ethical and regulatory aspects of embryonic stem cell research

Review

10.1517/14712598.5.2.153 © 2005 Ashley Publications Ltd ISSN 1471-2598 153

Ashley Publicationswww.ashley-pub.com

Cell- & Tissue-based Therapy

Ethical and regulatory aspects of embryonic stem cell researchKK JainJain PharmaBiotech, Blaesiring 7, CH-4057 Basel, Switzerland

Ethical issues concerning human embryonic stem cell (hESC) research arereviewed three years after the controversy became a public and politicalissue in the US and two years after the last article on this topic, which alsocovered the religious aspects. There are still no consistent regulations world-wide on the regulation of research on hESCs, and debate is still ongoing insome countries. New developments require a reassessment of the situation.In the US, the debate is politically driven. Regulations still vary from onecountry to another and there are no universally uniform ethical and regula-tory standards for hESC research. At present, the most liberal and favoura-ble environments for hESC research are in the UK, Singapore, Sweden, India,Israel and China. In the US, there is no change in the policy of the currentgovernment, but developments in the industrial sector and academic institu-tions, which are not dependent on government funding, are encouragingfor future progress. Considerable advances have taken place in hESCresearch during the past few years to justify a relaxation of restrictions, andsuggestions are offered to improve the ethical and regulatory environmentsfor hESC research.

Keywords: biomedical ethics, cell therapy, cord blood, embryo, fetus, human embryonic stem cells, in vitro fertilisation, nuclear transfer, NT stem cells, progenitor cells, stem cell lines

Expert Opin. Biol. Ther. (2005) 5(2):153–162

1. Introduction

Adult haematopoietic stem cells and embryonic tissue transplants have been used formany years in treatment of patients, but no controversy about the ethical aspects ofany new biotechnology has been as intense as that surrounding human embryonicstem cells (hESCs) in the US. Ethical issues came to public debate on 9th August 2001when President Bush stated that scientists could use US taxpayer dollars only to studythose lines of hESCs that had already been extracted from human embryos, and thatthe creation of new lines would not be allowed. This topic was reviewed in 2002, ayear after the controversy began, and included basic, religious and historical aspects ofstem cell ethics [1]. New developments require a reassessment of the situation, but dis-cussion of role of religions will not be repeated as there have been no changes in thereligious philosophies. There are ongoing changes in ethical concepts that run parallelto the scientific progress in hESC research. Conclusions and opinions are based oninformation available as of the end of 2004.

2. Basics of embryonic stem cells relevant to ethical concerns

The discussion on this topic comes after the following basic facts about hESCs thatare described in more detail elsewhere [2]. The term ‘stem cells’ is applied to thosecells in the embryo and the adult human body that retain the capability self-renewal and of making a range of other cell types. In the embryo, these cells are thestarting point for the development of the complete human being. In the adult,

1. Introduction

2. Basics of embryonic stem cells

relevant to ethical concerns

3. Embryonic stem cells

and cloning

4. Scientific developments

that impact on the human

embryonic stem cell

ethical debate

5. Ethical and regulatory aspects

of human embryonic stem cell

research in the US

6. Human embryonic stem cell

policies in countries other than

the US

7. Expert opinion, conclusions and

suggestions for improvement

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Ethical and regulatory aspects of embryonic stem cell research

154 Expert Opin. Biol. Ther. (2005) 5(2)

stem cells are one of the resources for repair and renewal ofcells/tissues. Embryonic stem cells are continuously growingcell lines of embryonic origin derived from the pluripotentcells of the inner cell mass or epiblast of the mammalianembryo. They may give rise to any cell type, but not to anindependent organism. Approximately 100 pluripotenthESCs can be obtained from a 5-day-old preimplantationhuman embryo. Although the procedure is performed onsurplus embryos from in vitro fertilisation (IVF) procedures,which would not normally be implanted or used for repro-duction, it raises ethical concerns among those who believethat embryos are human beings.

3. Embryonic stem cells and cloning

There is no controversy at present about ‘reproductive clon-ing’, as most countries have banned it. Issues concerningcloning have been mixed up with the stem cell debate.Nuclear transfer (NT) is used to create a cell or organism thatis genetically similar to an existing cell or organism. Stem cellsobtained by NT are referred to as nuclear transfer stem cells(NTSCs). The term ‘cloning’ does not accurately describeNT, and further use of the term ‘therapeutic cloning’ to dif-ferentiate this process from ‘reproductive cloning’ is mislead-ing because the therapies from NTSCs are not yet developed.The International Society for Stem Cell Research (ISSCR), anacademic community of stem cell scientists, recommends theuse of the term NT instead of ‘therapeutic cloning’.

