialiseret?

• Hvilke fælles nordiske værdier er relevante for disse emner, og har vibrug for retningslinier og lovgivning til at kontrollere stamcelleforskningog den fremtidige anvendelse heraf?

Denne rapport indeholder de inviterede oplægsholderes oplæg og et referatfra den generelle diskussion på konferencen. Nordisk Komité for Bioetikgiver til sidst i bogen en udtalelse baseret på præsentationerne ogdiskussionerne fra workshoppen. Selvom denne udtalelse måske er forud forsin tid, fandt vi det vigtigt at opsummere de nuværende indtryk af en nordiskanskuelse af fælles etiske værdier indenfor bioteknologi. Sådanne anskuelserer ikke mindst vigtige som basis for en videre debat, hvilket vi ser frem til.

December, 2000

Gisela DahlquistFormand for Nordisk Komité for bioetik.Umeå UniversitetSverige

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PROSPECTS AND PROBLEMS OF HUMAN STEM CELL THERAPY

Anne McLaren, Wellcome/CRC Institute, University of Cambridge, UK

Stem cells can divide to give a daughter cell like themselves as well as a celldestined to differentiate. Capable of self renewal, they are essential for themaintenance of every tissue in the body (e.g. skin, gut lining). Some stem cellsgive rise to a range of different cell types (e.g. haematopoietic for all thevarious blood cell lineages, neural for cells of the nervous system). Such stemcells are termed multipotential (many potentialities): they are valuabletherapeutically (e.g.bone marrow transplantation).Even with the aid of growthfactors, they cannot be multiplied indefinitely in culture and may be present inthe body only in very small numbers (e.g. neural stem cells in the postnatalnervous system). Some stem cells (e.g. heart muscle ) are hard to isolate.

Animal studies have revealed unexpected potentialities in somemultipotential stem cells. On injection into the brain, neural stem cellsisolated from new-born mice were successful in remyelinating the nervecells of genetically defective shiverer mice and reducing the level of tremor(9). Injected intravenously, neural stem cells have been reported todifferentiate into blood cells (1), while haematopoietic stem cells canapparently give rise to neural cells (3).

In general, however, multipotential stem cells are limited to specific lineages.By contrast, stem cells have been derived from early (blastocyst stage)mouse embryos that will not only proliferate indefinitely in culture, but onreintroduction into an early embryo will colonise all the cells lineages of theadult animal, including the germ line that gives rise, to the next generation.These embryonic stem (ES) cells are termed pluripotential (more poten-tialities). Mouse ES cells have been extensively used in genetic manipulation,including gene targeting to delete or replace genes by homologous recom-

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bination, for example, to produce mouse models of human genetic diseases.ES cells cannot on their own give rise to mice, since they cannotdifferentiate into the early cell lineages responsible for implantation in theuterus and formation of the placenta. Pluripotential stem cells, termed EGcells, have also been derived from embryonic germ cells at a later stage ofdevelopment, but EG cells reintroduced into embryos may be associatedwith foetal abnormalities (7).

Much interest and some ethical concern was aroused by the reports of theisolation of human EG-like cells from human foetal tissue resulting fromtherapeutic abortion (6), and human ES-like cells derived from blastocystsdonated for research by couples undergoing IVF treatment for infertility(8). Research on these EG cells is regarded as ethically unacceptable bythose who see abortion as wrong, while research on human ES cells isunacceptable to those who see all human embryo research as wrong –although the donated blastocysts were anyway destined to perish. At thepresent time the National Institute of Health guidelines permit funding ofresearch on both human EG and ES cells, but not on the recovery of ES cellsfrom human blastocysts.

Research on both mouse and human pluripotential stem cells is proceedingactively, with the aim of inducing directed differentiation to defined cell typesin culture. The ultimate objective is to provide transplant surgeons with areadily available supply of any tissue, for the repair of damaged or diseasedorgans. Production of whole organs (e.g. kidney, heart) for transplantation(“spare parts surgery”) would be a very much more complex task, involvingtissue engineering with 3D templates and different cell types. It might be morereadily achieved by xenotransplantation, taking organs from geneticallymodified pigs.

In the mouse, considerable success has been achieved in inducing ES cellsto differentiate in vitro into neural, haematopoietic, adrenal and cardiacmuscle cells, by exposing them to natural signalling molecules, such asretinoic acid, growth factors and cytokines. Greater purity can be achievedby transfection with an antibiotic resistance gene driven by an appropriatetissue-specific promoter, followed by antibiotic selection (5).

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Cardiac muscle cells derived from ES cells in this way can be incorporatedinto damaged hearts, and will beat in synchrony with the host tissue (4). ES-cell derived neural stem cells introduced into the brain of a mouse modelof multiple sclerosis differentiated into either glial cells or neurons in theappropriate regions (2). Research on the directed differentiation of humanpluripotential stem cells is believed also to be progressing, but nopublications have yet appeared, presumably for reasons of commercialsecrecy, since the research is primarily funded by the California-basedcompany Geron.

These advances hold out promise for the future treatment of a wide range ofhuman diseases: Parkinson’s, Alzheimer’s, stroke, multiple sclerosis, heartdisease, diabetes, rheumatoid arthritis, skin conditions, liver and kidneydamage, leukaemia and other blood diseases. For transplantation to the brain,immune rejection seems to be not much of a problem, but for other sitesimmunosuppresive drugs would be required to prevent rejection. Such drugsincrease the chances of both infection and cancer.A bank of stem cell linesmight allow the appropriate donor type to be found for any host, but it hasbeen estimated that several thousand lines might be required. Immunologicalmeans might be devised to render patients tolerant of transplanted tissue, orto render the tissue in some way non-antigenic. Alternatively, if it provespossible to re-programme human somatic nuclei by introducing them toenucleated oocytes, as has been done in sheep, cattle and mice, one couldenvisage the derivation of ES cell lines for each patient. A somatic nucleusfrom the patient would be introduced to a donated oocyte from which thenucleus had been removed, so that the ES cells derived from the resultingcloned blastocyst would be genetically and antigenetically identical to thepatient, with no risk of rejection for any cell or tissue transplant. Ethicalconcerns are voiced against the possibility of producing embryos in this way,initially for research purposes.To some extent these concerns arise from afear that such a procedure would constitute the “thin edge of the wedge”,making human reproductive cloning more likely. In general, however,“thin endof the wedge” objections are better met by regulation than by prohibition.

In the USA, Government funds may not be used for any form of humanembryo research, but can now be used for research on human ES cells that

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have been recovered using private funds.Whether the recovery of ES cellsfrom donated embryos will in the future be fundable using Governmentfunds is debatable, but producing embryos for research, whether by somaticcell nuclear transfer or by in vitro fertilisation, will almost certainly not befundable. On the other hand, human embryo research funded by privateagencies or corporations is unregulated.

In the UK, the 1990 Human Fertilisation and Embryology Act permitshuman embryo research under license, whether the embryos are producedfor infertility treatment or specifically for research, but only for certainlimited purposes.These purposes do not include cell and tissue therapy.AnExpert Group set up by the Government and chaired by ProfessorDonaldson, the Chief Medical Officer, has recently recommended thatresearch on human embryos, whether derived by fertilisation or by nucleartransfer, be permitted under strict license for the purpose of understandinghuman diseases and their treatment with cells or tissues.The Governmenthas accepted the Donaldson Report’s recommendations, but they have notyet been debated and approved by Parliament.

AcknowledgementI am grateful to the Wellcome Trust for financial support.

References1. Bjornson, C.R.R., R.L. Reitze, B.A. Reynolds, M.C. Magli, and A.L.Vescovi,

(1999) Turning brain into blood: a haematopoietic fate adopted by adult neuralstem cells in vivo., Science 283, 534-537.

2. Brustle, O., K.N. Jones, R.D. Learnish, K. Karram, K. Choudhary, O.D.Weistler, I.D. Duncan, R.D. McKay, (1999) Embryonic stem cell-derived glialprecursors: a source of myelinating transplants. Science 285, 754-756.

3. Eglitis,M.G., and E.Mezey, (1997) Haematopoietic cells differentiate into bothmicroglia and macroglia in the brains of adult mice. Proc. Nat.Acad. Sci. 94,4080-4085.

4. Klug, M.G., M.H. Soonpaa, G.Y. Koh, L.J. Field, (1996) Genetically selectedcardiomyocytes from differentiating embryonic stem cells form stable intra-cardiac grafts. J. Clin. Invest. 98, 216-224.

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5. Li, M., L. Perny, R. Lovell-Badge and A.G. Smith, (1998) Generation ofplurified neural precursors from embryonic stem cells by lineage selection.,Curr. Biol. 8, 971-974.

6. Shamblott, M.J., J.Axelman, S.Wang, E.M. Bugg, J.W. Littlefield, P.J. Donovan,P.D. Blumenthal, G.R. Higgins and J.D. Gearhart, (1998) Derivation of pluri-potent stem cells from cultured human primordial germ cells, Proc. Natl.Acad. Sci. 95, 13726-13731.

7. Tada, T., M. Tada, K. Hilton, T. Sado, N. Takagi and M.A. Surani, (1998)Epigenotype switching of imprintable loci in embryonic germ cells. Dev. GenesEvol. 207, 551-561.

8. Thomsom, J.A., J. Itskovitz-Eldor, S.S. Shapiro, M.A. Waknitz, J.J. Swiergid,V.S. Marshall and J.M. Jones, (1998) Embryonic stem cell lines derived fromhuman blastocysts. Science 282, 1145-1147.

9. Yandava, B.D., L.L. Billinghurst and E.Y. Snyder (1999) “Global” cell replace-ment is feasible, via neural stem cell transplantation: Evidence from thedemyelinated Shiverer mouse brain. Proc. Nat.Acad. Sci. 96, 7029-7034.

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HUMAN EMBRYONIC STEM CELLS:THE HUDDINGE EXPERIENCE

Outi Hovatta and Lars Ährlund-Richter, Respectively Department of Clinical

Science; Division of Obsterics and Gynaecology, Clinical Research Center;

Unit for Embryology and Genetics, Huddinge University Hospital, Karolinska

Institute, Sweden

In vitro fertilisation and human embryosInfertility is a common disorder. It affects about 15% of the population inEurope. In vitro fertilisation (IVF) with its variations, such as intracyto-plasmic sperm injection (ICSI), is the most effective infertility treatment forthe time being. According to Swedish national statistics, more than 2,000children are annually born in Sweden as a result of IVF and ICSI.The numberof treatment cycles with egg retrievals has been around 7,000 (6).

Twin pregnancies have been the greatest concern as regards these treat-ments (1).Triplets and higher order multiple pregnancies are avoided in theNordic countries by transferring no more than two embryos at a time. Butbecause the only real health problems of the children resulting from IVFhave are caused by premature births due to twin pregnancies, the transferpolicy has been changed towards one embryo transfers in cases with goodprognosis (9). For transfer, the best embryos are selected on the basis oftheir morphology. Based on clinical experience, we know that the likelihoodof pregnancy is high if the blastomers of the embryos are of equal size, thecells have one nucleus, the embryo contains less than 20% of cellularfragments, and it has reached four-cell stage on day two or eight-cell stageon day three after fertilisation. Such embryos can also be cryopreservedwith relatively good pregnancy results, but embryos which are of poorerquality do not survive freezing or thawing. If they do the transfer of suchembryos seldom results in pregnancy.

In order to achieve acceptable pregnancy rates like those mentioned above,good quality embryos, from which to choose, have to be available. If there isonly one embryo available, the pregnancy rate per transfer is not higher than

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20% (9). By using hormonal stimulation, follicle stimulating hormone, severaleggs survive in the ovaries to full maturity, and they can be retrieved throughtrans-vaginal ultrasound-guided puncture. During natural menstrual cycles,only one of the many growing eggs survive, while the others undergoprogrammed cell death. It is the mechanism by which multiple pregnanciesare avoided in natural situations in human. All the mature eggs which areobtained, are normally fertilised. From the resulting embryos, one or two areselected for transfer. If there are additional good quality embryos, they arecryopreserved for transfer on later occasions if the patient has not becomepregnant,or desires siblings for the child possibly born after the first transfer.

The embryos which cannot be transferred to the patient are either discarded,or donated by the couple to research after informed consent. Some coupleswho do not wish their good quality frozen embryos to be transferred or storedany more, often wish to donate such embryos for research instead of justdiscarding them.Thus, at IVF clinics there are regularly human embryos whicheither have to be discarded or could be used in research. Embryo research isacceptable according to the laws in the Nordic countries, up to the age of 14 days after fertilisation,excluding the time they are being cryopreserved.Eachresearch project has to be accepted by an ethics committee, and the donors of the gametes have to had given an informed consent.

Stem cell researchIn various organs, there are some stem cells which can give rise to new cellsin order to repair everyday wear and tear of the tissues. Such adult stemcells offer promising potential for clinical cell transplantation, and they arealready used clinically in several disorders. There are now methods toculture such cells from some organs, but not all, and the process is notsimple for the time being. Adult stem cells have differentiated to a certaindegree but have been shown to, at least under certain conditions, exhibit amost interesting developmental plasticity. According to a resent reportfrom the Karolinska Institute (2), differentiated stem cells from the rat braincould be dedifferentiated to other types of stem cells.

Embryonic germ cells, derived from the foetal gonads, are pluripotent stemcells, which have been used in studies regarding animal physiology (3).

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Embryonic germ cells have also been identified from human foetuses afterterminations of pregnancy (5).

Embryonic stem cells (ES cells) can be isolated from the early mammalianpreimplantation embryo, i.e. from the inner cell mass of a blastocyst.Theyhave proved to give origin to cell lines which theoretically are capable ofunlimited, undifferentiated growth in vitro. Cultured mouse ES cells havedeveloped features of progenitors for blood cells, nerve cells, cardiacmuscle cells, inner lining cells of blood vessels, pancreatic insulin producingcells and cartilage cells (e.g. 8). Recently,Thompson et al. (1998) describedalso human blastocyst-derived, pluripotent cell lines which had normalchromosomes and expressed high telomerase activity, which means thatthey can divide to renew themselves without limitation.They expressed cellsurface markers that characterise primate embryonic stem cells. Afterundifferentiated proliferation in culture for many months, these cells stillmaintained developmental potential to derivatives of all three embryonicgerm layers; gut epithelium, cartilage, bone, smooth muscle, striated muscle,neural epithelium, embryonic ganglia, stratified squamous epithelium.Human embryonic stem cells are thus of great potential value in studies ofhuman developmental biology, drug discovery, and transplantation medicine.

Human embryonic stem cells at the Huddinge campusHuddinge University Hospital is a large teaching hospital of the KarolinskaInstitute.There is an active IVF Unit,with good clinical results.The embryos areroutinely cultured to blastocyst stage (five to six days of culture). Clinical andexperimental embryologist work in close collaboration and pre-implantationgenetic diagnostics and improvements of the culture systems are examplesof previous and ongoing embryo research. Long experience in mouseembryology, including culture of mouse embryonic stem cells, is available.

We have recently initiated a project with the aim to culture human ES celllines. In the first phase the cells are characterised for differentiationmarkers. For this we have obtained an ethical permission (Applicationapproved by Karolinska Instituttet, Forskningsetiska nämnden Syd,Huddinge University Hospital. Dnr # 402/99). Before the application wasapproved it was also referred to the ethics committee of the Medical

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Research Council (Medicinska Forskningsrådet), and to the governmentalethics council (Statens Medicinsk Etiska Råd).

Further projects will be remitted to the ethics committee for evaluation.There was a legal question if culturing embryonic stem cells can beregarded as culturing a human embryo beyond the age of 14 days. Theanswer was that because stem cells are only a part of the embryo, and a cellline is not an embryo, culturing these cells are acceptable.

In our study we use blastocysts which cannot be used in the clinical treat-ment of infertility patients.The couple receive written and oral informationregarding the study already at their first visit to the unit.The gynaecologistwho asks for the consent is not involved in the project. Both partners ofthe couple sign the informed consent document. At a later stage of thetreatment, by the time of embryo transfer, the number and quality ofembryos is known and by that time it is known whether there are embryoswhich cannot be used for the treatment.This judgement is carried out bystaff at the embryo laboratory, by embryologists who are not involved inthe project.They use criteria which have been applied at the unit for severalyears (described also above). The blastocysts are de-identified beforehanded out to the research laboratory.

Cells from the inner cell mass of human blastocysts (hES cells) are culturedaccording to previously published protocols (4, 7). So far, cell cultures havebeen kept up to 4 weeks, with expected morphological characteristics.Analysis of karyotyping and various differentiation markers such as cellsurface markers, telemerase activity etc., is ongoing.

Future plansFuture plans include an extensive phenotypic and genetic analysis of thecultured cells, as well as the establishment of a biobank. Because of thepotential clinical application at later stages, the cells will be cultured underGood Manufacturing Practise (GMP) conditions.

Future planned projects include the ability of hES cells to differentiate ina controlled way to stem cells of different organ systems. New applica-

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tions for extended permissions from the ethics committee are beingprepared.

Several research projects are being planned in collaboration with otherresearch groups, also at other Swedish universities and with researchgroups in Finland.At the Huddinge University Hospital there are large trans-plantation and haematological units, which carry out haematological stemcell transplantations. There is an active research regarding stem cells andneurological diseases, and a unit for gene therapy. Stem cells for blood cellswill be among the first because of their clinical importance and the know-ledge which already exists in our hospital. Other examples are projectstogether with the Department of Cardiology and Department of ClinicalPharmacology at the Karolinska Instituttet.

References1. Bergh,T.,A. Ericson,T. Hillensjö, K.G. Nygren, U.B.Wennerholm, Deliveries

and children born after in vitro fertilisation in Sweden 1982-1995: a retro-spective cohort study. Lancet 354, 1579-1585, 1999.

2. Clarke, D.L., C.B. Johansson, J.Wilbertz, B.Veress, E. Nilsson, H. Karsltröm,U. Lendahl, J. Frisen, Generalised potential of adult neural stem cells. Science,288, 1660-1663, 2000.

3. Matzui,Y., D.Toksoz, S. Nishikawa, D.Williams, K. Zsebo, B.L. Hogan, Effectof steel factor and leukaemia inhibitory factor on murine primordial germ cellsin culture, Nature. Oct.24;353(6346):750-2, 1991.

4. Reubinoff, B.E., M.F. Pera, C.Y. Fong,A.Trounson and A. Bongso, Embryonicstem cell lines from human blastocysts: somatic differentiation in vitro. NatureBiotechnology 18, 399-404, 2000.

5. Shamblott, M.J., J. Axelman, S.Wang, E. Bugg, J.W. Littlefield, P.J. Donovan,P.D. Blumenthal, G.R. Higgins, J.D. Gearhart, Derivation of pluripotent stemcells from cultured human primordial germ cells. Proc. Natl. Acad. Sci. USA95, 13726-13731, 1998.

6. Socialstyrelsen: Assisterad beruktning. Statistik, Hälsa och sjukdomar12,1999, ISSN 1401-0224.

7. Thomsom, J.A., J. Itskovitz-Eldor, S.S. Shapiro, M.A. Waknitz, J.J. Swiergid,V.S. Marshall and J.M. Jones, (1998) Embryonic stem cell lines derived fromhuman blastocysts. Science 282, 1145-1147, 1998.

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8. Weiss, M.J., and S.H. Orkin, In vitro differentiation of murine embryonic stemcells. New approaches to old problems. J. Clin Invest 97, 591-595, 1996.

9. Vilska, S., A. Tiitinen, C. Hyden-Granskog, O. Hovatta, Elective transfer ofone embryo results in acceptable pregnancy rate and eliminates the risk ofmultiple birth. Hum. Reprod. 14, 2392-2395, 1999.

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POTENTIAL CLINICAL USE OF HUMANHEMOPOIETIC STEM CELLS

Ole Didrik Lærum, The Gade Institute, Department of Pathology, University of

Bergen, Norway

The clinical use of hemopoietic stem cells is technically relatively simple, butthe clinical situation is very complex. Their use rests on many years ofexperience, and in practice the number of patients and indications havebeen relatively stable during the last few years. However, the clinicalapplications are steadily increasing, and it is expected that there may be aneven more rapid increase in the next years due to an active ongoingresearch.Thereby, entirely new possibilities may emerge. Large commercialinterests are also involved, and not least, serious ethical questions arise.

In this short survey, a description of some physiological aspects ofhemopoietic stem cells is first given, followed by some notes on their actualclinical uses,which also form the background for outlines of innovations andpotential new uses.

General aspects of hemopoiesis and stem cellsAs a working definition stem cell is a cell capable of making all types of bloodcells in the body, and at the same time contribute to the maintenance of thestem cell population. This concept was developed in the 1950’ies and theearly 1960’ies on the basis of experimental systems where bone marrow cellsuspensions containing stem cells were injected into irradiated mice. It wasthen found that single cells were able to make colonies in the bone marrowand the spleen, consisting of the different types of blood cells. Later, it wasalso found that stem cells could develop into progenitor cells, a cell which inaddition to limited self-renewal also was able to make one type of bloodcells. Hence, when a stem cell enters the progenitor cell population, there isno way back to the original stage. It will now continue cell division andthereafter maturation ending with terminally differentiated cells.

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Today there is a large body of knowledge concerning the antigenic andother properties of stem cells. Thereby, they can be characterised andseparated by different methods, including physical separation withleukaperesis, separation by use of immunomagnetic beeds or by multi-parameter flow cytrometric analysis and cell sorting.Thereby, almost purepopulations of stem cells have been obtained, and their morphology as smallmononuclear cells has been characterised.

In general, an adult person contains between 1 1/2 and 2 1/2 kg of bonemarrow distributed all over the skeleton, and in particular in the pelvis,sternum and shafts of the long bones.The time from the stem cells divideand start maturation until it has reached the end-stage as a progeny familyof mature cells is in man usually around two weeks. In consequence, thereis a turn-over and replacement of the bone marrow usually twice everymonth, meaning that about half the body weight is produced as blood cellsevery year. In life-time a human being produces a magnitude of three tonsof blood cells. Still, the stem cells population is present and activelyrenewing itself even at high age.

RegulationUntil now a multitude of growth factors, including olegopeptides,polypeptides and larger proteins, classified as either stimulators orinhibitors have been described. Two main classes are the hemopoieticgrowth factors and chemokines in addition to some inhibitory molecules.Altogether around 50–80 different factors are claimed to be responsible forhemopoietic cell regulation, which also includes various hormones andmodifying factors. In consequence, there is an unstable equilibrium betweencell renewal and cell loss by maturation and also by apoptosis. In addition,there are pronounced circadian and circannual variations in the stem andprogenitor cell population.

The local environment in the bone marrow is of critical importance forstem cell functions. This is both related to the presence of adhesionmolecules and the extracellular matrix in general, as well as the presence ofspecialised fibroblastic cells which nourish, regulate and support both stemcells and their progeny. These stromal cells also secrete various growth

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factors, which again is under regulation of other secretory agents andgrowth factors. In addition, macrophages and T-lymphocytes as well asgranulocytes secrete growth factors which may influence the stem cells.

The clinical situationIn many pathological conditions the bone marrow may be depleted of stemcells, or they may be affected by disease so that they do not functionproperly.This can happen during the course of a leukemia, both acute andchronic, different other neoplastic diseases in the lymphoid andhemopoietic system as well as metastases to the bone marrow from othertypes of tumors.The bone marrow can also be the target of various growthdisorders and neoplastic conditions which later may end with leukemia.One of this is agnogenic myeloid metaplasia, where the marrow cavity canbe more or less replaced by fibrous tissue.

The loss or suppression of stem cells is a serious clinical condition, and forseveral reasons. By lack of the erythrocytes, an anemia may impair thetransport of oxygen to tissues. Lack of granulocytes and other immune cellsmay lead to severe infections, and lack of thrombocytes may lead to lifethreatening bleeding. Therefore the replacement of the lacking or mal-functioning stem cells may be an urgent clinical situation, as well as thepossibility to give transfusion of various blood cells.

Principles of chemotherapy of malignancy and current usesA main goal with cancer chemotherapy is to eradicate the malignant cellpopulation of stem cell transplantation. In the case of leukemia, where theneoplastic process effects hemopoiesis, it is important to eradicate allneoplastic cells able to divide. This can at the same time lead to theeradication of the normal stem cells, giving rise to a severe bone marrowaplasia. If recovery of the stem cells and the subsequent hemopoietic tissueis not possible, stem cell transplantation is a logical consequence.

In principle there are two main uses of hemopoietic stem cell transplan-tation.The first is called autotransplantation, where the normal stem cellsare removed from the body and stored outside during the period when thepatient receives chemotherapy or irradiation. This is usually obtained by

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various means of stimulating stem cell exit to peripheral blood, wherebythey can be recovered in a relatively simple way. These cells can also befrozen, and thawed immediately before they are reinjected.

The second main type is allo-transplantation, where the stem cells areusually removed from the bone marrow from a related or an unrelateddonor. One can also use stem cells from peripheral blood or from theumbilical cord of foetuses, although this is at present not a routineprocedure in the Nordic countries. Stem cells are infused into thecirculation, and they will find their way to the bone marrow cavity wherethey settle and make a new hemopoietic cell population.

The main indications for autotransportation is high dose chemotherapy fordifferent types of cancer. The main indications for allotransplantations areacute leukemia, aplastic anemia, different immune disorders as well asvarious congenital disorders with non-functional stem cells.

Some current research areasIn the recent years it has been shown that human multipotent stem cellsare not an entirely homogenious cell population.There are different degreesof proliferative activity, where some subpopulations may be actively proli-ferating, while others are in a resting state. Surface antigens for examplepositivity for the antigen CD34 may also vary according to their degree ofstemness. It has also been shown that subpopulations of the multipotentstem cells may also be pluripotent, since they also may give rise to stromalcells, adipocytes, bone cells and chondrocytes.The developmental stage isof importance for the production of lymphocytes in addition to the othertypes of blood cells.

Several laboratories are now studying gene expression patterns inhemopoietic stem cells. Several thousand different genes are characte-ristically expressed, where some are “common housekeeping genes” whileothers are responsible for more specific functions.

By cell culture the renewal of stem cells can be studied to a certaindegree, mainly in suspension culture on feeder layers of stromal cells.

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However, it has turned out to be difficult to stop apoptosis and get thestem cells to proliferate and be scaled up over longer periods.Therefore,it is difficult to amplify the stem cell population from a given patientoutside the body.

In addition, studies on their antigenicity has given important informationabout their possibility to be tolerated in a new host.The development ofimmunocompetent cells which can give rise to graft versus host-reaction,i.e. that the new cells react against the host cells, is also a great challenge.

Potential clinical usesIt is expected that either by gene transfer or other types of manipulation,that stem cells may be cultured in large quantities, and possibly thathemopoietic stem cell lines in vitro may be developed. Probably, this will beeasiest in embryonal or foetal cells.The fact that the need for stem cells ishigher than the actual offer of cells from compatible donors, makes suchresearch very urgent.

New knowledge about regulatory factors of importance for stem cellfunctions may also contribute to the possibilities for transplantation. Theuse of different growth and other regulatory factors has already madeimportant contributions to the understanding of stem cell replication invivo, but still needs further research.

Already now, stromal cells can be cultured and injected into patients withfailure of stromal cell function in the hemopoietic tissues, whereby the“take” of transplanted of hemopoietic stem cells may be greatly improved.Such cells seem to be well tolerated, although their clinical value so farcannot be evaluated.

Alterations of chemotherapy regiment which lead to less stem celldamaging side effects may also reduce the lead for transplantation. Onepromising approach is so-called chronotherapy, where knowledge aboutcircadian variations is used for finding time-points with less toxic sideeffects. Possibilities to purify the bone marrow cell population so that stemcells are obtained and neoplastic cells are avoided, are already in use.

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Through better monitoring of gene expression in the stem cells, one mightalso find ways of better adjustment of the cells to the new environment.Possibly, gene therapy in vitro as well as in vivo may contribute to this.

Through knowledge of the expression patterns, stem cells may theoretically bemodified to meet more specific requirements for e.g. red cells, thrombocytesand granulocytes according to the actual clinical needs. Modified progenitorcells may in this connection be an alternative. By manipulation with theirstemness, multipotent human stem cells may then have a potential aspluripotent cells and be used for other purposes, including making other typesof tissues. However, a critical issue is the avoidance of transplantationreactions, both as rejection and as graft versus house reaction.

In conclusion, it is expected that future research will give the opportunityto tailor stem cells and modify their behaviour for all clinical needs,including their tolerance in a new host.

References1. Ball, E.D, J. Lister and P. Law (eds) Hemopoietic stem cell therapy. Churchill-

Livingstone Publ., London, 2000.2. Young, N. (ed), Bone marrow failure syndromes.W.B. Saunders Publ., 2000.3. Bertolini, F., P. Mancusco, A. Gobbi, G. Pruneri, The thin red line: Angio-

genesis and malignant hemopoiesis. Exp. Hematol. 28:993-1000, 2000.4. Deans, R.J., and A.B. Moseley, Mesenchymal stem cells: Biology and potential

clinical uses. Exp. Hematol., 28:875-884.5. Laerum,O.D. Hematopoiesis occurs in rhythms.Exp.Hematol.,23:1145-1147,19956. Lévi, F., Cancer chronotherapy. Lancet Oncol, in press.7. Ando, K., Y. Nakamura, J. Chargui, H. Matsusowa, T. Tsuji, S. Kato et al.,

Extensive generation of human cord blood CD34(+) stem cells from Lin (-)CD34(-) cells in a long-term in vitro system. Exp. Hematol. 28:690-699, 2000.

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REPORT ON CNS STEM CELLS AND THEIRPOTENTIAL CLINICAL USE

Urban Lendahl, Laboratory of Genetics, Department of Cell and Molecular

Biology, Karolinska Institute, Stockholm, Sweden

Definition of stem cellsStem cell research is currently an area of very rapid scientific progress andexiting prospects for the future. Despite this, it has been very difficult toarrive at a globally accepted definition of a stem cell. An operationaldefinition of a stem cell, which is encompassed by many scientists in thefield, is a cell which is capable of both self-renewal, i.e. making more stemcells, and differentiation to one or more mature cell types (1). The wordprogenitor cell describes a cell with a more limited differentiation potential,and which can give rise to a narrower repertoire of differentiated cell types.

The fertilised egg can be seen as the ultimate stem cell, since it gives rise toall cells in all tissues of the body. It is however becoming increasingly clearthat we during our development retain various populations of stem cells,even as adults.The body uses stem cells to replace cells that are lost duringnormal life or after injury. It is not clear whether stem cells exist in allorgans, but they are clearly present in for example the hemopoietic (blood)system, muscle, nervous system and in skin (2). I will now focus on what wehave learned about stem cells in the nervous system and how these cellsmay be used in cell based therapy for various types of CNS disease.

Stem cells in the embryonic and adult CNSThe development of the human central nervous system (CNS, i.e. the brainand spinal cord) begins in the embryo during the fourth week afterfertilisation. At the back of the embryo a shield of cells, called the neuralplate, is formed.A few days later, the neural plate folds to form the neuraltube, which is the origin of the brain and spinal cord.The relatively few cellsin the neural plate are thus the origin of the huge numbers of neurons andsupporting glial cells found in the adult brain and spinal cord.To accomplish

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this task, there is an initial phase of very rapid cellular proliferation, followedby differentiation to the various types of neurons and glial cells required. Itis well established that at least some of the rapidly dividing cells in theembryonic CNS are endowed with stem cell qualities.

It has become increasingly evident that also the adult CNS contains stemcells. The first evidence that the adult brain was not totally “dormant” interms of cellular proliferation actually came from studies in the 1960’ies,which provided evidence for proliferation in the mouse brain (3). Thedogma for a long time, however, was that the adult brain was largely devoidof proliferation. This changed dramatically in the early 1990’ies, WhenReynolds and Weiss (1992) demonstrated that cells taken out from a regionnear the ventricles of the adult rodent brain could be induced to proliferatein vitro, i.e. when cultured in the laboratory.

It is now clear that there are at least two regions in the adult brain, in whichsignificant proliferation occurs. One region is the subventricular zone,which is located quite near the ventricles, below the ependymal zone. Cellsoriginating from this region travel from the subventricular zone to replacelost cells in the olfactory bulb, an organ important for the sensation ofsmell. The other region is the subgranular zone of the dentate gyrus inhippocampus, which supplies new cells to the hippocampus (5).There arehowever also proliferation in certain other brain regions.

An interesting issue is to determine precisely where in the brain the adultCNS stem cells are located.This is a somewhat controversial issue, but itseems clear that at least in rodents there are two populations of stem cells,one located in the subventricular zone and a second in the ependymal celllayer, i.e. the cells that line the ventricles of the brain (6).The finding thatependymal cells, and also cells lining the central canal in the spinal cord, arestem cells (6) is of potential therapeutic interest, since these cells may bemanipulated from the brain ventricle side, since they are immediatelyadjacent to the ventricles. For obvious reasons, we know less about thesituation in humans. It is established, however, that cells taken out from theregions close to the brain ventricles of humans also can be induced toproliferate and to differentiate to neurons, astrocytes and oligodendrocytes.

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Differentiation potential of CNS stem cells and other cellsEmbryonic CNS stem cells can give rise to all major types of CNS cells, i.e.neurons, astrocytes and oligodendrocytes, although this potential may besomewhat restricted over time during embryogenesis. We also begin tounderstand some of the factors that are required to steer thisdifferentiation of embryonic CNS stem cells in vitro. Of considerableinterest here is that the differentiation of so called dopaminergic neurons,which are lacking in patients with Parkinson’s disease, can be generatedfrom embryonic CNS stem cells in large numbers (7).

A recent interesting development is the analysis of CNS differentiation fromanother type of cell, the ES or embryonic stem cell. ES cells do not originatefrom the nervous system, they are in fact derived from cells from the veryearly preimplantation embryo called a blastocyst. ES cells from the mouse arecapable of differentiating into all types of cells, including the nervous system,and they have been extensively studied and used in the gene targeting (knockout) technology in the mouse. Here, ES cells that are transferred ex-perimentally into early mouse embryos can generate a complete mouse.These observations have attracted a lot of interest also from the perspectiveof ES cell differentiation to CNS cells in vitro. It was recently shown that EScells, like embryonic CNS stem cells, can be steered to differentiate todopaminergic neurons in large numbers in vitro (8). Furthermore ES cellscan generate oligodendrocytes following transplantation (14).

Adult CNS stem cells from both rodents and humans can generateneurons, astrocytes and oligodendrocytes when cultured in vitro (4, 6).Here we yet know less about which individual growth factors and intrinsicfactors that control the choice of cell fate, but this is an area of intenseresearch, so rapid progress is expected.

A very interesting recent observation made in different laboratories is thatadult stem cells may not be able to give rise only to the expecteddifferentiated cell types in the tissue they are derived from, but may have aconsiderably wider differentiation potential. This was demonstrated foradult CNS stem cells, when they were transplanted into early mouse orchick embryos after they were cultured in vitro. The transplanted adult

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CNS stem cells, in their new embryonic environment, could give rise tocells typical for liver, gut, kidney and other organs, strongly suggesting thatadult CNS stem cells are highly plastic and dynamic in terms ofdifferentiation (9). Similarly, stem cells from the hematopoietic system cangive rise to skeletal muscle, and vice versa (10, 11). Furthermore, adult CNSstem cells can give rise to hematopoietic cells (12). These observationssuggest that there is a considerable degree of plasticity in the differentiationpotential of various types of adult stem cells.

The potential of using CNS stem cells and other cells fortreating CNS diseaseFor the potential clinical use, it is important to consider which types ofCNS disease may be most approachable by cell therapy and which cells arethe best candidates for transplantation. It is clear that the most advancedexperiments have been performed for Parkinson’s and Huntington’sdisease, and I will discuss the current status for these diseases, as well as forepilepsy, stroke and spinal cord injury (13).

a. Parkinson’s diseaseIn Parkinson’s disease, cells in substantia nigra degenerate, which leads to aloss of cells releasing the neurotransmitter dopamine in the striatum.Thereare good animal models for Parkinson’s disease, both in rodents andprimates, which has facilitated the preclinical research considerably.Techniques to transplant fetal ventral midbrain cells (some of whichpresumably are CNS stem cells and progenitor cells for dopaminergicneurons) to striatum in lesioned animals have proved quite successful.Clinical experiments on Parkinson patients have been conducted for anumber of years, and the results are quite encouraging. Clinical improve-ment is reported gradually over 6–24 months after transplantation of fetaltissue, and effects are long-lasting (5–10 years).The first results from double-blind tests have also been recently reported,and clear differences are observed (13).

b. Huntington’s diseaseIn Huntington’s disease, cells in the striatum and cortex degenerate, whichis fatal.The strategy here is to transplant fetal striatal cells to restore striatal

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function. Similar to Parkinson’s disease, adequate animal models for thedisease have been established. Transplantation of fetal striatal tissue fromthe developing forebrain leads to substantial recovery in the experimentalanimal models, but there are so far very few reports from clinical studies.Clinical studies are underway, but most of the data thus far come fromdiseased patients that participated in such studies, and although these datasuggest that innervation occurs in the transplant, we have to await moredata before firm conclusions can be drawn (13).

c. EpilepsyStudies on epilepsy are less advanced, for a number of reasons. Animportant factor is that epilepsy most likely is a heterogenous group ofdiseases, and that there is no common pathological change, which could bea target for cellular therapy. Epilepsy is caused by hyperactivity in neuronsand one theoretical approach would be to supply inhibitory neuro-transmittors (e.g. GABA) in the form of transplanted tissue rich in cellsproducing such inhibitory neurotransmittor.This type of experiments are ata very early stage in animal models, but despite this fact there have beenclinical attempts using porcine tissue as a graft to human patients(http://www.diacrin.com)

d. StrokeStroke is caused by lack of oxygen (ischemia) in the brain. Ischemia can bethe result of a global shutoff of blood supply to the brain (global ischemia)or by locally blocking an artery (focal ischemia). Both forms can bereproduced in experimental animal models, and the latter form is what isnormally referred to as stroke. Some work has been carried out totransplant CNS tissue to regions damaged by focal ischemia, but this workis still in its infancy, and more experiments in animals are clearly requiredto evaluate the effects. Despite the lack of animal data, clinical trials havebeen started, but apparently put on hold, at least temporarily(http://www.diacrin.com/stroke.htm, http://www.laytonbio.com).

e. Spinal cord injurySpinal cord injury leads to paralysis because the neuronal projections in thespinal cord are disrupted, and cannot regenerate. It is yet not known why

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neuronal projections in the central nervous system fail to regenerate, whilethis is not the case in the peripheral nervous system. Spinal cord injury thusdiffers from for example Parkinson’s and Huntington’s disease, since it is notcaused by loss of cells and tissue. Cellular therapies are therefore currentlynot applicable to spinal cord injury, but a theoretical possibility would be touse transplanted cells as “biopumps”, i.e. sources of specific factors.A supplyof neurotrophic factors from transplanted cells may facilitate regenerationof the neuronal projections, but the introduced cells may not necessarilyhave to integrate in existing neuronal networks.

f. Other nervous system diseasesThere are other diseases in the nervous system, in which specific cell typesdegenerate and which therefore may be suitable for cell therapy. Twoexamples are multiple sclerosis (MS) and amyotrophic lateral sclerosis(ALS). In patients suffering from MS, oligodendrocytes, i.e. the glial cellsgenerating myelin around neuronal axons, degenerate. It has recently beenshown in an animal model that ES cells can differentiate to oligodendrocytesin vitro, and also generate new myelin following transplantation in a ratmodel (14). In ALS, motor neurons degenerate.This leads to a progressiveand fatal loss of motor co-ordination, and it may be possible in the futureto test cell therapies also for this disease.