4. Scientific developments that impact on the human embryonic stem cell ethical debate

4.1 Embryonic versus adult stem cellsRestrictions on the use of hESCs in the US has led some sci-entists to redirect their research to adult stem cell sources.Adult stem cells have the potential of self-renewal and of dif-ferentiation into certain specific types of mature cells. Neuralstem cells, for example, can produce neurons and their sup-porting cells, glia. Although cells for adult sources may besuitable for some purposes, they may not cover all of thepotential applications. Cells from adult bone marrow arefairly easy to collect, but they do not grow well outside thebody. hESCs can be grown in large amounts and, beingpluripotent, are more proficient in producing a variety oftissue-specific cell types, for example, dopamine-producingneurons, insulin-producing cells or cardiomyocytes. For thesereasons, access to embryonic sources of stem cells appears tobe important for making unrestricted progress in the area.

4.2 New methods of culture of hESCsIn November 2003, scientists at the Johns Hopkins Univer-sity (Baltimore, MD, USA) stated that it was unethical andrisky to treat patients with any of the 12 currently availablecell lines because they were all cultured using mouse cells asfeeder cells. According to their report, this could possibly

expose patients to an animal virus that could not be control-led by the human immune system. Researchers are nowdeveloping methods of growing hESCs without the use ofmouse feeder cells. A proteomics approach was employed tocharacterise the environment that supports the growth ofundifferentiated hESCs and to identify factors critical fortheir independent growth [3]. Several unique protein specieswere identified, which included some that are known to par-ticipate in cell growth and differentiation, extracellular matrixformation and remodelling. Candidates from the initial list ofidentified proteins can be further investigated for their effectson the growth and differentiation of hESCs in a definedculture environment.

No widely accepted, workable method is yet available, butone may be available in the near future. Researchers mightprefer to use hESCs grown with the non-mouse recipe in clin-ical trials. However, that would require establishing new celllines and allowing federally financed scientists to work onthem. Private researchers can legally do so, but those withgovernment support are not allowed.

4.3 Ethical aspects of procuring adult stem cellsThere are ethical issues related to the procurement and dona-tion of adult stem cells from living persons or post mortem.These are not much different from donation of other tissues orcells and are well recognised. An example is given of the use ofumbilical cord blood (UCB) as a source of haematopoieticstem cells for transplantation. Banking of UCB for use as asource of stem cells for transplantation is associated with a setof ethical issues. These vary according to the planned use of theUCB – whether as a donation or banking for future use by thedonor in case of an illness requiring stem cell transplantation.

Although the placenta and the umbilical cord are usuallydiscarded after child birth, the issue is rather that these tissuescannot be used without consent to donate them. Questionshave been raised over the ownership of the cord blood – theinfant, the mother, or both parents. Although an infant ownsits blood, the parents have the legal guardianship both of thechild until the age of maturity, as well as of the cord blood if asample has been preserved at birth. Consent can be obtainedfrom the parents until the time the infant can give consent(which may be before 18 years in some countries). Importantethical aspects of the use of UCB are:

• During the investigational phase, secure linkage should bemaintained of stored UCB to the identity of the donor.

• Marketing practices for UCB banking and recruitment forbanking in the private sector need to be scrutinised.

• The process of obtaining informed consent for collection ofUCB should begin before labour and delivery.

• Preimplantation selection of HLA-matched embryos toobtain a donor of cells for cord blood transplantation for asibling with a life-threatening disease has raised the issueof the extent to which this approach complies with theprinciples of bioethics [4].

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Expert Opin. Biol. Ther. (2005) 5(2) 155