Summary and perspectivesIt is already clear from the development in the Parkinson field that celltherapy can become a very useful treatment of CNS disease, and this mayalso be expanded to other types of disease. The choice of cells fortransplantation will however have to be discussed in detail. Current clinicalprotocols rely on the use of fetal tissue, which raises both ethical andpractical issues. The use of fetal material from abortion material iscontroversial per se, and the supply of tissue will most likely always belimiting, precluding large scale use.The prospect of using either stem cellsderived from the patient him/herself or more generic stem cells as culturedES cells is therefore a potentially interesting alternative. The use of stemcells from the patient would remove the problems of immune reactions(host versus graft reactions), but may be technically cumbersome. Here, it ishowever interesting to note the recent observations in plasticity among

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different stem cell populations, i.e. one may in the future use stem cellsderived from a different, and more easily accessible, organ. More generic celllines, for example a human ES cell line, may become another important tool,since ES cells can be grown in large numbers, and we improve ourunderstanding of how to differentiate these cells in vitro. A futuristicscenario is to combine transplantation paradigms using human ES cell lineswith a cloning approach, i.e. to replace the cell nucleus in the ES cells witha nucleus from the patient. In this way the ES cell line may be recognised as“self” by the patient. Finally, an option to consider in the future is toreactivate the patient’s own CNS stem cells in vivo, i.e. in the patient, andto steer their differentiation and migration to relevant places. This wouldclearly be the least invasive strategy, but we yet know very little of how thiscould be accomplished, also in animal models. In conclusion, we have duringthe last years witnessed very rapid progress in all the areas discussed above,and we are likely to see at least some of these approaches gradually makeit into the clinic. It should be noted however, that this progress shouldfollow an ordered plan, and proceed via very carefully controlled in vitroand animal experiments, before any clinical attempts are made.

References1. Morrison et al., (1997) Cell, 88, 287-298.2. McKay, (2000) Nature, 406, 361-364.3. Altman, (1963) Anat. Rec., 145, 573-591.4. Reynolds and Weiss, (1992) Science, 255, 1707-1710.5. Björklund and Lindvall, (2000A) Nature, 405, 892-895.6. Johansson et al., (1999) Cell 96, 1-15.7. Studer et al., (1998) Nature Neurosci, 1, 290-295.8. Lee et al., (2000) Nature Boitech., 18, 675-679.9. Clarke et al., (2000) Science, 288, 1660-1663.10. Gussoni et al., (1999) Nature, 401, 390-394.11. Jackson et al., (1999) PNAS USA 96, 14482-14486.12. Bjornson et al., (1999) Science, 283, 534-537.13. Björklund and Lindvall (2000B) Nature Neurosci, 3, 537-544.14. Brüstle et al., ( 1999) Science, 285, 754-756.

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EUROPEAN AND AMERICAN ETHICAL DEBATESABOUT STEM CELLS – COMMON UNDERLYINGTHEMES AND SOME SIGNIFICANTDIFFERENCES

Søren Holm, Institute of Medicine, Law and Bioethics, University of Manchester

and Senter for medisinsk etikk, Oslo University, Norway

The ethics of stem cell research is being discussed in many countries, andalthough there seems to be widespread agreement on what the relevantethical issues are, there is far less agreement on how these issues should beanalysed and what conclusions to reach. In this paper I want to comparetwo recent reports on stem cell research from government bodies in theUSA and the UK respectively. The first of these is the American NationalBioethics Advisory Commissions (NBAC) report from September 1999 (1),and the second is the report of a British expert group lead by the ChiefMedical Officer (CMO) which is dated June 2000, but which was only madepublic in August 2000 at the same time as the British Governments’response to the report (2,3)i. Both these reports were produced inresponse to a request from the government in the country in question.

The purpose of the comparison of the two reports is to draw out some ofthe implicit assumptions underlying discussions about research in and useof embryonic stem cells.These assumptions are often not clearly stated butmay have a profound impact on the conclusions that are reached.

The comparison of the two reports will look at both the recommendationsand the reasoning behind the recommendations, but before such acomparison is made it is important to note the differences in the positionof the two groups writing the reports.

NBAC is advising the American president on bioethics and is thus placed inthe federal administration. It is an independent and permanent body, and hasdealt with a large number of ethical issues since its establishment in 1995.Under the American division of powers between the federal government

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and the states, the states regulate medical research and reproductive tech-nologies (within the limits set by the constitution), and the federalgovernment therefore has no direct jurisdiction over stem cell research ortreatment. A large part of the public research funding for stem cell researchdoes, however, come from federal sources like the National Institute ofHealth (NIH), and the federal government can regulate the work ofinstitutions receiving federal money.The conclusions of NBACs’ report aretherefore mainly couched in terms of what should be funded or not funded,and what institutions receiving funding should be allowed to do.

The CMO is a British government official, and since the responsibility forregulating research has not been devolved (to Scotland), he can directlyadvise the government about legislation and other regulatory measures.Theexpert group who wrote the report was a group established only for thispurpose, and was headed by the CMO. During the work of the expertgroup the Nuffield Council of Bioethics published a discussion paper onstem cell therapy that was submitted to the CMO and possibly influencedthe thinking of the expert group (4).

Is stem cell research a good thing?Both reports agree, not surprisingly, that if the potential therapeuticbenefits that stem cell research promises to deliver actually materialises,this would be a very good thing. Ethically speaking the relief of humansuffering and the treatment and alleviation of disease are very laudable aims.There is, however, a significant difference in how much the currentlypotential nature of these benefits is underlined in the reports.The Britishreport shows the least amount of doubt as to whether science can reallydeliver on the promises. It says:

“Based on extrapolation from the animal research and the limited researchin human cells undertaken so far the Expert Group concluded thatrepairing nerve cells lost in Parkinson’s disease and Alzheimer’s disease […]all seemed realistic prospects if the research fulfilled its potential.ii” (2, p. 29)

The report then mentions all the problems that have to be solved beforethe research can fulfil its potential, but these problems are not taken to be

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reasons to doubt whether the potential will actually be fulfilled, but only asreasons to allow even more research to take place.

This raises the more general problem of how we should take account ofthe uncertainty inherent in potential benefits predicated on possiblescientific breakthroughs. Over the years many scientific breakthroughs havebeen promised that have never materialised, or the difficulties in achievingany practical benefits from the science have been grossly underestimated(gene therapy is a recent example, but there are many others).There canbe no doubt that uncertain benefits should be discounted in some way, butthere seems to be no way to device any precise numerical discountingformula, and neither of the two reports try to do so.

Based on the assessment of the therapeutic potential both reportsadvocate that embryonic stem cell research should be allowed and fundediii,but their views on exactly what kinds of research that should be fundedturn out to be very different.

Is embryonic stem cell research necessary?Both reports agree that the most contentious form of stem cell research isresearch involving the creation of embryos for the purpose of producingstem cells, and that the most contentious category of this is the creation ofembryos by nuclear replacement. The reports do, however, differ in theirevaluation of these very contentious forms of research. These differentevaluations turn out to be based on different assessments of whether aparticular type of research is necessary at the present time for the fieldto progress towards therapeutic use of stem cells.

In the NBAC report it is recommended that the federal government should not:

“…fund research involving the derivation or use of human ES [EmbryonicStem] cells from embryos made solely for research purposes using IVF.”(1, p. 71, Recommendation 3)

and that it should not:

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“…fund research involving the derivation or use of human ES cells fromembryos made using SCNT [Somatic Cell Nuclear Transfer] into oocytes.”(1, p. 72, Recommendation 4)

Both of these recommended restrictions on federal funding of embryonicstem cell research are based on an argument balancing the current need forthis particular kind of research against the additional ethical problems itraises in comparison with similar research on cells derived from surplusembryos in IVF programs. Concerning the current need for the researchthe Commission writes:

“Currently, we believe that cadaveric fetal tissue and embryos remainingafter infertility treatments provide an adequate supply of researchresources for federal research projects involving human embryos.Therefore, embryos created specifically for research purposes are notneeded at the current time in order to conduct important research inthis area.” (1, p. 71)

and,

“We conclude that at this time, because other sources are likely toprovide the cells needed for the preliminary stages of research, federalfunding should not be provided to derive ES cells from SCNT. Never-theless, the medical utility and scientific progress of this line of researchshould be monitored closely.” (1, p. 72)

One way of understanding NBAC’s argument is that given that the researchis fundamentally ethically contentious it should only be funded, if it ispresently necessary in order to secure the promised benefits.There is noreason to perform research which is more ethically problematic, if the sameknowledge can be derived from research which is less ethically problematic.

Another way of understanding the argument is to see it as a response tothe fundamental uncertainty concerning the reality of the potential benefits.The more certain we become that the large potential benefits will actuallybe realised the more they should count in our ethical deliberations, and the

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more ethical problems they can outweigh.We should therefore start withthe ethically least contentious types of research and only move on, whenthe results indicate that the likelihood of benefits actually occurring in thefuture has increased sufficiently.

On this issue the Nuffield Council on Bioethics seems to agree with theNBAC since they conclude:

“As long as there are sufficient and appropriate donated embryos fromIVF treatments for use in research, the Council takes the view that thereare no compelling reasons to allow additional embryos to be createdmerely to increase the number of embryos available for ES cell researchor therapy.” (4, p. 1)

In the CMOs’ report it is very clearly stated that not only is embryonicstem cell research necessary, but stem cell research using cell nuclearreplacement techniques is also necessary. In section 4.19 we read:

“For some people, particularly those suffering from the diseases likely tobenefit from the treatments that could be developed, the fact thatresearch to create embryos by cell nuclear replacement is a necessarystep to understanding how to reprogramme adult cells to producecompatible tissue provides sufficient ethical justification for allowing theresearch to proceed.” (2, p. 40, my emphasis)

What is stated here is that since stem cell research using cells fromembryos created by nuclear substitution is a necessary step in the processleading to all the potential benefits of stem cell therapies, this researchshould be allowed. It is, however, questionable whether this argument issound. Firstly it is unclear in what sense this type of research is necessary?Are we to believe that it is necessary in the strong sense that it is the onlyway to get the knowledge we need for stem cell therapies, or is it necessaryin the much weaker sense that scientific progress will be slowed down andwill be much more costly, but will eventually lead to stem cell therapies anyway. Secondly we do not at present know for a fact that embryonic stemcell research is necessary in any of these two senses. Many people believe

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that it is necessary, but new findings concerning the potentialities of adultstem cells have shown them to be surprisingly versatile.Thirdly we have noreason to believe that human embryonic stem cell research is necessarynowiv.There is still plenty of research to do in animals.

The NBAC report takes the view seriously that there are potentiallyrelevant ethical differences between the various methods for producingembryonic stem cells, whereas the CMO’s report in the final analysis justlumps them all together. The CMO’s report therefore ends with therecommendation that:

“The Research Councils should be encouraged to establish a programmefor stem cell research and to consider the feasibility of establishingcollections of stem cells for research use.

The Department of Health should seek to encourage Research Councilsto give high priority to this research through its Concordats with them.Research programmes might focus on the derivation of cell lines fromembryonic tissue and other sources, the production of stem cell lines bycell nuclear replacement, reprogramming the somatic cell nucleus toderive stem cell lines and the differentiation of stem cell lines fortherapeutic purpose.” (2, p. 48)

The slippery slope towards reproductive cloningOne argument which has been put forward in the debate about researchinto so-called therapeutic cloning, i.e. nuclear replacement with the aim ofgenerating embryonic stem cells, is that such research will place us on theslippery slope towards reproductive cloning.The argument is not discussedin the NBAC reportv, but it is soundly rejected in the CMOs’ report. In theexecutive summary of the CMOs’ report we read the following assessmentof the argument (and this assessment is actually longer than the one in thetext of the main report):

“Concerns have also been expressed that allowing research on embryoscreated by cell nuclear replacement would be a first step on a ‘slipperyslope’ towards human reproductive cloning. The Expert Group con-

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cluded that an inadvertent slide into reproductive cloning was not arealistic prospect because of the stringent controls operated in the UKby the Human Fertilisation and Embryology Authority in its licensingboth of research involving embryos outside the human body and ofinfertility treatment. The 14 day limit on keeping embryos outside thehuman body and the very clear position adopted by the Authority thatthey will not license the implantation of embryos created by cell nuclearreplacement, provide clear and effective controls to prevent any accessto reproductive cloning.Additional controls would require a new Act ofParliament” (2, p. 8)

This is, however, a rather problematic rebuttal of the slippery slopeargument. Firstly very few are worried about an “inadvertent” slide towardshuman reproductive cloning. What worries people is that nuclearreplacement research in humans will inevitably generate knowledge thatmakes reproductive cloning much easier, and that there are people whoquite deliberately will use this knowledge and perform reproductive cloning.

It is also interesting that a few weeks after the publication of the CMOs’report the front page story in the British newspaper “The Independent”was “Human cloning is now ‘inevitable’” (5).The paper had polled 32 leadingBritish scientists, many of whom had presumably also given writtenevidence to the CMOs’ expert group, and more than half of them hadclaimed that reproductive cloning is now inevitable within 5-20 years.Thereporter writes:

“A majority of the scientists interviewed, who included Lord Winstonand professor Richard Dawkins, also believe that if the use of limited“therapeutic cloning”, in which cells from a cloned embryo are used togrow tissue for transplants, is successful, it will lead to a reevaluation ofthe present law banning reproductive cloning.” (5, p. 1)

and later:

“One medical director of a London fertility unit, who did not wish to benamed, went as far as to say:“The equipment needed for cloning is simple

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and cheap, and, whether it is approved of or not, it will happen. It isunstoppable.”” (5, p. 1)

The CMO’s report is likely to have underestimated the likelihood thattherapeutic cloning will lead to reproductive cloning, and overestimated theability of legislation and regulation to prevent this from happening. Seenfrom a scientific point of view successful reproductive cloning is (para-doxically) probably easier to do than therapeutically effective therapeuticcloning.

By adopting this stance towards the slippery slope argument the group hasmade its own work much easier. If it had accepted that there was even theremotest likelihood of therapeutic cloning leading to reproductive cloningit would have had to discuss: 1) whether and why reproductive cloning is asbad as it is currently perceived to bevi, and 2) if reproductive cloning isproblematic what weight should then be given to the fact that research intotherapeutic cloning will make reproductive cloning more likely. These areclearly different problems, but their analysis might have led the expert groupto be more sceptical towards allowing nuclear replacement research now.

Why different conclusions?The analysis has shown that although the two reports discuss the same ethicalproblems, and the same benefits with regard to stem cell research they cometo rather different results.The NBAC report advises caution concerning theethically most contentious forms of stem cell research (i.e. those that involvethe production of embryos solely in order to get stem cells and those involvingnuclear replacement) whereas the CMO’s report sees no major problems andadvocates a high priority to specific funding to this area.What is the reason forthese differences? One possibility is the different political climates in the USAand the UK, but I will suggest that this is not the whole explanation.

Part of the explanation could be that the two groups have simply con-ceptualised their tasks, and the relevant context differently.

Both reports rely on a conceptualisation of ethical analysis as a balancingbetween competing interests or arguments. The NBAC report discusses

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this at length, including the distinction between “pure” ethical analysis andethical analysis in the context of public policy formulation, whereas theCMO’s report is less explicit as to its methodologyvii.

On a closer reading it does, however, become clear that the balancing thetwo groups have performed is a very different balancing. In the CMO’sreport chapter 4 deals with the ethical considerations and early in thischapter we read the following concerning the debate about the general useof embryos for research:

“The purpose of this Chapterviii is not to revisit that earlier debate. Itfocuses only on whether research involving the extraction of stem cellsfrom embryos, or the creation of embryos for such research using cellnuclear replacement, raises any new ethical issues, as the terms ofreference of the Expert Group requiredix. In particular it considerswhether these new possibilities for research cross a new moralboundary, representing an unjustified extension of the uses of embryosalready authorised by the 1990 Actx.” (2, p. 37, my emphasis)

The balancing that the CMO’s expert group is performing is thus notbetween the new research and the ethical problems it entails, but onlybetween the new research and any new ethical problems it entails.All oldethical problems associated with the research are removed from the scalesand are not allowed to influence the balancing. Such a restricted balancingcan in general not be a valid method of ethical reasoning, since it can beused strategically by splitting up an ethical problem in a number of stagesand only counting a subset of the ethical problems at each stage. Suchincremental analysis can easily justify even very bad acts, if sufficientingenuity is invested in the analysisxi.

This restricted balancing could, however, be a legitimate strategy if ourprevious public policy decisions, for instance allowing IVF and research onembryos until 14 days after fertilisation, are based on an explicit view thatthere are no ethical problems connected with these techniques. But thatseems not to be the case.The CMO’s expert group itself acknowledges thatthese previous decisions involved a balancing between the good that could

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be done, and the ethical concerns connected with the creation and use ofhuman embryos.These ethical concerns were not declared to be invalid, butonly declared to be overridden in the concrete context. That the ethicalconcerns about the status of the embryo or about creating embryosdirectly for research were not deemed to be totally irrelevant when theregulations were written can also be seen by the fact that currentlyresearch using embryos is restricted in the UK to research aimed improvingreproductive techniques or produce knowledge which can in the long runimprove reproductive techniques (including contraceptive techniques).If the ethical worries had really been deemed to be irrelevant such arestriction makes no sense.

What distinguishes NBAC and the CMO’s expert group is thus the con-ceptualisation of what it is that should be allowed to weigh in the negativescale in the balance against the potential positive therapeutic and scientificbenefits.

References1. National Bioethics Advisory Commission. Ethical Issues in Human Stem

Cell Research. Rockville: NBAC, 1999.2. Stem Cell Research: Medical Progress with Responsibility – A Report from the

Chief Medical Officer’s Expert Group Reviewing the Potential of Developmentsin Stem Cell Research and Cell Nuclear Replacement to Benefit HumanHealth. London: Department of Health, 2000.

3. Government Response to the Recommendations made in the ChiefMedical Officer’s Expert Group Report “Stem Cell Research: MedicalProgress with Responsibility”. London: Department of Health, 2000.

4. Nuffield Council on Bioethics. Stem Cell Therapy: the ethical issues – a discussion paper. London: Nuffield Council of Bioethics, 2000.

5. Human Cloning is now ‘inevitable’. London: The Independent, 30. August2000, p. 1 & 4.

i The government’s response accepted most of the recommendationsfrom the CMO’s Expert Group, except the recommendation to set up anew oversight body for this kind of research.The government felt thatthis could be handled by widening the remit of some of the alreadyexisting bodies.