5. Ethical and regulatory aspects of human embryonic stem cell research in the US

A review of the situation 3 years after President Bush’s initialannouncement shows that the US Federal Governments stillhad not approved stem cell research. On 27th February 2003,warning that human cloning amounted to a dark and danger-ous step into an unethical realm of science, the US House ofRepresentatives voted to ban not only reproductive cloning,but also NT to obtain hESCs. The bill, adopted by a vote of241 to 155, is nearly identical to one that passed the House in2001. In 2003, a movement was under way in state capitols,universities, charitable foundations, hospitals and companiesin the US to counteract President Bush’s 2001 order sharplylimiting federal money for hESC research. Lawmakers in somestates, notably California and New Jersey, have authorisedhESC research and have allocated funds to help launch statestem cell research institutes. California had already authorisedthe use of state money in 2002 to support research usinghESCs. Proposition 71 of 2004, the California Stem CellResearch and Cures Initiative, would provide US$300 millionper year over 10 years for stem cell research in California. Cali-fornia is also considering a US$3 billion state bond to fundstem cell research, including work on hESCs. New Jersey isaiming to push forward on stem cell research. On 24th April2004, representatives from leading drug companies, such asPfizer and Merck & Co, biotechnology companies, such asAmgen and Geron Corporation, as well as bankers andresearchers, met to discuss and formally launched the projectto promote stem cell research. Around the same time, HarvardUniversity (Cambridge, MA, USA) announced that seven ofthe school’s affiliated teaching hospitals and ∼ 100 researcherswere joining to explore new areas of stem cell research.

Privately funded research in the US is not subject to thisrestriction. An opinion poll conducted on the website ofGenetic Engineering News in March 2004 showed that 67%considered it acceptable to circumvent US Governmentrestrictions on hESC research by using private funding and33% were against this [5].

5.1 Public opinion on hESC researchEarlier public polls in the US following the 2001 announce-ment by President Bush indicated public support for hESCresearch. As of March 2004, support for hESC researchamong the public continues, as reflected by the Coalition forthe Advancement of Medical Research (CAMR), which hasfocused its advocacy in two related areas:

• Ensuring that NT remains a legal and viable form of scien-tific research, and opposing any effort that would allowreproductive cloning.

• Protecting and preserving continued federal funding ofhESC research.

On 14th July 2004, CAMR characterised the Bush adminis-tration’s announcement of a stem cell bank as a ‘wholly

inadequate’ response to millions of patients who awaitprogress from stem cell research, as the initiatives announceddo nothing to remedy a fundamentally flawed stem cell policy.According to CAMR, ‘creating a bank to house stem cell linescreated before August 2001 does nothing to increase thewholly inadequate supply of stem cell lines for research.’

Stem cells became an issue in the US presidential electionsof November 2004. President Bush, who won the election, isholding onto his previous position on hESCs, whereas hischallenger, John Kerry, had promised to remove restrictionson hESC research if he was elected.

5.2 Viewpoint of NIH on hESC researchA statement on 28th November 2003 by the director of theNational Institutes of Health (NIH), Elias Zerhouni, indi-cates that the 78 cell lines approved for use by the US Govern-ment are enough to meet scientific needs. He maintains thefollowing viewpoints:

• The existing policy is appropriate for the stage of thescience at present.

• There are fundamental safety questions that must beanswered before hESCs could be considered for therapeu-tic use and this can be done by using the existing approvedcell lines.

• The limiting factor in stem cell research is not the numberof cell lines available for study, but the number of researcherstrained to do the work.

• The US government is openly and easily providing stemcells to researchers. Hundreds of specimens have been sentto laboratories in the US and other nations.

• The FDA has concluded that there are safety practices inplace to evaluate the risks if a researcher ever proposes touse one of the approved cell lines to treat patients.

• If the situation arises that the existing regulations are ham-pering the potential healthcare applications of hESC, thematter will be brought up for discussion with the Presidentof the US.

In response to continuing criticism of its hESC policy, the USgovernment has opened a ‘National Embryonic Stem CellBank’ to better grow the only hESCs eligible for government-funded research. In addition, the NIH plans to spendUS$18 million over 4 years to establish three ‘centres ofexcellence’ in 2005 to speed research on the cell lines availableat present. The hESC bank would get samples from today’s19 approved sources – companies or others who created them– and grow them under specially controlled conditions. Onecentral source is expected to lower the cost from several thou-sand per shipment some researchers pay today to a few hun-dred dollars. The ‘centres of excellence’ would pair biologiststem cell researchers with physicians to accelerate researchinto useful therapies. The proposals do not satisfy critics whosay that the existing policy is stifling groundbreakingresearch, particularly by severely limiting the number of celllines available for study.



As of July 2004, the NIH plans to fund three translationalresearch centres in fiscal year 2005, for ∼ US$18 million over4 years. The new hESC bank will also be set up in 2005, andcell lines will be available for only a few hundred dollars.

5.3 Viewpoint of the US scientists on hESC researchResearchers at the Harvard University have derived and identi-fied 17 new hESC lines, in addition to the 15 that are currentlyknown to be available for publicly funded research in the US [6].The new hESC lines were derived from human embryos thatwere produced through IVF for clinical purposes, afterinformed consent from parents and approval from a HarvardUniversity institutional review board. The researchers startedout with 286 frozen embryos, but were able to derive only 17individual stem cell lines. Under additional testing, the 17 newhESC lines showed the capacity to form differentiated cell typesin vitro. Under existing US law, the new cell lines cannot beused in research that is funded, even partially, by federal researchfunds. The cell lines are being made available under a materialtransfer agreement to selected researchers. However, scientistswho are supported by government grants – the vast bulk of bio-medical researchers – cannot use the cell lines because they werederived after the US Government cutoff date of 9th August2001. The authors of the new publication have called on theNIH to make the cell lines available to researchers funded bythe institutes through inclusion in the hESC registry. Thisreport will provoke controversy in the US, and Harvard Univer-sity already drew criticism when it announced that it plans tolaunch a multimillion-dollar centre to grow and study hESCs.

On 22nd June 2004, the ISSCR issued the following fiveprincipals for responsible support and regulation of the fieldof human stem cell research in a letter to the US President.

• Research on all types of stem cells warrants increased fed-eral funding. These include hESCs, stem cells found in

adult tissues and pluripotent stem cells isolated fromblastocysts or derived by NT.

• Federal funding for basic research should be allowed forall human embryonic/pluripotent stem cell lines derivedfrom excess IVF blastocysts that would otherwise bedestroyed, following appropriate informed consent anddonation practices.

• The derivation of new human pluripotent stem cell lines byNT should be supported and publicly funded.

• Appropriate regulation of research is important and shouldbe developed by scientists and regulators working togetherto provide ongoing scientific and ethical oversight toensure compliance with the above, as well as to establishnorms for good basic research, clinical investigation andlaboratory practices.

• Given the existing scientific and medical safety concerns,and widespread moral and ethical consensus, human repro-ductive cloning, defined as implantation into a uterus ofmorulae or blastocysts derived by NT, should be prohibitedat this time. In this context, ISSCR commends the FDAfor its successful interdiction of such practice in the US.

According to a statement issued on 13th July 2004, the JohnsHopkins University (Baltimore, MD, USA) recognises thathESC research raises significant ethical concerns and thatpublic policy on stem cell research must carefully balance theethical and medical considerations, yet it should enableresearchers to fulfil the promise of stem cell research for pro-viding medical therapies. Johns Hopkins strongly supports theuse of hESCs for legitimate research and therapeutic purposes,as well as NT techniques for the purpose of producing stemcell lines. However, Johns Hopkins strongly opposes the use ofstem cell technology and NT for the purposes of creating acloned human being.

6. Human embryonic stem cell policies in countries other than the US

As there is no universal policy regarding hESCs, any discus-sion of this topic should consider the differences in ethical aswell as regulatory issues among various countries. The NIHregistry contains cell lines originating in other countries andalso those that are exported to countries that do not have anycell lines of their own. In 2001, there were 78 registered hESClines worldwide that conformed to the criteria of eligibility forUS funding for research, but only a small number were actu-ally available. If one adds to it the 17 new lines obtainedthrough non-NIH supported research, the total comes to 95.hESC policies in various countries are shown in Table 1.

6.1 AustraliaThe Australian legislation puts Australia midway between thestrict US rules and a liberal regimen in the UK. The govern-ment’s bill ‘Research Involving Embryos and Prohibition ofHuman Cloning’, passed in December 2002, bans cloning

Table 1. Embryonic stem cell policies around the world.

Policy Countries

No human embryo research permitted

Norway, Ireland, Austria, Poland, Brazil, Italy

No human embryo research permitted, but permission to import already derived ESC lines

Germany

Use of already derived hESCs permitted, but not the derivation of new hESC lines

US (government-funded research)

Derivation as well as use of hESCs from discarded embryos permitted

Canada, Japan, Spain, Israel, Sweden, Switzerland, Finland, Australia, France

Derivation and use of hESCs from embryos created for research permitted

UK, US (privately funded research), China, Singapore, South Korea

ESC: Embryonic stem cell; hESC: Human ESC. © Jain PharmaBiotech

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and regulates research involving human embryos, but allowsresearchers the use of some 70,000 spare frozen IVF embryosfor deriving stem cell lines. An agreement between federal andstate leaders allows scientists to work with established hESClines and derive new cell lines from surplus IVF embryos cre-ated before 5th April 2002. A centre funded by the Australiangovernment hopes to generate 20 new hESC and adult stemcell lines. However, scientists will not be able to access newlymade embryos for a period of three years. NT and the creationof animal/human hybrid embryos is not permitted. The situa-tion differs from that in the US, where government-fundedresearch using stem cells is restricted to existing, commerciallyavailable stem cell lines. There is ongoing debate on the ethicaland legal issues involving hESC research in Australia [7].