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ii There seems to be a tautology here involving the desired outcome beinga realistic prospect if the research fulfils its potential, but I won’t analysethis further here.

iii Recommendation 2 in the NBAC report (1, p. 70) and recommendation1 in the CMO’s report (2, p. 45)

iv And even less reason to believe that research involving nuclearreplacement in humans is necessary now. Such research will only become“necessary” in any relevant sense of necessary when the basic researchon establishment and differentiation of human embryonic stem cell lineshas been performed.

v It is, however, addressed in some of the many briefing papers that NBACcommissioned during their work on the report.

vi In the Independent article Peter Brinsden who is medical director at theprestigious Bourn Hall IVF clinic is quoted as saying: “Reproductivecloning for ethically approved, very limited indications would now beacceptable to a large portion of society if explained properly.” (5, p. 1)

vii For the purposes of this paper I am not going to discuss whether itmakes sense to balance consequentialist and non-consequentialistconsiderations against each other.

viii And presumably the whole report.ix It is questionable whether this is actually what the Terms of Reference

require since they relevant sections there talk about assessing the risks,benefits and any alternative approaches that might be pursued: and in thelight of this to consider whether there are any new ethical and socialimplications. New ethical implications is not the same as new ethicalissues.The issue might be the same, but if the balance between positiveand negative ethical considerations shift the ethical implications might bequite different.

x The Human Fertilisation and Embryology Act 1990.xi This is a fairly general problem when an argument rests on serial uses of

arguments based on analogies. It may very well be that situation A issufficiently analogous to situation B to warrant a similar conclusion in thetwo situations, but when we have drawn further analogies between B andC, C and D, and D and E it is far from certain that there is any connectionstill remaining between A and E.

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FOR WHAT PURPOSE CAN HUMAN STEMCELLS BE USED? A THEOLOGICAL VIEW POINT

Jaana Hallamaa, Faculty of Theology, University of Helsinki, Finland

In Padua, Italy, at one of the oldest universities in the world there are threerooms, very different from each other but all displaying a history that theuniversity cherishes with great pride. First there is the main hall where allthe festivities and solemn ceremonies of the university take place. Thedecoration of the room speaks a strong language in its many symbols: thetask of the university is not to take heed of any limits or borders in itsservice to knowing, knowledge, science, and in the end, truth.

In the second room, there is only one item but as it is large and very robustin its form, it captures the attention at once. It is the lectern of GalileoGalilei behind which he gave all his lectures, explaining his observations andbuilding them into a theory that was, gradually, to change the whole viewon the cosmos, and the place of humanity within it.

And finally, there is a room that is furnished with steeply rising woodenplatforms that form the auditorium of an amphitheatre. There is onlyenough room too stand very close together and steady oneself againstwooden railings, and ones attention is drawn to a table in the middle of theroom.This is the famous anatomical theatre, the first in the world, wherethe professors of the medical faculty of Padua revealed the secrets of thehuman body to their students.This is where modern medicine has one ofits points of departure.

The anatomical theatre in Padua is said to have been built upon asubterranean river and the operation table on which the bodies wereexamined was placed just where the stream had its course.The table wasnot just any kind of a table but one especially designed for its purpose.The

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top of the table could be opened by running a small mechanism attached tothe table, and whatever was lying on it dropped down to the inside of thehollow table, and because there was no floor underneath, further downuntil it reached the river and was carried away by the stream.

Why build the anatomical theatre upon a subterranean river, and whydesign the table as a piece of magician’s paraphernalia? These were accord-ing to the story necessary security measures to make sure that the studyof anatomy could go on undisturbed. The mechanism was put to workwhenever the guard outside the theatre gave a warning of an ecclesiasticalofficer, a priest, coming to inspect what was going on at the anatomicallecture. To lose a body was a lesser evil than the abolition of anatomicalresearch. It was feared that the influential ecclesiastics would forbid thestudy of anatomy if they found out that medical teaching and research werebased on violating the sanctity of the human body, something the churchhad defined as sinful and blasphemous.

The anatomical theatre of the university of Padua is now a museum. Still,what it once contributed to medical science continues to be valid: the basisof all medical cure and care is the experimental knowledge which has thephysical nature of the human body as its starting point. Something elseseems also have remained the same: the Church that so strongly opposedthe ways of learning what the human body is all about in its anatomicalconstruction is the church that puts its foot down against experimentationand research on embryonic stem cells.

Were I representing the Roman Catholic Church, my task would be botheasy and uneasy. It would be easy to stand here, referring to the papalstatements on reproductive technology, the status of embryos, the sanctityof human life, and the metaphysical nature of different kinds of stem cells,embryonic as well as those of a more differentiated kind in an adult humanbeing. The doctrinal commissions of the Roman Catholic Church havedrawn the lines which ethical thinking should follow.The uneasiness of thetask would stem from the fact that there are few in the Nordic countrieswho accept the statements of the Catholic Church or, even more unlikely,the pope as one’s moral guide. I am not a Roman Catholic theologian but

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one from the Lutheran tradition, and there is no pope and no doctrinalcommission to set the guidelines for correct ethical thinking to lend meauthority.

What does a Lutheran theologian have to contribute to this discussion?Until now all that I have said seems to have very little to do with stem cellresearch. European countries are secularised and pluralistic societies inwhich church and religion seems to play a very minor role in publicdiscussion. Although religion has by no means vanished as many peoplethought it would with the progress of science religion is regarded as aprivate matter that does not affect the society at large.There are, however,rather striking differences among European countries, in their culturalatmosphere, their kinds of public ethical discussion and policy making.Thesedifferences can partly be traced to implicit but strong religious traditions thatgive certain characteristics to peoples way of thinking and living, and to theirway of reasoning as well as to their ethical evaluation. I wish to point out somefeatures in the Nordic religious tradition which I think are worth consideringas we discuss experimental and therapeutic use of human stem cells.

The old capital of Sweden, Uppsala, is known by its old royal castle up onthe hill. Still grander than the castle, however, is the Uppsala cathedral.Youcan spend many an hour marvelling at the beautiful simplicity of thebuilding. When leaving the church, your eye is certainly caught by thebuilding opposite the main entrance of the cathedral.There you can see thedome of the once extremely modern and progressive anatomical theatre ofthe medical faculty of the university of Uppsala.This theatre was not builtin secrecy but it was given a central place in the city.There was no need tohide what was going on in that building, and it could be built just where thechurchgoers would see it. And also the other way round: standing at thedoor of the anatomical institution gives a view of the cathedral under thefloor of which professors of medicine might in the 17th century hope to beburied, if they excelled in their careers as scientists and teachers.

Do I wish to propagate a view of the Lutheran church as a friend of scienceand research, telling that Nordic Lutherans are much more liberal thansouthern Roman Catholics? No, there has been enough animosity between

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church and science that such a claim would be false. Even Nordic Lutheranchurches have a reputation for stale conservatism, exaggerated cautious-ness and rigid morality. But there is a difference between NordicLutheranism and Southern Roman Catholicism, and the two anatomicaltheatres and the degree of openness of their work display this difference.Comparisons of Roman Catholic and Lutheran theological traditions oftenrefer to differences in theological anthropology. Evil and suffering are,according to the Roman Catholic view, a deprivation, the fall has deprivedthe world of its original goodness though not destroyed it. Every movementand action in the world displays a yearning towards this original goodness,and therefore, to God. Because of this tendency towards good, everythingbelongs to God.The Roman Catholic Church represents God on earth, andit is for this reason that the Pope, as the vicar of Christ, can act as the moralspokesman for all human beings, irrespective of their faith or religiosity.TheChurch serves all people by trying to restore the original, true nature ofexistence.

Lutherans are known for their pessimism. Sin and human depravity belongto their vocabulary. Behind this emphasis there is a conception of the worldthat is very different from the Roman Catholic understanding of reality.According to Lutheran understanding, we cannot read a tendency towardsGod from our reality. The world we live in – theologically speaking – is afallen, secular world, and not a divine world.

This theological difference between Catholics and Lutherans has a greatimpact on the moral thinking of these traditions. Catholics represent atheological naturalism on the basis of which they can combine biologicalfacts with their theological conceptions, and thus, e.g., refer to a fertilisedegg as a human being. The Lutheran tradition does not give us means forthis kind of an interpretation. We cannot read theological truths fromworldly facts.This means that science is independent from any theologicaldemand. Faith cannot rule reason. You can build an anatomical theatreopposite the cathedral.

The Nordic countries have their differences but there are still many sim-ilarities that make them a very special place in the world.There is a strong

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egalitarian and democratic tradition in these countries, a well-defined senseof mutual responsibility displayed by the strong welfare state and firmsentiment against bribery and nepotism. The Nordic countries are oftenreferred to as very pluralistic and the most secular societies in the world.Religion is kept as a strictly personal matter that plays a rather insignificantrole in public discussion.Against this background, it is paradoxical that thesecountries form one of the most uniform corners of the world as far as theinhabitants’ religious commitments are concerned. We in the Nordiccountries are secularised but, as such, we are Lutherans. It is noteworthythat this secularism cannot only be explained in sociological terms but it hasits roots firmly in the Lutheran theological tradition that has contributed tosecularising our societies.

I stand on a very unfirm ground: have I not deprived myself of all means ofsaying anything substantial on human stem cell research from a theologicalpoint of view? Science is independent from religion, the world is secular andnot divine and we cannot infer normative conclusions from facts. I am goingto weaken my position further by saying that the Lutheran tradition doesnot give any specific value to religious ethics: all ethics are a worldly matterof reason and the reason of the believers is not necessarily any better thanthat of the non-believers. It is often quite the contrary.Thus the church andthe theologians cannot put themselves above anyone else in any ethicaldiscussion.The church does not have any secret wisdom or holy revelationin ethical matters but we are all equal partners in the same dialogue.

In spite of everything I have said so far, the Lutheran ethical tradition is notempty. It is a powerful instrument in ethical assessment although it does notcome with clearly cut answers to any question. The two values of theLutheran tradition that are relevant in this context are the undeniableworth of every human being and equal moral responsibility. Human beingshave a rational mind and a moral capability to see themselves in the positionof the other, especially the weak, to see their needs and to reason whatmust be done to meet these needs.

These are rather general lines of moral thinking and they are not to be usedas abstract principles but as an expression of a living tradition that meets

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new challenges. I will now try to see what a theologian can say about thequestion: For what purpose can human stem cells be used? This is not aquestion any (Lutheran) theologian can answer. I cannot answer this questionbut I can, using the religious and moral tradition that has been and still is verystrong in the Nordic countries, suggest something that should be consideredas we face the possibilities of different uses of human stem cell research.

It is typical of the Western cultural, moral and religious tradition that it isnot uniform and monolithic but manifold.We tend to cherish several valuesand normative standpoints in our thinking that cannot always be combinedwith each other without tension. A very strong impetus in Westernintellectual life has been knowledge for the sake of knowledge. Knowledgeis an intrinsic value that does not need any instrumental legitimisation.Thethree rooms of the University of Padua that I have described are all strongsymbols of this ideal. Another strong Western ideal is the attempt toovercome the limits of nature. Most technological innovations that arethere to make our daily life easier are outcomes of the underlying wish inour culture not to respect the limits nature sets to our freedom.

Both these ideals have strongly influenced Western medicine: the anato-mical theatre in Padua was not built for any therapeutic purpose as such butfor the sake of knowledge concerning human anatomy. Medicine would beuseless without the thought of overcoming the limits of nature: diseases arenatural phenomena, and medicine seeks ways to combat them. Besidesthese theoretical ideals of the Western tradition medicine has been – andstill is led by the ethical ideal of curing, helping and supporting the sick, thesuffering, the weak and the dying. In the end, the urge to examine the humanbody and its functions and the attempt to overcome the limits sickness anddeath put on human life, are motivated by the ethical ideal to cure, alleviatepain and help the suffering. It is for this purpose that human stem cellresearch should and can be used.

Things are not of course that simple.There are two things that worry me.Let me name my worries according to a question and an answer in thebeginning of Genesis: the first one is God’s question to Adam after the Fall,and the second Cain’s answer to God after having killed his brother Abel.

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Adam, where are you? is God’s question to Adam.We must ask: Medicine,where are you? Unlike the first human beings in the story of Genesis,medicine has not fallen from an original perfection to corruption, on thecontrary it has been able to present great achievements and unbelievableprogress.And still I think that this question is appropriate: Medicine, whereare you?

Researchers and doctors are human beings and human motives lead themin their work.There is the idealistic motivation to help and cure but thereare also other incentives such as greed, search for fame and acknowled-gement, power and position, etc.The time of the lonely researcher who hasa small laboratory in the cellar of his house is gone for good. Research isteam work and it is very unlikely that any of the best research is doneoutside the well-established research institutes.This means that it is nearlyimpossible to achieve anything remarkable without a lot of money. Investingmoney in medical research is motivated by a wish to make a profit. Privatemoney funds the medical research that is most likely to producecommercial results.The laws of market economy also rule over the use ofpublic funds.There is an implicit wish behind the funding of medical researchthat it will make people healthier and increase their well-being so that theymay be more effective in the service of the market.

A market economy system may be the best way to take care of human well-being and a wish to make a profit and serve the suffering can be combined.Still, I think it appropriate to ask: Medicine, where are you? Is medicine aninstitution that modifies its product according to the demands of themarket, that is to say, the wishes and the folly of the rich, or is it a traditionand a profession that has an ethical code that is not inherently dependenton the market?

Am I my brother’s keeper? is the answer Cain gives to God’s questionWhere is your brother Abel? The ethical dilemmas in human stem cellresearch concentrate on the need of IVF- embryos, aborted fetuses and eggcells. Can we use them for research, and later on, for curing purposes? I donot think that this question is about ontology, i.e., the essence of, say, ahuman embryo, but rather about social ethics.We already produce and use

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IV-embryos, aborted fetuses and donated egg cells, and this fact is inde-pendent of human stem cell research. Even if we do not think that eggs,embryos or fetuses are human beings, they are not just any biomass, either.Some people stress potentiality: they could, under certain circumstances, allhave become or become human beings. I am not sure if the difference liesthere. I would rather say that we discern what is essential in the questionof Cain: am I my brother’s keeper? The fact that there are already donatedeggs, IV-embryos and aborted fetuses is a consequence of the, for a greatpart, socially determined causes that lie behind abortions and fertilitytreatment. The need of women to interrupt a pregnancy and the growingamount of infertility among couples are not (just) indicators of people’sindividual and private choices but speak strongly about the conditions ofpeople’s life in Nordic societies.We cannot utilise the full potential of humanstem cell research without embryos and aborted fetuses but the supply ofthem depends on other people’s misfortune, unhappiness or even tragedy.

I think the Nordic community will make similar rules for stem cell researchas have been suggested in Great Britain.The special nature of IV-embryos,aborted fetuses and donated eggs will be taken into ethical considerationand certain norms will be formed to regulate first the research and thenthe use of this material. I do not think that this will threaten the moralintegrity of our societies.We can predict many of the positive outcomes ofthis research for future patients.What we cannot, however, anticipate is theimpact that stem cell research and its use will have on our self-image.Wecannot tell how it will effect our understanding of good human life andsociety.The most difficult thing is to discern the direction where our well-meaning little steps will lead us. The biggest issues cannot be decided bylisting the likelihood of different pros and cons of stem cell research.Thebiggest issues are decided in the answer to the question:Where are you? Ifwe remain true to the tradition that has formed us and our societies, theanswer shall not be:Am I my brother’s keeper?

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STEM CELL RESEARCH.PHILOSOPHICAL ASPECTS

Göran Hermerén, Department of Medical Ethics, Lund University, Sweden

IntroductionFour imagesConsider these images or narratives:

In the world scheme, there is man, God and all the animals and plants.Mankind is created by God. Every human being is unique. Human beingshave a special position in the world order, distinguishing them from the rest.They have a free will, and could have chosen differently, and on that groundhuman beings are responsible for their actions, but have no responsibilityfor the creation.

Another image:In the world scheme, there is man, no God but all the other animals andplants, and human beings are the result of the struggle for survival. Everyhuman being is unique. But human beings have no special position in theworld order, distinguishing them from the rest. They have a free will, andcould have chosen differently, and on that ground human beings areresponsible for their actions. But they have no responsibility for the welfareof other human beings, animals and plants.

A third imageIn the world scheme, there is man, no God but all the other animals andplants. Human beings can be the result of intentional actions by otherhuman beings by IVF (in vitro fertilisation), PID (pre implantation diagnosis),cloning and by modification of our genetic heritage. Every human being isunique. But human beings have no special position in the world order,distinguishing them from the rest.They experience that they have a free will,

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and could have chosen differently, and on that ground human beings areheld responsible for their actions. They have some responsibility for asustainable development of the ecosystem and for the welfare of otherhuman beings, animals and plants.

A fourth imageIn the world scheme, there is no God but survival machines of differentlevels of complexity, and man is one of them. The ultimate goal of such asurvival machine is to function as a vessel or vehicle to protect a collectionof genes during a limited period of time and to reproduce these genes,preferable in large numbers, before this vessel of transportation collapsesor is ruined. Every human being is unique. But human beings have no specialposition in the world order, distinguishing them from the rest. Theyexperience that they have a free will, and could have chosen differently, andon that ground human beings are held responsible for their actions, andhave some responsibility for the creation.

What implication, if any, has stem cell research for these images? And whathas that got to do with philosophy?

To discuss and illuminate the relations between stem cell research andphilosophy, the possible impact of one on the other, and/or to discuss stemcell research from a philosophical point of view, it will be necessary to beginwith a few simple distinctions.

Some distinctionsFirst, as to stem cell research (=SC research below), there are two basicavenues of research being pursued today: basic research and clinicalresearch.

Basic research on human stem cells can use adult stem cells, stem cells fromthe umbilical cord blood, stem cells from foetal tissues or from embryonicblastocysts. Such basic research can be pursued in order to study theconditions necessary for reprogramming adult human cells, to learn tocontrol the differentiation process of cells, and how to stop this process atvarious stages, etc.

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Clinical research on human stem cells includes trials carried out on patientssuffering from severe conditions such as Parkinson’s disease, heart diseaseor diabetes, raising issues about free and informed consent, risk-benefitassessment, protection of the health of persons involved in trials, as well asanonymity of donation and prohibition of commerce.

As to philosophy,we have to distinguish between philosophy as a method andas a substantive theory. Methods have been developed in philosophy foranalysing and clarifying concepts and statements, for making hiddenassumptions explicit, for defining terms and concepts – as well as for criticisingand questioning concepts and statements, hidden assumptions and proposeddefinitions.There is a long tradition in philosophy for this, from Socrates tocontemporary analytic philosohy. Many people would say, and I would beamong them, that this is certainly a very central aspect of philosophy.

But in addition to these methodological contributions of philosophy,philosophers have over the years developed more or less coherent andspeculative theories.They include theories about man, about man's place innature and in the world order, theories about what it is to be a human beingand what separates human beings from machines and physical objects aswell as about the nature of the physical world.There is a long tradition inphilosophy also for this, from Plato via Spinoza, Leibniz, Hegel, Marx toKierkegaard, Cassirer and contemporary existentialist thinkers.

Thus, to sum up, by combining these two distinctions, we get the followingdiagram:

philosophy as method philosophy as theory

basic SC research 1 2 ____________

clinical SC research 3 4

All combinations are interesting in the present context. I will begin with 1and 3. But first a few words about stem cell research at present.

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Present directions of SC researchBy culturing human stem cells insights can be obtained that cannot beachieved by studies directly of the human embryo or via the use of animalmodels, particularly concerning the normal development of human beingsand the causes of birth defects. By observing how differentiated cellsrespond to different chemicals, it will also be possible to sort out potentialdrugs that are harmful to human beings.

As I have learnt from Anne McLaren and some of my Swedish friends doingresearch in this area, in particular Olle Lindvall and Anders Björklund, stemcells could also be used as vectors in gene therapy, and stem cell therapy incombination with somatic cell nuclear transfer could be used to avoidadverse immunological reactions etc.

The potential outcome of basic or clinical stem cell research has, as Iunderstand it, rather little to say about the concept of man and how mandiffers from other living beings.Thus, if there is an implicit view of humanbeings underlying such research, it appears at first sight to be verymeagre.

But how does the latter square with the often-heard statement that abreak-through in this research will revolutionise our self-understanding?Clearly, the possibility of somatic cell nuclear transfer (SCNT) is perhapsthe greatest challenge to our image of ourselves.The creation of embryosfor research purposes and theoretically also for reproductive purposesraises difficult ethical as well as general philosophical issues.

Philosophy as methodClarification of controversies and underlying value conflictsThree obvious ethical controversies raised by research on human stem cellsconcern the (1) sources of the stem cells, in particular the use of embryonicand foetal stem cells and the creation of stem cells for the sole purpose ofresearch, (2) the purpose and methods of such research, in particular theuse of somatic cell nuclear transfer, and (3) finally the commercial aspects,including the patenting issues, especially patentability of human geneticmaterial.

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The methods of philosophy can be used to clarify first of all the contro-versies just mentioned and in particular the underlying conflicts of interestsor values.The controversies may, at the same time, involve several differentissues that need to be separated because they are solved by differentmethods: terminological problems, empirical issues, normative issues, as wellas questions how the present laws are likely to be interpreted and appliedin coming court cases.

As to the underlying value conflicts, one important principle, related tobasic human rights like freedom of thought and freedom of expression, isfreedom of research. This principle, however, may clash with otherlegitimate interests and values. Therefore it has to be balanced againstseveral other principles, well-established in our culture and discussedextensively in the literature on medical ethics.

They include the principle of respect for human dignity, the principle ofautonomy (which is the basis of the requirement of informed consent), theprinciple of beneficence (here in particular interpreted in terms ofimproving the health and quality of life of present and future patients), andthe principle of non-maleficence. This latter principle is the basis of thesafety requirements, including a precautionary approach requiring that longterm consequences need to be considered and that irreversible changesinvolving more than minimal risks should not be introduced.This principlecan also be a basis of the requirements concerning respect for privacy andconfidentiality of personal data, since violations of these requirements maycause harm. Last, but not least, there is the principle of justice, which entailsthat health care resources are to be distributed in a fair way.

The way this balance is struck depends on the problem at hand, the existinggaps in our knowledge and the promises and potential risks in each situation– as well as the ethical starting point chosen. For instance, the varioussources of stem cells for basic research raise different issues. The mostcontroversial sources are obviously foetal tissues and embryonic blastocysts.

The former requires informed consent of the donor, time to consider, andthat the abortion is not induced in order to obtain the tissues and that the

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time of termination and the method used for the abortion is not influencedby the research interest.The latter raises the issues of the moral status ofthe human embryo, when the fertilised egg becomes an individual withhuman rights (a person) – questions to which I will return later in this paper.

Some important argumentsResearch on spare human embryos is permitted under certain conditionsfor the purpose of improving IVF methods, not only in Sweden but also inmany other countries. For those who have no ethical objections to suchresearch (and I am among them), it would be difficult to find any relevantarguments against allowing also research on human embryos during a 14day period for the purpose to cure severe diseases or injuries, likeParkinson or diabetes.

The underlying assumption of this argument is that the purpose ofdeveloping methods to cure severe diseases like Parkinson is (at least) justas important a medical goal as the purpose of improving methods oftreating involuntary fertility. The obvious necessary condition is then thatthe embryos are not put back in the uterus on any woman after research.But since the use of foetal tissues and embryonic cells for researchpurposes is sensitive, transparency, openness and public control is essential.

Embryos can be created for research purposes by means of somatic cellnuclear transfer (=SCNT). In that way pluripotent stem cells can be derivedwith perfect histocompatibility. Theoretically, they can be transplanted tothe patient from which the stem cells were derived without rejection.Strong immunosuppressive drugs need then not be used, which is anotheradvantage.This research interest is quite legitimate. However it has to bebalanced against other concerns and other interests.

For example, the respect for human dignity must not be undermined. Theuse of oocytes must not be trivialised and used merely as means for otherpeople. Pressure must not be put on women to deliver oocytes.At present,one further important consideration is the high level of inefficiency in SCNT,which means that a large number oocytes is required.Another considerationis that these therapeutic possibilities are still in the future. It is hard to tell

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today how far away this future is.A third consideration is that many kinds ofresearch in this area can still be carried out with stem cells from spareembryos, foetal tissues and adult stem cells. Such considerations suggest thatit would at present be advisable to stick to a restrictive position outlinedbelow.The implication here is that if and when the situation changes in thefuture in these respects, such a restrictive position should be reconsidered.

In other words, at present it would seem, given these assumptions, that a goodcase could be made for saying that frozen embryos created for a differentpurpose can be used for research.A necessary condition for research use ofan embryo might then be: this is morally acceptable, only if the donors havedeclared that they are no longer interested in having the fertilised eggimplanted. Or, according to a more strict alternative: only if explicitinformed consent for the specific research purpose has been obtained.

To further clarify the relevance and tenability of the arguments mentionedhere, both they and the theses they can be used to support or criticise needto be made more precise. Sometimes it may help to replace a general, openquestion like “Is it morally acceptable to use fertilised human eggs forresearch?” – a question which invites “yes or no” answers – with thequestion “Under what conditions, if any, is it morally acceptable to usefertilised human eggs for research?” The latter question invites hypotheticalanswers, where the conditions are stated explicitly.

Clarification of goals and meansAgreement on goals can be combined with disagreement over whatmethods should be used to achieve these goals.And conversely, agreementon what methods are the best (most cost-effective, safest, …) to achievecertain goals could be combined with disagreement as to which goalsshould be achieved.The methods of philosophy can also be used to clarifythese agreements and disagreements over the explicit or implicit goals ofresearch and therapy, in particular, the extent to which they involveterminological, normative or empirical issues.

If the goal is to maximise human welfare (interpreted in terms of health),the means to achieve this today may be different in the future. The first

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question is obviously, how welfare and health is defined or measured.Clearly, not only welfare but also health can be understood and measuredin different ways, taking life expectancy and quality of life as points ofdeparture. Second, we need to separate what is sometimes called the totalview from the distributional view. In the former only the amount – assumingit can be quantified – of welfare is considered. But the latter requires acertain distribution of the welfare as well.

According to some philosophers, social engineers can make the calculusrequired to decide what is the best option in the short or long term forsociety at large. Utilitarians traditionally assume that benefits can be addedand harms can be subtracted from the total amount of benefits obtained,not only intrapersonally but also interpersonally. These assumptions havebeen very much under fire lately.The best option for society at large maynot be compatible with individual human rights and with other normativeassumptions. Other philosophers, inspired by Rosseau and Rawls, want toapproach these problems in a different way.The basic idea is that thinkingabout what is right and wrong requires thinking that could be justified toothers in ways they could not reasonably reject.

These contractualist thinkers begin by outlining the basic principles thatwell-informed and rational people would agree on, assuming what is calleda veil of ignorance, that is, assuming that they know nothing about their sex,fortune, colour of skin, diseases, and so forth.Then, the analysis proceedsvia a process called reflective equilibrium. Here our basic principles andpreliminary, intuitive decisions in cases covered by the principles aremutually adjusted to each other until there is full agreement between them.In other words, after reflection, adjustments can be made both of the ruleswe accept and in the decisions we are prepared to make in particular cases.In that way, it would hopefully be possible for those involved in a debate toreach a consensus on what should be morally acceptable in society,considering what sort of society they would like their children andgrandchildren to grow up in. The methodology outlined here very brieflyand in an over-simplified way is in my view interesting and fruitful. It has alsobeen refined in different ways, recently by Tim Scanlon (1999) in order totake into account the plurality of values in society.

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There are also other alternatives, however.They need to be made explicit,since they can come into conflict with each other. Those who argue thatembryos must never be instrumentalised and used for research purposeson the basis of deontological principles like the sanctity of human life arenot likely to be moved by the considerations above. Nor are they likely toabandon their views as the potential benefits increase and the risks anduncertainties diminish. Whatever the consequences for human welfare,whether in the short or long perspective, in their view research onembryos should not be permitted, legally or morally. Nor is it morally orlegally acceptable to derive stem cells from embryonic blastocysts, not is itacceptable to create embryos by SNCT for the sole purpose of research.

A personal positionLet me briefly indicate what my own position is on some of thesecontroversial issues, first concerning basic research and the concerningclinical research, and make explicit my main reasons for this position.Personally, I am most tempted by the contractualist approach, as to possiblestarting points. From other starting points, somewhat different conclusionsmay be derived. Given the uncertainties at present, it seems premature toallow the creation of embryos by SCNT for research on stem cell therapy,given this point of departure.

A softer position, for which there are also good reasons,would be to acceptthat embryos are created for research only under certain specifiedconditions. Such conditions might include: only when (a) this is necessary(when supernumerary embryos cannot be used) for important research ortherapeutic purposes, (b) when these reasons can be explained to an ethicscommittee in a convincing way, and (c) the ethics committee accepts andapproves the explanation – thus an application to research ethics com-mittee is obviously necessary in each particular case.

The contractualist method requires a dialogue between the differentstakeholders and those concerned. An essential idea is that each person in the debate has one vote, and nobody has more than one vote – only thestrength of the arguments count. This dialogue takes time, if a reflectiveequilibrium is to be achieved. Assumptions made by those involved in the

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dialogue have to be examined critically. I have no difficulty in imagining thatthe outcome of this process might be different in two societies, if theeconomic situation of the countries, the needs of patients at large, as wellas the medical research carried out (including the qualities of the labora-tories available and the competence and resources of the researchers) aredifferent enough.

But to apply the methodology described by Rawls, Scanlon and other to theproblems raised in this paper and demonstrate in detail how these tentativeconclusions, given certain assumptions, can be derived in a step-wise fashionrequires more space than is available here.

Clinical research on human stem cells has a great potential, particularly forpatients suffering from several severe diseases (Parkinson, diabetes etc).Therefore it should be easier to obtain a reflective equilibrium here. On thebasis of the principles mentioned earlier (autonomy, beneficence etc) anumber of more specific requirements are made, which those concernedwould have to agree on in the sort of contractualist debate mentionedearlier.

For example, in addition to the usual requirements of free and informedconsent (from donor as well as recipient), based on the principle ofautonomy, risk-benefit assessment is an essential requirement.This is basedon the principles of beneficence and non-maleficence, and here safety andsecurity aspects are of utmost importance, since it can not be excluded thattransplanted stem cells may induce tumours or cancer. Obviously, theseprinciples also include the requirements that the health of persons involvedin clinical trials must be protected and that data must be kept confidential.

Finally, there is a requirement of traceability, which can be related to thesafety and security aspects mentioned above: if undesired side effects occurafter the transplantation, both donor and recipient have to be traceable.

For a further discussion of some of these points and the argumentsmentioned earlier, see the recent report by EGE on stem cell research(2000).

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Commercial aspectsSince it is obvious from the recent debates in the European Parliament thatthe commercial aspects (involving patentability issues) of stem cell researchand SCNT is a very hot and contested issue, it is important to make thereasons for (and against) the various proposals explicit. For example, oneposition might be that genes and DNA sequences cannot be patented,because they belong to the common heritage of mankind.Another might bethat genes and DNA sequences can be patented, because this is already beingdone in the US and because big commercial interests are at stake.The idea isthat we ought or must jump on the band-wagon, or we will be left far behind.

My own personal view is that embryos, or human genetic material, genes orDNA sequences should not be patentable.They are discoveries rather thaninventions. Essentially, my basic position is that methods or processes canbe patented, only if these methods or processes solve a specific problemand satisfy the usual conditions of inventive step, usefulness etc. But I amwell aware that these issues are quite complex and should be left for aseparate discussion (Hermerén 2000). That discussion should focus par-ticularly on the patentatibility of functional genes.Anyway, I think there is awidespread agreement that embryos must not be bought or sold, nor evenoffered for sale.

A further problemThere are also other problems that need to be addressed. For example, inthe choice of research persons, different strategies can be used – each withtheir pros and cons.The differences between the these strategies need tobe spelled out and appreciated before the relevance and tenability ofvarious arguments for and against these strategies can be assessed in arational way, which is not easy, given the present gaps in our knowledge.

The principles justifying the selection of patients and research subjectsshould be made explicit and reviewed. For example, the following fourprinciples may be considered and separated:

(1) If there is a risk, then expose as few patients or research subjects aspossible to the risk (minimise the risk).

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(2) Select those in the first place, who have nothing to lose (minimise theloss) because death is imminent or the prognosis is pessima, very poor.

(3) Select those who have most to gain (maximise the medical benefit),because the prognosis is fair and their immune system is functioningwell

(4) Select those from whom it is possible to learn as much as possible(maximise the gain of knowledge).

Then we may try to identify and compare the consequences of adoptingone or more of these positions – in the short and long run.

Philosophy as theoryLet us now leave philosophy as a method and move to philosophy as atheory. This distinction is not a sharp one. Nor is it unproblematic. Themethodology chosen is often based on assumptions of different kinds – andwill have consequences for what sort of answers can be obtained. But theimportant thing is that in philosophical literature we will in addition tomethodological discussions also encounter some speculative views whichoften function as a sort of basic, or ultimate, hidden premises also indiscussions of ethical problems.

Some of these issues concern the place of man in nature and the possibilityof creating human beings or changing their genetic make-up – obviously, achallenge to those who believe that man is created by God, and that manshould not try to play God. But it is a challenge also to those who see manas a product of chance or of the struggle for survival – and think that thatis the way it should be. How does SCNT for research or reproductivepurposes fit in with various world views or conceptions of man, some ofwhich were briefly hinted at in the introduction?

The uniqueness of every human beingSeveral of the images in the introduction contain a clause about theuniqueness of human beings.This clause can be spelled out as follows: Everyhuman being is unique, with some important qualifications: (a) this concernsin the present context only their genetic make-up, (b) it allows for excep-tion of monozygotic twins, and (c) uniqueness is not a ground for value-

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judgements. Thus, to comment on (c), this claim about uniqueness is onlyintended as a statement of fact and not as a statement, explicit or implicit,of value. It does not imply anything about the value or dignity of humanbeings.

The key concepts in the explanation of uniqueness are those of identity,difference and individuality, as well as human being and person. This isrelevant also for an analysis of the question: How is a human embryodistinguished from a cell line derived from a stem cell? According to aphilosophical tradition going back to Leibniz, any objects or events areidentical, if (and only if) any property of one of them is also a property ofthe other (a principle called identitas indiscernibilium). It is then of someimportance what is counted as properties. As suggested above, theproperties are limited to genetic features. Two identical twins, having bydefinition the same genetic make-up, need not look exactly the same. Forexample, one of them could have received a scar in a duel across hisforehead.This would make it easy for anyone knowing this to tell who waswho of the twins.

But there is more to be said about the notion of identity and its relationsto the concept of a person. I agree with Ludger Honnefelder and DavidWiggins in their criticism of a reductionist account of a person, where theperson is reduced to a series of events or phases connected by somepsychological relation (such as memory).

We do suppose that persons “remain the same, even if they change”(Honnefelder 1996:150) and that individuals “go through developments andhave a certain biography”,“can be subjects of blame and be held responsible”(loc. cit.; c.f.Wiggins 1987:303-305).Thus I am inclined to think that we needto assume some kind of diachronic identity in order to be able to describeour experiences in a coherent and consistent way. How far back can thisdiachronic identity be extended in the life of a person? To the beginning ofthe process of fertilisation? To the implantation? The gastrulation?

I also agree with Strawson, Honnefelder and others (a) that we can and doapply mental predicates (intentions, thoughts, emotions, and memories) as

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well as material predicates (weight, size, shape, position and movement,chemical structure…) to persons, and (b) that an account of personsmerely in mentalistic terms – i.e. with the help of mental predicates only –is untenable, and that the same holds for an analogous account solely inmaterialistic terms. But does it follow from this that mental and materialpredicates mutually imply each other? A test case could be a description ofsomeone in a permanent vegetative state. Moreover, does it follow that theterms “human being” and “person” have the same reference? I have notbeen convinced; it seems to me that additional premises are needed todraw these conclusions.

In my view, the key question here is, as Ludger Honnefelder puts it: “If wetake the diachronic identity of a person to be the endurance of a continuant,…how far can we backdate our personal identity? (Honnefelder 1996:154).Two scientific discoveries are relevant here.The first is that the zygote up tothe end of the implantation can divide into several cells, each of which willdevelop into a new individual. The second is that sometimes zygotes mayrecombine with another different cell to become a new individual.

These discoveries can be interpreted in several ways. The conclusions Iwould be inclined to draw are the following two:

(1) like Honnefelder and many others that “that the beginning (just as muchas the end of life) is not a point in time, but a process… (Honnefelder 1996:154, cf also 155: “Whichever way we interpret the scientific results, it is afact that we are talking about a process…”), and(2) that we need to distinguish between genetic uniqueness and ontologicalindividuality in the sense that the zygote is genetically unique but that wehave an individual human being only at the formation of the so-calledprimitive strip.

Every distinction can be debated, and the ones above are no exception. ButI think they help to clarify the situation.

The uniqueness of every human being, in the sense explained above, couldcertainly be challenged by SC research in combination with SCNT. In

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principle, every human being could be the origin of an unlimited number ofgenetic copies, some of which could be born long after the person of originhas died. Every individual could in this way theoretically in the futureprovide a supply of tissues and organs with perfect histocompatibility(which means that no rejection of the transplanted tissues would takeplace), should the need arise.

Moreover, if a technique called embryo-splitting is used, any embryo beforeand up to the 8 cell stage could, at least in theory, be an eternal source ofnew embryos, all of which are genetically identical, if I am correctlyinformed. But bearing in mind the distinction between a gene and itsexpression, there is little risk that we or our offspring will have to take partin dialogues like the following one:

– Hello, George, how are you doing?– Hello Bill, not too bad. But I have had problems with my left knee sincelast Friday.– So do I. Besides, my doctor told me that my blood pressure is far too highand has been increasing in an alarming way since last week.– So did my doctor say to me too. I wonder why. I live like a monk. Butyesterday I went with my wife and our two children Bill and Sue to the Zoo.– So did I.

What would be lost, if this idea of uniqueness is given up? How would thataffect important and morally interesting concepts of personal identity? Forwhom would the effects be harmful? Personally, I feel that very little is lostby these potential scientific possibilities – but, of course, others may thinkdifferently, and then we could have an interesting discussion of thearguments pro and against this.

Other challengesLet us now return to the fourth image mentioned in the introduction,which I propose to call the DNA view of man:

“In the world scheme, there is no God but survival machines of differentlevels of complexity, and man is one of them. The ultimate goal of such a

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survival machine is to function as a vessel or vehicle to protect a collectionof genes during a limited period of time and to reproduce these genes,preferable in large numbers, before this vessel of transportation collapsesor is ruined. Human beings have no special position in the world order,distinguishing them from the rest.They experience that they have a free will,and could have chosen differently, and on that ground human beings areresponsible for their actions, and have some responsibility for the creation.”

If we grant that man is more than a collection of DNA, there is clearly aproblem of explaining the relations between the potential outcome of basicstem cell research and our conception of man. But if indeed man is no morethan a collection of DNA, the challenge is perhaps even greater. It is boundto meet with psychological resistance and will have a profound impact onour self-image and world view.

In other words, suppose we distinguish between a humanistic and a naturalscience view of man.We would then have to add as a qualification of thelatter the DNA view of man, which seems perfectly compatible with theresults of basic stem cell research. Or suppose we chose as our startingpoint Stevenson's more historic approach, distinguishing between Platonic,Cartesian, Freudian, Marxist etc views of man. How does the DNA view ofman and the discoveries of stem cell research fit it here?

Or suppose we distinguish between the somewhat different views of humannature I have discussed elsewhere: man as a machine, as a complexcomputer, as a self-healing and self-regulating organism, as a conditionableanimal, as an aggressive wild animal, as a thinking and acting being, onlypartly aware of what goes on in his or her mind, as a social being, as anelement of a certain physical environment – or as combinations. Is the DNAview of man, saying that man is nothing more than a collection of genes orDNA or a transportation vessel for such a collection, a qualification or aclarification of one of the earlier mentioned views, or a supplement: anaddition to this list?

To answer this question, we would have to take a somewhat closer look atthe underlying views of man, ultimately based on various concepts of man.

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I am not saying or suggesting that there is only one concept – there areprobably several. Philosophy can be useful by putting the discoveries of stemcell researchers in a perspective by providing a context or theoreticalframework for discussions of what these researchers have shown, what theconsequences of their discoveries are for our self-image, our view of humanbeings and their place in the universe.

Concepts of manThere are many definitions of man, or theories of the nature of man, in theliterature, ranging from the materialistic and mechanistic “man is a machine”to theories inspired by Freud or Konrad Lorenz. These definitions ortheories contain clauses of different kinds – some contain all types ofclauses indicated below, others only some of them. I then take a view ofman, and the underlying concepts, to contain speculative, empirical andnormative components.

The speculative ones include statements to the effect that man has a freewill, a holistic view of man implying that man is more than the sum of his orher parts (organs, tissues, cells), the belief in a life after death, the belief thatthere are innate ideas, the belief that injustices in life will be compensatedby after death, that man will exist as long as there is life on our planet – aswell as denials of such statements. Needless to say, I do not exclude thatempirical evidence in the future sometimes may support or underminesome of these speculative views.

The empirical ones, which in principle could be tested by ordinary scientificmethods, include views about the driving forces of human action and whathuman beings are striving for (love, recognition, fame, fortune, …or moregenerally: self-assertion, or to maximise what is in their long-range selfinterest), as well as more or less well established theories about defencemechanisms and subconscious strata in the mind of human beings.

Finally, the normative ones include views about what makes human lifevaluable, what the essential value of life consists in (exciting experiences orself-sacrifices, doing your duty or perhaps maximising your own happiness),the rights and duties of various players or stakeholders in different situa-

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tions, views about under what conditions human beings ought to get theirneeds or demands satisfied, as well as the thesis that man is the master ofnature and has a right to exploit nature for his or her own purposes – aswell as denials or alternatives to these statements, implying that humanbeings are part of nature and ought to live in harmony with nature.

Whatever starting point we chose, we would then have to explore theconsequences of these views in order to pave the way for a rationaldiscussion of the pros and cons of these views: what they have to say, or ifthey have nothing to say, on themes included above in the characterisationof a view of man, including what separates human being from others (suchas the uses of symbols, language, ability of self-reflection…); the drivingforces of human action (such as altruism, egoism, aggression, …); and thegoals of human life (what we strive to achieve, and why).

After this general note on definitions I now propose to consider in some moredetail a particular definition,proposed by Ernst Cassirer in his An Essay on Man.

Chapter II of this book has the telling title: “A Clue to the Nature of Man:the Symbol.” In this chapter Cassirer writes:

The fundamental circle of man is not only quantitatively enlarged; it hasalso undergone a qualitative change. Man has, as it were, discovered a newmethod of adapting himself to his environment. Between the receptorsystem and the effector system, which are to be found in all animalspecies, we find in man a third link which we may describe as the symbolicsystem.This new acquisition transforms the whole of human life (1962:24).

Two pages later, he continues and elaborates on this idea:

Reason is a very inadequate term with which to comprehend the formsof man's cultural life in all their richness and variety. But all these formsare symbolic forms. Hence, instead of defining man as an animal rationale,we should define him as an animal symbolicum. By so doing we candesignate his specific difference, and we can understand the new wayopen to man-the way to civilisation.

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These ideas are further developed in the chapter VI entitled “The Definitionof Man in Terms of Human Culture”. Cassirer stresses the functional natureof his definition – man is not defined in terms of his nature but in term ofhis activities or achievements – and he concludes this chapter by writing:

Myth, religion, art, language, even science, are now looked upon as somany variations on a common theme – and it is the task of philosophyto make this theme audible and understandable. (1962:71)

The question is whether this concept of man is compatible with the DNAview of man or not – or, more cautiously, under what conditions, if any, thisconcept or definition of man is compatible with the DNA view of man.I shall argue that there are conditions under which this question can beanswered in the affirmative. But an elaboration of this answer would takeus into the age-old battles between naturalistic and non-naturalistic onto-logical theories. For reasons of space, I can only indicate very briefly whatthis battle-ground looks like.

The status of the human bodyParticularly interesting is the potential impact, if any, of stem cell researchon the status of the human body and its parts and on our attitudes towardthe body.Analogously, attitudes toward the body and its parts may also havean impact on SC research, and particularly on some of the ethical issuesraised by such research.The status of body tissues have to be considered inrelation to the organic bodily whole and to the self.

Key questions here include: has the body a phenomenal reality, what is itsontological status, and is it intrinsic or incidental to personal identity? Onthe basis of answers to such questions, we may distinguish betweendifferent versions of, and attitudes to, monism and dualism, and betweenidealism and materialism, all of which have been elaborated and muchdiscussed in the history of philosophy.

Dualists argue that some form of idealism has to be combined with somesort of materialism.We must assume that mind and matter both exist, toput it simply, in order to be able to give a coherent and exhaustive

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description and explanation of ourselves and the world. Cartesius is theclassic or standard example of a dualist. Monistic theories can be eitheridealistic or materialistic. In the first case it is argued that mind (thoughts,ideas, emotions etc) can be reduced to matter (physical objects, energy, …)and in the second case it is the other way around: it is then argued thatmatter can be reduced to mind, that is, to ideas, perceptions, mental events,etc.To be is to be perceived – esse est percipi, as Bishop Berkeley once putit.This can be combined with seeing the mind as essentially something goodand the body as something bad, or vice versa.

In more contemporary and sophisticated versions of these theories it isargued that statements about ideas, thoughts, and experiences can betranslated – without changing the truth value or the meaning of thestatement – to statements about material objects, energy etc.An alternativeis to argue that for any statement in the first category there is a statementor group of statements in the second category such that the truth con-ditions for these statements are the same. Analogously, it could be arguedthat for any statement in the second category there is a statement or groupof statements in the first category such that the truth conditions for thesestatements are the same.

Emergence emergingObviously, what I call the DNA view of man is at first sight a challenge to,and at odds with, dualistic and idealistic concepts of man. It can easily becombined with a materialistic view of man, or be used to make moreprecise a variety of such a view. But the DNA view of man could also becombined with what is sometimes called an emergent view of man, basedon the theory that mind (thoughts, experiences, emotions, attitudes,perceptions etc) are emergent properties.

This in its turn presupposes that there are levels of aggregation within thehuman body, from DNA, cells, tissues, organs … etc to a human body, and thatmental predicates can be explained or understood as emerging properties. If inone way or another this process is controlled by the DNA, then the existenceof mental attributes could be combined with a DNA view of man. In my view,this is a very interesting possibility,which deserves to be discussed more widely.

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These ideas about emergence were proposed by the British psychologistand biologist Lloyd Morgan (who died 1936) and the Australian-Britishphilosopher Samuel Alexander (who died in 1938). As mentioned above,they imply that there is a hierarchy of levels in nature, where the propertiesof the higher levels cannot be explained from the properties of the lowerlevels, from where they originate.According to this theory consciousness isa property that emerges when an organism has reached a sufficientlycomplex level.

Such views have been further developed by the immunologist GeraldEdelman. In his view, the human brain is a self-organising, self-learning system.He argues that there is a distinction between a primary consciousness,existing in all higher animals, and a higher form of consciousness, existing inhuman beings and e.g. the chimpanzees.This is the basis of self-reflection andlanguage. It is tempting to assume that the higher form of consciousness isan emergent property in the sense indicated above, and that it is due to thehigher form of complexity of the human brain. If this is correct, biologyshould be sufficient to describe not only the mental life or mental states ofdogs and cats but also the mental states of human beings.

The upshot of all this is that the value of human beings or human dignity, orthe unique qualities of any human being, need not be due to the inter-vention of God: that God created the world, including human beings. Ofcourse, it could be assumed that the genes or the stem cells are created byGod. In the last analysis, such an assumption would be difficult to refutedefinitely. But the naturalists would argue that such an assumption isunnecessary – and that one should not make unnecessary assumptions.Thenaturalist position often is met not only with counter-arguments but alsowith resistance and dislike, because the obvious implication is that thespecial position of man in the world order is undermined. If what I havesuggested here is correct, this is a truth with some modification. Humanbeings and some of the primates, particularly the chimpanzees, have aspecial position, due to the complexity of their brains.

This is not to say that theories of emergence are without difficulties. On thecontrary, they raise many problems. But they avoid many of the obvious

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pitfalls of the reductionism inherent in standard ontological naturalism.These two concepts, reduction and naturalism, may need a brief comment.

In general, a theoretical reduction of theory A to theory B presupposes thatall basic concepts in theory A can be defined by means of basic concepts intheory B, and all axioms or basic laws in A can be translated to, and provedwithin, theory B. In reductionism, an ontological implication is sometimesalso made to the effect that the entities referred to in theory A are thenreally entities of the sort referred to in theory B.A reductionist approachin this area of medicine would then imply that all concepts and basic lawsor statements in higher level medicine can be translated to the basicconcepts and laws of stem cell research, and that the basic fabric of humanlife really are stem cells and their components.

Ontological naturalism implies or asserts that everything that exists can bereduced to, and explained by, the entities and forces assumed in the naturalsciences. Since these entities and forces have varied, there are many formsof naturalism.As the natural sciences, in our case particularly the biologicalsciences, develop, this view will take different positive forms. Negatively,naturalism denies that there is a transcendent God and that man has a freewill, a position taken by philosophers from Democritos in antiquity tocontemporary thinkers like Armstrong and Smart.

The ontological naturalism (a theory on what there is) should bedistinguished from epistemic naturalism (as a theory of what can be known,and how). In epistemic naturalism it is argued that everything that exists canbe described and explained (and hence known) by the methods used in thenatural sciences, in particular biology. The theory is a precursor tobehaviourism of the sort advocated by Skinner and to logical positivism. Italso is often combined with an ethical naturalism according to which thereis no sharp distinction between facts and values.Accordingly, descriptions ofmoral statements can be tested against, and decided by, descriptions by themethods of the natural sciences.

Is it correct to say that conscious states are physical states in the centralnervous system, and that the brain is the consciousness? Can experiences

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of pain be regarded as stimulation of certain fibres? It would carry us toofar afield to discuss the arguments for and against these various claims. Ihave perhaps already digressed too much from the philosophical issuesraised by stem cell research.What I have tried to do here is to provide aphilosophical context for the arena of research where new discoveries ofthe properties and potential use of stem cells from various sources (adultstem cells, foetal stem cells and embryonic stem cells) are made. Butneedless to say, no claim of completeness is made.

References 1. Cassirer, E. An Essay on Man. An Introduction to the philosophy of

human culture. New Haven:Yale University Press, 1962 (1944).2. Dawkins, R. The Selfish Gene. New York & Oxford: Oxford University

Press, 1976.3. Dennett DC Consciousness explained, Boston: Little, Brown & Co,

1991.4. Edelman, G. Bright air, brilliant mind, New York: Basic Books, 1992.5. EGE 1998. European Group on Ethics in Science and New Technologies,

Human Tissue Banking (21/07/1998), rapporteur: Octavi Quintana Trias.Brussels: European Commission.

6. EGE 2000. European Group on Ethics in Science and New Technologies,Ethical Aspects of Human Stem Cell Research and Use. (14/11/2000).rapporteurs:A. McLaren and G. Hermerén. Brussels: EuropeanCommission.Gärdenfors, P. Blotta tanken, Nora: Nya Doxa, 1992.

7. Gärdenfors, P. The nature of man – games that genes play? In: Action,Logic and Social Theory, ed. G. Holmström & A. Jones,Acta philosophicaFennica, 38, 1985.

8. Hermerén, G. På spaning efter en människosyn. In: Människosyner,Statens medicinsk-etiska råd, Stockholm 1994.

9. Hermerén, G.“Patents and licensing, ethics, international controversies”,article on patentability of biotechnological inventions In: Encyclopedia ofEthical, Lewgal and Policy Issues in Biotechnology, ed. Thomas Murrayand Maxwell J. Mehlman, New York: John Wiley, 2000.

10. Honnefelder, L. The moral and philsophical status of the embryo.Council of Europe. Conference report. Strasbourg, 1996.

11. Jersild, P.C. Darwins ofullbordade, Stockholm: Bonnier Alba, 1997.

7 7S T E M C E L L R E S E A R C H . P H I L O S O P H I C A L A S P E C T S

12. Lorenz, K. Das sogennante Böse.Wien: Borotha-Shoeler, 1963 (sv övers.Aggression – det så kallade onda, Stockholm: Norstedts, 1986).

13. Scanlon, T.M. What we owe to each other. Cambridge, Mass.: HarvardUniversity Press, 1999.

14. MFR Medical Research Council, Forskningsetiska riktlinjer för utnytt-jande av biobanker, särskilt projekt innefattande genomforskning.Stockholm: 1999. Skinner B.F., Beyond Freedom and Dignity, London:Penguin, 1988. (Swedish translation of earlier edition, Bortom frihet ochvärdighet, Stockholm: Norstedts, 1973)

15. Stevenson, L. Seven views on human nature, New York, 1987, (Swedishtranslation: Sju teorier om människans natur, Stockholm: Forum, 1990)

16. Wiggins, D. On personal identity. Oxford, 1987.17. Wilson, E.O. On Human Nature, Cambridge, Mass.: Harvard University

Press, 1978.

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COMMERCIAL INTEREST IN STEM CELLS

Nils Axelsen, Head, Dept. Clinical Biochemistry, Statens Serum Institut,

Copenhagen

As discussed earlier in this workshop recent stem cell research has revealedexiting new possibilities for treatment of many devastating diseases.There ishowever a long way from the basic scientific observations to safe treatment.To undertake such a development is financially risky and requires resourcesof a size, which generally cannot be made available from public funds.

During the last 20–30 years the financial markets have experienced thatbroad investment in new scientific discoveries, properly protected bypatents, leads to highly satisfying returns as compared to other investments.The creation of profit in this way is growing and has changed the financialmarkets considerably.This kind of enterprise has been coined “the new eco-nomy” where ideas and potential developments in information technologyand biotechnology often are traded a long time before real products havematerialised.The creation of new products has been speeded up in this way.Pension funds are major players in the financial markets, and therefore weare all capitalists and participants in this development.

Also the life of public scientists has changed due to this development sincethere is an increasing commercial interest in new original scientific results,an increasing need for scientists in private companies, and an increasing needfor collaboration between academia and the private sector. In my view thisis a positive development, provided that governments without hesitationsecure public basic research, as a fundamental democratic institution.

On this background it is no surprise that several commercial companies arealready operating in the field of stem cells, even if it is only 2 years since itwas discovered by James Thomson that human embryonic stem cells couldbe grown in vitro.

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In an article in Science in February 2000 Eliot Marshall (1) has listed 10companies working on stem cells; see the table.

Stem cell companies*)Company name Location Employees Specialty

Aastrom Biosciences Ann Arbor, MI 33 Hematopoietic stem cells

Geron Corp. Menlo Park, CA 100 Embryonic, fetal stem cells

Layton BioScience Atherton, CA 25 Fetal neural stem cells

NeuralSTEM

Biopharmaceuticals Bethesda, MD 14 Fetal neural stem cells

Neuronyx Inc. Malvern, PA 10 Neural stem cells

Nexell

Therapeutics Inc. Irvine, CA 120 Hematopoietic stem cells

Osiris Therapeutics Baltimore 75 Mesenchymal stem cells

ReNeuron London 17 Neural stem cells

Stem Cell Sciences Melbourne -- Embryonic stem cells

StemCells Inc. Sunnyvale, CA 16 Adult neural stem cells

*) Marshall, E. the Business of Stem Cells. Science,Vol. 287, 1419, 2000.

It appears that 5 companies are working on fetal stem cells. GeronCorporation is the biggest of these, and has the first right to exploit thecommercial potential of James Thomson’s cells and also some primordialcells discovered by John Gerhardt of Johns Hopkins University.

Several companies are working on adult stem cells and have attracted muchlarger investments (1).

Some of the large pharmaceutical companies will probably also announcetheir interest in stem cells.

In conclusion the commercial interest in stem cells is considerable and infull agreement with the “new economy” and rapid exploitation of newpromising scientific results.

Reference1. Marshall, E.The Business of Stem Cells. Science, 287, 1419, 2000.

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LEGAL PROBLEMS DEFINING LIMITS FOR STEM CELL RESEARCH

Linda Nielsen, Institute of Law, University of Copenhagen, Denmark

1. IntroductionThere is no regulation in the Scandinavian countries, regarding stem cellresearch as such or therapeutic cloning. The regulation at national andinternational level is primarily concentrated on reproductive cloning.This doesnot mean, however, that stem cell research is not embraced by regulation orpractise, limiting cloning methods, research on embryos, human tissue etc.

The following outline describes and evaluates the Scandinavian regulationon the collection, research, storing and use of embryonic stem cells andother stem cells. International regulation, especially the Council of Europe’sConvention on Human Rights and Biomedicine will be included in thepresentation of the regulation.

The legal situation in the Scandinavian countries will be compared to thepresent situation and proposals on legal changes in the United Kingdom.Moreover, the Opinion of the European Group on Ethics in Science andNew Technologies to the European Commission on human cell researchand use1 will be presented. Finally, the legislative challenge for the Scandi-navian countries is outlined.

Reproductive cloning, which is covered by legislation and regulation, bothnationally and internationally, transplantation and patent issues are notcovered by the description of the legal situation.

2. Collection and donation of stem cellsA major source of stem cells are human fertilised eggs.Thus limitations onthe creation, donation and collection of such eggs are of interest regardingthe legal situation for stem cell research.

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In the future it is hoped that also other kinds of stem cells than thosederiving from the use of human eggs can be used for therapeutic cloning.The difference of the legal situation in such cases are also briefly outlined.

2.1. Embryonic Stem CellsA. Council of Europe – Convention on Human Rights and BiomedicineThe convention on Human Rights and Biomedicine has the followingprovision limiting the collection of embryos for research:

Article 18 – Research on Embryos in Vitro1. …2.The creation of human embryos for research purposes is prohibited.

The Convention of the Council of Europe has been signed by theScandinavian countries, but they have not all ratified the Convention yet.

B. Legislation in the Scandinavian CountriesNorway has included a ban on embryo research in their legislation onbiomedicine2. Thus creation, donation and collection of embryos forembryo research is not relevant.

Sweden allows embryo research, within a time limit of fourteen days afterfertilisation3.After that period of time the egg is to be destroyed.

Denmark allows embryo research,but has indirectly a prohibition on the creationof embryos for research. The legislation on assisted reproduction4 regulatestreatment with assisted reproduction performed by a doctor and biomedicalresearch involving fertilised eggs and gametes. § 14 limits the donation andcollection of human eggs. Only women, who are in an IVF-treatment candonate eggs with the purpose of inducing another woman’s pregnancy.Thus,the donation and collection of human eggs specifically for researchpurposes is not allowed. Creation of fertilised eggs for research is not legal.

Finland has enacted legislation on medical research in 19995.This legislationbans the implantation of an embryo which has been subject of research.

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Iceland has enacted legislation on assisted fertilisation in 19976.

C. EnglandEngland has not ratified the Convention on Human Rights and Biomedicine.The Human Fertilisation and Embryology Act from 1990 allows the creationand use of embryos for research if this research is within five areas,specified in the legislation, and has a permission from the authority –Human Fertilisation and Embryology authority. This authority makes surethat the use of embryos is necessary for the research.

2.2. Other Stem CellsStem cells which do not derive from fertilised eggs are not regulated by thelegislation on assisted reproduction etc. Normally, a permission accordingto the legislation or practise of biomedical research and ethical review isneeded. Moreover, a consent from the person, where the tissue derivesfrom, is necessary.

3. Research on stem cells

3.1. Embryonic Stem CellsA. Convention on Human Rights and Biomedicine

The Council of Europe’s Convention on Human Rights and Biomedicine hasthe following provision on embryo research:

Article 18 – Research on Embryos in Vitro1. Where the law allows research on embryos in vitro, it shall ensureadequate protection of the embryo.

According to the explanatory report the Article does not take a positionabout the admissibility of the principle of research on in vitro embryos.

B.The Scandinavian Legislation and PractiseIn Norway the legislation7 includes a prohibition against research on embryos.

In Denmark biomedical research on fertilised human eggs and gametes intended

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to be used for fertilisation can according to the legislation only be carried outif the purpose is to improve in vitro fertilisation or similar techniques with theaim of inducing a pregnancy8.Fertilising of eggs with the aim of carrying throughother kinds of research is not allowed9. Moreover, fertilised eggs may only bekept alive outside the woman’s womb for fourteen days from fertilisation10.Finally, fertilised human eggs, which have been subject of biomedical researchmay only be implanted in a woman if the fertilised egg is genetically un-modifiedand the research according to a scientific evaluation cannot be presumed tohave damaged the egg in its further development11.Even if the primary purposeof the legislation is to make provisions on gametes aiming at being used forfertilisation, § 25 says in general, that it is not allowed to take out and fertiliseeggs with the aim of carrying out other research than the research allowed bythe legislation.Thus, it is my opinion that research on human eggs with the aimof cloning embryonic stem cells is embraced by the legislation on assistedreproduction.The consequence is, that it is only allowed to perform scientificresearch on human fertilised eggs and gametes aiming at being used forfertilisation, if the purpose is to improve the in vitro- or the pre-implantationtechniques. This leads to the conclusion that any other form of research isprohibited, including research with cloning of stem cells using human eggs.

When embryo research is allowed, it is embraced by the legislation onscientific-ethical review, see below.

In Sweden embryo research is embraced by law. Research with the purposeof developing methods for establishing hereditary genetic effects arebanned.When research has been performed on a human egg, it may not beimplanted in a woman’s body.

When embryo research is allowed a scientific-ethical evaluation is based onthe Helsinki Declaration, see below.

In Finland and Iceland embryo research is allowed.

When embryo research is allowed, it is common that the research isconditional of consent from the persons donating the embryos for research.

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C. EnglandIn England embryo research may only be carried out in accordance with thelegislation and with the permission of the HFEA. Embryos used for researchmay not be developed further than fourteen days (periods of cryo-preservation not included).

3.2. Other Stem CellsIn the Scandinavian countries it is also common that ethical review is neededregarding both embryo research and other kinds of research on humans orhuman tissue.The composition and task of the committees differ.

In Denmark the ethical review is based on legislation12. The purpose of thescientific-ethical review is to secure the protection of research personsparticipating in biomedical research projects and at the same time createpossibilities for development of new valuable knowledge.The County Councilsappoint regional scientific ethical committees, whereas the central ethicalcommittee is appointed by the Danish Minister of Research according to morespecific rules for appointing members.The majority of members are lay people.New medical research projects involving research on a.o. human gametes,human fertilised eggs and foetuses are to be reported to the regional ethicscommittee and cannot be started until a scientific ethical review has beenmade and permission has been given from the regional committee. Thecommittee ensures that the risks that may be attached to the project arecarefully evaluated, that informed consent has been given, that the researchproject according to its purpose and methodology will present good scientificstandard, and that there is sufficient reason for carrying through the project.

In Sweden, Norway and Finland scientific ethical committees are not based onlaw but on the Helsinki declaration, and are mostly hospital based ethicalcommittees making the evaluation and approval. In Sweden the Medicalresearch Council plays an important role in this respect. In Norway NEMco-ordinates the regional committees.

4. StoringRegarding storing of stem cells the question is to which extent consent isneeded.

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According to the Convention on Human Rights and Biomedicine storagemay need consent but it is not an obligatory provision.

Article 22.Disposal of a removed part of the human body.

When in the cause of an intervention any part of a human body isremoved, it may be stored and used for a purpose other than that forwhich it was removed only if this is done in conformity with appropriateinformation and consented procedures.

In Iceland legislation on biobanks has been enacted in 2000.

In Sweden a bill on biobanks has been presented to Parliament in 2000,based on a report.The proposal includes provisions on informed consent,control, registers etc.

In Denmark a law reform commission has been established with the task ofconsidering legislation.

In Norway and Finland the question on biobanks is also on the agenda.

5. Use of stem cells for therapy/treatmentNo specific legislation creates a framework for the treatment. The stemcells may be taken from embryos or other sources, e.g. aborted foetuses or adult cells. General legislation on practitioners etc. may embrace theactivity.

6. Legislative initiatives?In England an expert group, established by the British government, with thechief medical officer as a chairman has evaluated possible advantages in thearea of new research using human embryos including risks and alternatives.The conclusion and recommendation from the expert group is that thecreation of embryos by transfer of nucleus and their use in research shouldbe allowed with the aim of increasing the understanding of human diseasesand treatment with application of new cells. It is, however, important that

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such research is thoroughly controlled by the Human Fertilisation andEmbryology Authority. Especially in connection with this type of research,the authority must ensure that the creation of an embryo by replacementof the nucleus is necessary for the research and that alternatives could notas well be used for the research purposes.

The group of experts concluded that supplementary research types shouldbe added to the Human Fertilisation and Embryology Act of 1990, whichwould have as a consequence that stem cell research with human embryoscould achieve permission from the authority HFEA, but that HFEA beyondfeeling certain in each case that the research was necessary and desirable(as the legislation already demands) also needs to ensure that no othersources of stem cells could fulfil the purpose of the research.

The European Group on Ethics in their opinion to the European Commis-sion recommended a.o., that the creation of embryos for the sole purposeof research is ethically not acceptable, since spare embryos are available,and that prevention of burden on women as donators of eggs is important,and that embryonic stem cell research, when legally permitted, must beunder strict public control by a centralised authority.

7. EvaluationIn my opinion there is a need for explicit regulation of the research on anduse of human eggs for therapeutic cloning in the Scandinavian countries, ifthe method is to be introduced.

It is a new area of research and therapy, where public accept and control isessential, and it is not sufficient to include this new development and itsconsequences in legislation and practise, when it has not been establishedwith this development in mind.Areas of creation and donation of embryosfor research, the methods of embryo research, collection of other kinds ofstem cells, treatment with stem cells, import and export of stem cells,transplantation and patent issues may be relevant.

Considerations of the need for legislation must include protective measure.In this respect both the person, donating eggs or tissue, the person receiv-

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ing treatment with stem cells, and ethical values in connection with the useof human eggs and tissue and the creation of stem cells must be includedin the considerations and evaluation.

1 Opinion No 15 of 14 November 2000 on “Ethical Aspects of HumanStem Cell Research and Use”.

2 Act of June 1994 relating to the application of biotechnology inbiomedicine, chapter 3: Research on Embryos.

3 Legislation has been enacted in 1991–1991:115 – on fertilised humaneggs in connection with research and treatment (Åtgärder i forsknings-eller behandlingssyfte med befruktade ägg från människa).

4 Act on Assisted Reproduction etc. § 4 and the Legislation on BiomedicalResearch § 28.

5 Lag 488/1999 om medicinsk forskning.6 Regulation on Artificial Fertilisation, Ministry of Health and Social

Security, 30.9.1997.7 Act of June 1994 relating to the application of biotechnology in bio-

medicine, chapter 3: Research on Embryos.8 The same provision has been issued is if the purposes to improve the…

of pre-implantation diagnozis.9 Act on Artificial Reproduction in Connection with Medical Treatment

Dignostics and Research (Act 460 of 4 June 1997, § 25).10 Act on Assisted Reproduction etc. § 26. Any period of type/prior

preservation is not included.11 Act on Assisted Reproduction etc. § 27.12 Legislation on a scientific-ethical committee system and treatment of

biomedical research projects – “Lov om et videnskabs etisk komité-system og behandling af biomedicinske forskningsprojekter”.

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USING HUMAN EMBRYOS – THE GREATESTETHICAL DILEMMA WITH STEM CELLRESEARCH

Inger Atterstam, Svenska Dagbladet, Stockholm, Sweden

Report from the first discussion, October 10, 2000A discussion about the real ethical problems concerning human stem cellresearch should focus on the patient, penetrate the needs and the wishes of allthose seriously ill people.And from that point of view it must be highly unethicalnot to give a cure, if progress is made and if research shows to keep what itpromises.Those were the last words as a summing up of the first session of theworkshop on ethical issues in human stem cell research arranged by the NordicCommittee on Bioethics. They were said by Marja Sorsa from the FinnishMinistry of Education and a member of the committee. Her statement mirrorsa strong belief that further research in this promising but ethically hardhandledfield is justified for the best of the many individuals suffering from devasting anddeadly diseases that today do not have any cure.And this cautious perceptionwas shared by most, but maybe not all, of the participants of the meeting.

Different levels of problemsThe many ethical problems surrounding stem cell research can be dividedinto different levels and different time tables. It once again gives attentionto the relation between science and society, to scientific responsibilitytowards freedom of research and particularly in this field to thecommercialisation of scientific results, the growing economical pressure inthe medical research society. It also raises old ethical issues that may havebeen considered solved and in that way illustrates the so called slipperyslope, that is to say small well-meaning acceptable scientific steps that maylead to an unwanted and unethical application in the future.

Human embryos – most sensitiveThe basic and most sensitive ethical question in stem cell research is ofcourse the use of early human embryos from IVF treatment against

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infertility and of aborted fetuses as the source of cultivated stem cells lines(so called ES-cells).

Jaana Hallamaa who gave the introductory speech on the theological viewpoint on the purpose of human stem cell research was the one who moststrongly questioned the effect of using human embryos.

– What does it do to our self image, to our human dignity, she asked.Thisdevelopment may create fear, helplessness and confusion.What is the rightthing to do? What will we think twenty years ahead? Will we slowly acceptsomething that today for many seem unacceptable and get blind?

– Embryos and aborted fetuses may be considered as only biomass thatotherwise would have been destroyed, she continued. Maybe we can dosomething good with it instead. But all people know that they themselvesderived their origin from that kind of biomass.And now this biomass maybe transformed into money. What does it tell about ourselves and whatdoes it tell our children generation after generation?

Other participants in the discussion pointed to the fact that in all Nordiccountries abortion is accepted and so is in vitro fertilisation (IVF) whichproduces the embryos that can be used for stem cell cultivation, twoissues that earlier have been subject of intense ethical and politicaldiscussions.

A slippery slope?Linda Nielsen characterised this development as a good example of theproblems with the slippery slope.

– A new ethical risk is put on the top of the others, she said. And thequestion is if not permitting embryo research can lead to that kind change.But others argued that since we allow IVF treatment and since thisprocedure creates thousands of fertilised eggs.

– embryos – that never will be used for its original purpose it is notunethical to take advantage this “surplus” (about 48,000 fertilised eggs in

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UK, more than 5,000 in Sweden and almost 300,000 in Europe per year)and create stem cell lines for research.

– If we accept IVF we also accept that embryos are being destroyed.To usethem does not for me create any additional ethical problems, explained forinstance Ingileif Jónsdottir, chairman of the National Bioethics Committeeof Iceland.

Anne McLaren from the Wellcome CRC Institute in Cambridge, UK said:– Jaana Hallamaa’s view is rather confusing to me.To create embryos andjust destroy them is considered positive, but doing something with thembefore they are destroyed that might be good is considered negative. Andthe fact is that use of early IVF-embryos for stem cell research seems to getmore and more acceptance in many countries. Both the reports on stemcell research from the American National Bioethics Advisory Commission(NBAC) and the one from a British expert group lead by the Chief MedicalOfficer (CMO) support the idea.

In Sweden the local ethical committee of the Huddinge University Hospitalat the Karolinska Institute, after discussion with the Ethics Board of theMedical Research Council and National Ethics Board, made the samejudgement almost one year ago as one of the first ethical bodies in theworld. It stated that spared embryos from IVF treatment may be used forresearch after information and permission from the donors.The cultivatedcell lines are not to be considered embryos any more, just growing celllines, and therefore not regulated by the Swedish legislation prohibitingembryo research after fourteen days.

Create new life only for researchThe next and considerably more difficult ethical problem is then if it is rightto make new embryos for the only purpose of cultivating stem cell lines ormake stem cell research, that is to say fertilise donated eggs with spermwithout the aim to treat infertility, or as you also may express it to createlife only to destroy the embryo and use it for research for instance makingcell lines.

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So far this fertilisation procedure for research purpose is known to havetaken place only in United Kingdom where it is legal since 1990. 118 suchembryos have been made between 1991 and 1998.

Anne McLaren explained the background and defended this approach:– It is a valuable research, she said. It has been used after special permissionsin order to make the methods of freezing unfertilised eggs (cryo preser-vation) more secure.The frozen eggs must be thawed and then fertilised, tocheck whether there is evidence of chromosomal or other damage in theembryos.Also the technique called ICSI where one uses one single spermto fertilise one single egg demands research the effect of ICSI fertilisationon subsequent embryo development and so do studies of the effects oneggs after different hormonal treatment of the women.All are experimentsthat can not be done on animal embryos or on spare human embryos. Shesaid that scientists in this field in UK do not consider this method to bewrong or as some people have called it evil.

Peter Sylwan compared this research to abortions and to transplantations:– Are those techniques any better, he asked. By making embryos we createlife to give life to a dying person.What is wrong with that? How can thatseparate us from human dignity?

Søren Holm pointed out that in normal reproduction three pregnancies outof four fail, that is to say three embryos have to die to manage one success-ful pregnancy.

– Is this project of Nature different from making embryos and stem cells? he questioned.

Other participants were much more sceptical and even reluctant. Theywanted to draw a sharp line between using spare IVF embryos and makingnew embryos only for scientific purpose. Also the Council of EuropeConvention on Human Rights and Biomedicine signed by all Nordic statesdoes not permit this kind of research.

Although nobody said it openly one important circumstance might be that

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the great amount of available spare embryos in this phase of the researchmakes the need for specially made embryos less, at least for the nearestfuture.

Cloning for therapyThe third ethical question in stem cell research that probably will dominatethe discussion for a long time ahead is the different thinkable proceduresthat can be done with embryos and the stem cells derived from them.

The application that so far has got most attention is what is called nuclearreplacement technique, which means that the nucleus with its DNA in theegg cell is taken away and replaced with a new nucleus from anotherindividual. By that method the growing number of developing cells will havea new DNA-content that will be copied and transferred to all the followingcells, that is to say a type of cloning.

The main purpose of this change is to create stem cells and hopefullyspecialised cells for different organs containing DNA from a special patientneeding the new cells for treatment. By using DNA from that particularperson the hope is to avoid reactions from the patient’s own immunesystem so that the new cells might be accepted and not rejected. Thisprocedure is called “therapeutic cloning”.

The British CMO-report is the first in the world to recommend researchusing this cell nuclear replacement technique leading to “therapeuticcloning” as “necessary” in the ambition to find help for the patientssuffering from diseases that might benefit from stem cell research. Thisstandpoint is highly controversial and of many looked upon as too earlyawakened.The potential future advantage of this procedure is rather easyto understand and might be necessary to achieve the goals of findingfunctional treatments based on stem cell lines in the future.

Possibilities for human cloningBut many critics are warning for a dangerous slippery slope developmentwhere this technique could end up in “reproductive cloning”, that is to saycreate possibilities to make human cloning like the Dolly story in animals.

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To be able to manage that kind of cloning will however demand that theDNA-changed embryo must be put in the uterus of a woman to developinto a fetus. But this technique has been suggested as one thinkable methodto cultivate new organs or more organ like tissue to use in human trans-plantations in the future.

Urban Lendahl talked about that the scientific landscape is rapidly changingand new technologies are developing, like for instance reproductive cloning.– But we have to realise that it is a matter of long time ahead and we haveto discuss the different implications when they come and many of them wewill probably never be used.

Too early for only adult cellsMost of the many different ethical dilemmas with stem cell research wouldbe solved if adult tissue and adult stem cells could be used as the source ofstem cells instead of embryos.

Recent research also gives hope of success for this approach and somecritics have demanded that more or maybe all resources in stem cellresearch should be given only to research on adult stem cells.

Also in the workshop many questions were asked about the possibility ofonly make research on adult cells. But the participating scientists opposedall those proposals:– It would be a terrible mistake to limit stem cell research and only allowsome applications like nothing else than adult cells, explained Lars Ährlund-Richter.

Urban Lindahl stated that at this stage of the research development it isimpossible only to work with adult cells. Cells derived from embryos arestill highly needed to get all the answers and to develop the necessarytechniques. But this may change in maybe five or ten years.

Research with great cautiousness demandedReport from the final discussion, October 11, 2000Continue the stem cell research, but with great cautiousness, with re-

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sponsibility, with openness and transparency, with respect for ethicalprincipals and with humbleness.

That was the message and advice to involved scientists and to the medicalresearch society based upon the final discussion during the workshop onethical issues in human stem cell research organised by the NordicCommittee of Bioethics.

– We can not deny that the potential benefits of this research are extrem-ely promising, says Gisela Dahlquist, chairman of the Committee. But thehopes and expectations can lead to an overoptimistic view that may makeus blind for possible presumptive repercussions and lower our ethicalconsciousness.That is why it is so important to have a continuing discussionabout these issues involving all kind of actors in society, not only scientists.

Step by step with cautionIn her final remark she said that the stem cell research has special ethicalaspects and that the future research have to be made step by step withcarefulness and renewed ethical considerations during the way. Shedeclared that some kind of regulation for this research probably will benecessary, but that prohibition would be wrong.

The main ethical problemAs in the earlier discussion the main ethical problem was pointed out to bethe use of human embryos for making stem cell lines.A procedure that canbe interpreted as using one human being to solve the problem of anotherhuman being without having his or her consent, a violation of basic ethicalrules like not to harm and only to do good things.

What is life?The participants then tried to analyse what is a human being, when does lifestart, is a soul necessary to be a human being or is a body or a bodymass enough.

It was clear that in the Nordic countries and in the Lutheran Church thereare no established point of view concerning these sensitive questions unlikefor instance in the Catholic Church.

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And maybe the growing use of embryo research will force this difficultissues for instance when it comes to our opinion about abortion to beopenly discussed in the society.

Søren Holm pointed out that the hundreds of thousands of spared embryosin the clinics today are not a result of Nature. They are created by IVFprograms and by legal abortions, both old decisions based uponcompromises, ethically and politically, and both controversial with dividingopinions.

– Are we now supposed to be consistent with those old compromises onlybecause we once allowed them, he asked.

Finding good compromisesGisela Dahlquist with support from Martti Lindqvist replied that ethics is tofind as good compromises as possible and that the guideline should be theintention to make good and to take care – not the method in itself. AndErlandur Jónsson explained that the decision whether an embryo is ahuman being or not might need that kind of necessary compromise.

Linda Nielsen said that the view on embryos being used for researchpurpose may be more a matter of belief and values in the society than strictscience.

But some of the scientists involved in this research like Outi Hovatta andAnne McLaren on the other hand declared that donated female eggs haveno human dignity.They are cells with the potential of being humans, but aseggs they are just cells.

– Most of them die during the lifetime of a woman just like even moremillions of male sperms are destroyed, said Outi Hovatta. And we do notconsider sperms to have human dignity.

Many other potential risksOn a direct question on what other risks that might be involved with stemcell research and stem cell therapy in the future many interesting aspects

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were raised. They were mainly discussed by Anne McLaren, Ole DidrikLœrum and Kerstin Hagenfeldt.

*Human cloningThe method of cell nuclear replacement in embryos for the purpose oftherapeutic cloning might lead to experiments with reproductive cloning,that is to say to try to create cloned humans.

The risk is most obvious in countries without any regulation or control ofresearch, but might happen also in countries where human cloning isbanned.

Kerstin Hagenfeldt told that the WHO is trying to involve all governmentsin the world to create some common rules for scientific conduct, includingcloning. But the work is not yet finished and as long as there are those gapsin the regulatory system this kind of research might very well go on some-where, she explained.

*Exploiting womenKerstin Hagenfeldt also mentioned another ethical dimension: the fact thatstem cell research have been criticised by feministic ethical experts ascommercial misuse of women and the “property” of women. They meanthat eggs from women are exploited for scientific purposes and/or in orderto make money.

*Lack of information – a threatOle Didrik Lœrum pointed out that modern medical history have shownmany examples of great hopes that have shown not to be fulfilled or evendangerous. One example is gene therapy.

– To avoid those mistakes in stem cell research it is therefore very impor-tant to give all the information about the research, both the good news andthe bad news, he declared.

He warned like many others that the strong commercialisation of stem cellresearch, the fact that so much of the research especially in the US is done

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by private companies, is a threat to this necessary openness, honesty andtransparency and in the long run may be a threat to this whole scientificfield.

– It must be the duty of all scientists in this area to report all their findingsand results in scientific papers and not withhold any information fromcolleagues and from the public, he said. Unfortunately this is not happeningtoday. We do not know all the things that are going on. We do not haveaccess to all the information.

*Cancer – greatest hazardDevelopment of cancer, what might happen if the injected new therapeuticcells do not stop dividing and continue to proliferate in the body, is so faridentified as the greatest hazard with future stem cell therapy.

– If the therapeutic cells are not properly made and if they are given to thepatients without very careful control, cancer development might be anenormous risk,Ann McLaren said.

Ole Didrik Lœrum also talked about other unknown risks with changingthe balance in the body by supplying maybe huge amounts of new cells.

– We do not know if this might give side effects. Cancer is of course thefirst you think of, but it may very well be other unwanted reactions too, heexplained.

Too early trialsHelena Kääriäinen warned that too early clinical trials on patients withpotential risks of creating serious side effects could jeopardise the goodreputation of medical science as a whole and especially stem cell research.Outi Hovatta admitted the danger of starting treatment on patients tooearly, but meant that the only way to prevent that from happening is tosupport academic research outside the companies and thereby achievebetter control and guarantees that properly and well controlled clinicaltrials will be done.

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Explore the opportunitiesDag Helland explained that the stem cell research must continue in spite ofpotential risks. He reminded of the fact that many medical procedures usedtoday have serious side effects but still benefit the individual patient.

– The stem cell strategy arises so many promises that it would be verywrong not to explore its opportunities. But of course we must do it withcaution.

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OPINION FROM THE NORDIC COMMITTEE ONBIOETHICS BASED ON THE WORKSHOP“ETHICAL ISSUES IN HUMAN STEM CELLRESEARCH”,10–11 OCTOBER, 2000

Since the first successful culturing of human stem cells in 1998 hopes aroseof the potential of this research to enable new therapies for several pre-sently incurable diseases such as Parkinson disease, autoimmune diabetesand other chronic disorders from which large numbers of individuals nowsuffer.Although routine therapies based on embryonal stem cells are still along term perspective, presently available evidence from animal models andhuman foetal and cord blood stem cells support the prospect. However,also potential risks have been indicated and they need to be fully explored.

Stem cells can be derived in humans from:1) adult tissues, e.g. bone marrow2) umbilical cord blood3) aborted foetuses4) early embryos

a) spare embryos, created by in vitro fertilization for reproductive purposes

b) embryos created specifically for research purposes

c) embryos created by inserting the nucleus from an adult cell into anenucleated egg cell, somatic cell nuclear transfer (SCNT).

Although not yet fully explored, it seems that stem cells derived fromembryos may have the greatest potential to develop into most types ofcells. Even if still a lot of research on basic mechanisms on cell growthdifferentiation and programming can be performed efficiently using exper-

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imental animals there is a scientific need to compare results from otherspecies with those from human stem cells.

Except for Norway, the present legislation in the Nordic countries allowsresearch on human embryos produced by in vitro fertilisation (IVF) but nomore needed in the infertility treatments (“spare embryos”) until day 14 ofthe embryonal development in cultured conditions. All Nordic countrieshave legislation on induced abortion under legally authorised conditionsallowing foetal tissues to be used as a limited source for e.g. neural stem cells.

In the US it has until now been illegal to use federal funding for research onhuman embryos, but recently the NIH established guidelines implying thatresearchers may now apply for federal funds for work on cell lines derivedfrom spare embryos resulting from fertility treatment. The US guidelinesreject public funding for work on stem cells derived from embryos madesolely for research purposes and also cell lines created by somatic cellnuclear transfer. In contrast, in the UK the Expert Advisory Group onTherapeutic Cloning has recommended to allow the use of nuclear transferto create embryos specifically for research on stem cells. In the UK also thecreation of embryos for research has been allowed since 1990 providedthere are no other means of meeting the objectives of the research. If so,specific groups could be licensed by the Human Fertilisation andEmbryology Authority. So far only 118 embryos had been created forresearch purposes between 1991 and 1998 in UK. During the same timeabout 48000 “spare embryos” were available for research in the UK.

Although stem cell research has the future potential to benefit disabled andseriously sick people, the main ethical concern raised in the Nordicworkshop was the production of embryos solely for research purposesmight interfere with our intuition on human dignity and lead toinstrumentalisation of human embryos. Concerns were also raised thatallowing research on embryos created by cell nuclear transfer would be astep on a “slippery slope” towards human reproductive cloning. Themanipulation of human embryos is also challenging the views on thebeginning of human life.The potential to use “human beings” as a source ofcell lines and organs with a potential of commercialisation was also felt as

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a threat to human dignity. It was recognised that many people also in theNordic countries feel that a newly created embryo has a moral status as ahuman being whereas others consider the early embryo as a “potential”human being, and the moral status of the embryo and foetus will increaseas it develops. Still, there were great concerns for the potential of creatingand selling embryos. Commercialisation of stem cell lines might be moreacceptable.

In conclusion, most of the members of the Nordic Committee on Bioethicsas a result of this workshop, shared the opinion that stem cell research maybe carried out both in animal and human materials, specified as follows:

• The use of stem cells, derived from human spare embryos produced forin vitro fertilisation but no more needed, was considered acceptable untilday 14 of embryonal development.The provision must be the high qualityof the research proposal and accept and by an independent ethicscommittee. Special concern should be put on the free and informedconsent from the donating couple.

• Stem cell research on foetal tissues after induced abortion was con-sidered ethically acceptable under the provision of high quality research,acceptance of an independent ethics committee and proper informedconsent.

• The creation of human embryos solely for research purposes seemednot necessary at the present stage of research. The Council of EuropeConvention on Human Rights and Biomedicine (article 18), signed by allNordic Countries, prohibits the creation of human embryos solely forresearch purposes.The Committee also felt that at the present stage ofresearch, production of embryos for research is not necessary.

• The potential future advantage of the technique of transferring somaticcell nuclei into an enucleated ovum to yield transplantable cell linesimmunologically compatible with a patient donating the nucleus wasclearly recognised. Still, the therapeutic perspectives of this techniqueseemed very remote and the “slippery slope” possibilities to reproduc-

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tive cloning are to be seen, even if legally prohibited. Therefore, at thisstage of embryonic stem cell research and waiting for more definiteresults on the potential of using adult stem cells it was felt that use ofthe somatic cell nuclear transfer technique in humans should not beallowed in the Nordic countries.

Three members of the committee disagreed on this statement and haveadded following commentary.

Minority opinion from the Nordic Committee on Bioethics:A minority consisting of three members of the committee do agree thatthere is promises held out by the technology. However, several seriousscientific problems have to be overcome before any revolutionary therapieswill be developed. Some of the basic problems that need to be solved arerelated to the potential for embryos to develop into fully differentiated cellswithin an acceptable developmental stage. Scientist’s do often proclaimunrealistic potentials related to new technologies that need to be balanced.A recent example was the great potential held out by xenotransplantationtechniques which is now reduced dramatically.

Based on a need for ethical restriction, these members would thereforespecifically focus on the following aspects related to human stem cell research:

Human stem cell research should be focused on adult stem cell lines.Thesecell lines have a potential for developing/specialising, and for being used tocure diseases where specific tissues or cells are affected.

Utilisation of the possibilities held out by this technology has less ethicalimplications than the methods described below.

Stem cell research utilising embryos (either early embryo established fromfertilised eggs, or embryos created by inserting an adult nucleus into anenucleated egg) involve fundamental ethical problems that can not bejustified by an uncertain future application. More experiments on animalmodels should take place before evaluating the need for experiments onhuman embryos.

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As for stem cell research utilising embryos, also stem cell research on foetaltissues after induced abortion involve the use of a human (or a potentialhuman) entirely as a mean. The potential of this research should also becarefully examined first applying animal models.

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UDTALELSE FRA NORDISK KOMITÉ FORBIOETIK BASERET PÅ WORKSHOPPEN“ETHICAL ISSUES IN HUMAN STEM CELLRESEARCH”, 10–11 OKTOBER, 2000.

Siden den første succesfulde dyrkning af menneskelige stamceller i 1998 harder været håb for at denne forskning vil muliggøre nye behandlinger afforeløbigt uhelbredelige sygdomme, som Parkinsons, sukkersyge og andrekroniske sygdomme, som mange mennesker lider af. Selv om rutine-behandlinger baseret på stamceller fra fosteranlæg også kaldet embryonerstadig ligger langt ude i fremtiden, støtter nuværende resultater fra forsk-ning med dyrevæv og menneskelige stamceller fra henholdsvis fostre ogblod fra navlestrenge muligheden af sådanne behandlinger. Der findes dogflere mulige risici, og det er nødvendigt at udforske disse til bunds.

Stamceller fra mennesker kan udledes af følgende væv:

1. Væv fra voksne, f.eks. benmarv.2. blod fra navlestrengen.3. aborterede fostre.4. tidlige embryoner

a. Reserve-embryoner, skabt ved in vitro befrugtning til reproduktive formål.b. Embryoner skabt til forskningsformål.c. Embryoner skabt ved at indsætte en cellekerne fra en voksen i en

ægcelle, hvor kernen er fjernet (somatisk cellekerneoverførsel, SCNT).

Selv om forskningen på området endnu ikke er fuldført, synes stamceller fraembryoner at have det største potentiale for at udvikle sig til de fleste typerceller. Selv om stadig meget forskning i de grundlæggende mekanismeromkring differentiering og programmering af cellevækst kan udføres virk-ningsfuldt ved brug af dyremodeller, er der et videnskabeligt behov for at

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sammenligne resultater fra forskning med andre arter med forsknings-resultater fra menneskelige stamceller.

Den nuværende lovgivning i de nordiske lande, undtagen i Norge, tilladerforskning på menneskelige embryoner produceret ved in vitro befrugtning(IVF). Embryoner, der ikke mere er brug for i fertilitetsbehandlingerne,må bruges indtil den 14. dag i fosterudviklingen under særlige dyrknings-betingelser. Alle nordiske lande har lovgivning om, at fostervæv fra frem-kaldte aborter udført under autoriserede, lovlige forhold, kan blive brugtsom en begrænset kilde til f.eks. nervesystemets stamceller.

I USA har det indtil nu været forbudt at bruge midler fra føderale fonde tilforskning på menneskelige embryoner, men for nylig etablerede NIHretningslinier, der antyder, at forskere kan søge føderale fonde til arbejdemed cellelinier, der stammer fra reserve embryoner, der er fremkommetved fertilitetsbehandlinger. De amerikanske retningslinier afviser offentligstøtte til arbejde med stamceller taget fra embryoner, der er udviklet iforskningsøjemed og også cellelinier skabt ved somatisk cellekerneover-førsel. Omvendt har The Expert Advisory Group on Therapeutic Cloning iEngland, anbefalet at tillade brugen af cellekerneoverførsel til at skabe fostrespecielt til forskning i stamceller. I England har det været lovligt at skabefostre til forskning siden 1990, forudsat at der ikke var andre måder at nåforskningens mål på. Hvis det ikke var tilfældet, kunne særlige grupper fåtilladelse fra Myndigheden for “Human Fertilisation and Embryology”.Mellem 1991 og 1998 var kun 118 fostre blevet skabt i forskningsøjemed iEngland. I den samme periode var ca. 48.000 reserve embryoner tilgænge-lige for forskning.

Selv om stamcelleforskning har det fremtidige potentiale at komme invalideog alvorligt syge mennesker til hjælp, var den største etiske bekymring, derblev rejst på den nordiske workshop, at produktion af embryoner til brugfor forskning vil gribe ind i vores umiddelbare opfattelse af menneskeligværdighed og føre til instrumentalisering af embryoner fra mennesket. Derblev også udtrykt bekymring for at en tilladelse af forskning på embryonerskabt ved cellekerneoverførsel, ville være et skridt på vejen mod repro-duktiv kloning af mennesker. Manipulation med embryoner fra mennesket

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udfordrer også anskuelser af begyndelsen til menneskeligt liv. Mulighedenfor at bruge mennesket som en kilde til cellelinier og organer, med mulig-heden for kommercialisering, blev også betragtet som en trussel modmenneskets værdighed. Det blev præciseret, at mange mennesker også i denordiske lande føler, at et nyskabt embryon har en moralsk status sommenneske, mens andre mener, at det tidlige embryon er et potentieltmenneske, og at embryonets og fostrets moralske status øges med detsudvikling. Der var dog stadig stor bekymring omkring muligheden for atskabe og sælge embryoner. Hvorimod kommercialisering af stamcelleliniermåske kan være mere acceptabelt.

Alt i alt, efter workshoppen, deler de fleste medlemmer af Nordisk Komitéfor Bioetik opfattelsen af, at stamcelleforskning kan udføres i væv både fradyr og mennesker, specificeret som følger:

• Brugen af stamceller fra reserve embryoner fra mennesker skabt til invitro befrugtning, men som ikke mere er nødvendige for behandlingen,blev accepteret indtil den 14. dag i embryonets udvikling. Forudsat atkvaliteten i forskningsdesignet er høj, og at forskningsprojektet er accep-teret af en uafhængig etisk komité. Særlig opmærksomhed skal tildeleserklæringen om frivilligt, informeret samtykke fra det par, der donerer.

• Stamcelleforskning på fostervæv efter provokeret abort blev anset foretisk acceptabelt, forudsat at forskningen er af høj kvalitet og er accep-teret af en uafhængig etisk komité krav om et frivilligt, informeretsamtykke.

• Skabelsen af menneskelige embryoner kun i forskningsøjemed syntesunødvendigt på det nuværende forskningsstadie.The Council of EuropeConvention on Human Rights and Biomedicine (artikel 18), underskrevetaf alle de nordiske lande, forbyder skabelse af menneskelige embryonerkun til forskningsbrug. Komitéen føler også, at det på nuværende tids-punkt er unødvendigt at producere embryoner kun til forskningsbrug.

• Den mulige fremtidige fordel i teknikken at overføre somatiske cellekernerind i en ægcelle hvor kernen er fjernet, for at udvinde transplanterbare

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cellelinier, der immunologisk stemmer overens med den patient, derdonerer kernen,blev klart anerkendt.Men de terapeutiske perspektiver veddenne teknik syntes meget fjerntliggende og skråplanet mod reproduktivkloning er tydeligt, endda selv om kloning er forbudt. På det nuværendestadie indenfor stamcelleforskning i embryoner, hvor man afventer mereendelige resultater omkring muligheden af at bruge stamceller fra voksne,føler man ikke, at brugen af somatisk cellekerneoverførsel i menneskeligeægceller skal være lovligt i de nordiske lande.

Tre medlemmer af komitéen var uenige i denne udtalelse og har tilføjetdenne kommentar.

Minoritetsudtalelse fra Nordisk Komité for Bioetik:En mindre gruppe på tre medlemmer af komitéen er enige i, at teknologienskaber løfter. Men flere alvorlige videnskabelige problemer må løses, førrevolutionerende terapiformer vil blive udviklet. Nogle af de basaleproblemer, der må løses, er relateret til muligheden for, at embryoner kanudvikle sig til fuldt differentierede celler indenfor et rimeligt ud-viklingsstadie. Videnskabsmænd proklamerer ofte urealistiske muligheder,relateret til nye teknologier, som må afbalanceres. Et nyligt eksempel var detstore forventede potentiale ved xenotransplantationsteknikker, hvilket nuer reduceret dramatisk.

Baseret på et behov for etisk forbehold, ville disse medlemmer derfor isærfokusere på de følgende aspekter relateret til menneskelig stamcelle-forskning:

Menneskelig stamcelleforskning bør være fokuseret på stamcellelinier fra voksne.

Disse cellelinier er i stand til at udvikle/specialisere sig og at kurere syg-domme, hvor særligt væv eller celler er berørt.

Brug af mulighederne, som denne forskning skaber, har mindre etiskindblanding, end metoderne som er beskrevet i det følgende.

1 1 0 T H E E T H I C A L I S S U E S I N H U M A N S T E M C E L L R E S E A R C H

Stamcelleforskning, der bruger embryoner (enten tidlige embryoner frabefrugtede æg, eller embryoner skabt ved at indsætte en voksen kerne i enægcelle, hvor kernen er fjernet), involverer fundamentale etiske problemer,som ikke kan retfærdiggøres af en usikker fremtidig anvendelse. Flereeksperimenter på dyremodeller bør finde sted, før behovet for eksperi-menter på embryoner fra mennesker evalueres.

Med hensyn til stamcelleforskning, hvor der bruges embryoner, involvererogså stamcelleforskning på fostervæv efter provokeret abort, brugen af etmenneske (eller et potentielt menneske) som et middel til at nå målet.Potentialet i denne form for forskning bør også være nøje undersøgt førstved brug af dyremodeller.

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