6.2 CanadaUnder Canada’s Assisted Human Reproduction Act, whichbecame effective in March 2004, so-called ‘spare’ embryos leftover from IVF can be used for research, including stem cellresearch, if that is the only way the research can be under-taken. All cloning, therapeutic or otherwise, is prohibited.Creating embryos for any purpose other than IVF is also pro-hibited. Federal funding agencies allow experiments onembryos up to 17 days old, but ethics committees mustapprove each project. Any altered human embryo, however,would also have to be destroyed 14 days after its creationwhen its cells begin to differentiate. Public funding for hESCresearch is restricted to embryos that were created for repro-ductive purposes and are no longer required, and that werenot part of any commercial transactions.

6.3 ChinaThere are debates on ethical issues involving hESC researchby various National Bioethical Committees in China and byresearch centres at various institutions of higher education,such as the Chinese Academy of Medical Sciences and theCentre for Applied Ethics located in the Chinese Academy ofSocial Sciences. The Ethics Committee of the ChineseNational Human Genome Centre at Shanghai has proposedethical guidelines for hESC research [8]. China opposes anyexperiments for the purpose of human cloning, but will allow‘closely monitored’ hESC cell research for the treatment andprevention of disease. Chinese scientists have made rapidprogress in all areas of hESC research over the past few yearsand have mastered the technology for separating, purifying,freezing and rejuvenating stem cells from embryonic, fetal, aswell as adult sources. There is a large advanced hESC trans-plant centre in Tianjin, which is able to store 500,000 hESCcell packets and provide on-site treatment for patients.

6.4 European UnionHistorically, the European Convention on Human Rights andBiomedicine of 1997 (Oviedo convention) and its article 38regulates research on embryos in vitro. On 9th July 2003, theEuropean Union (EU) Commission adopted a proposal for

guidelines on EU-funded hESC research. The EU 6th ResearchFramework Programme (FP6 2003-2006), as adopted by theCouncil of Ministers and the European Parliament in 2002,allows for the funding of hESC research in relation to the fightagainst major diseases. Such research, in particular when itinvolves the derivation of hESCs from human supernumeraryembryos, can only take place within a framework of clear andstrict ethical guidelines. The EU research programme includesethical provisions related to sensitive areas of research. InNovember 2003, members of the European parliament pavedthe way for the EU to fund medical research involving hESCsderived from surplus human embryos. The parliament’s sup-port for ending the existing moratorium has placed furtherpressure on EU governments to go down the same path. Atpresent, as of February 2004, there are no limitations for theprocurement of stem cells within research projects funded bythe FP6. In 2004, ∼ US$40 million will be available for Euro-pean stem cell scientists. Funding will only be granted when theresearch is in accordance with the national regulations.

A coherent set of strict ethical guidelines will apply to theEU funding of research projects involving the derivation ofstem cells from human supernumerary embryos. In parallel,the Commission is publishing a call for proposals for the setup of a European registry of stem cells and for contributing tothe establishment of public stem cell banks. In this way, theEU will contribute to an optimal access to and use of stemcells, ensuring that the results of research ultimately becomemore quickly available to all patients across Europe. TheCommission proposal deals with a very precise research topic,namely the derivation of hESCs from supernumeraryembryos with no parental project. These embryos, maximum5 – 7 days old and of a microscopic dimension, are frozen as aresult of IVF treatment and are donated by parents forresearch. They will, at some point, be disposed of withoutbeing used either for IVF or for research purposes. The pro-posal does not aim to create human embryos for the purposeof stem cell procurement, including by means of somatic cellNT. The creation of human embryos for research is explicitlyexcluded from the scope of FP6 funding. To meet a concernthat EU funding would provide indirect incentives for theproduction of more embryos than needed for IVF, theCommission proposes that only supernumerary embryos canbe used that were created before 27th June 2002, the date ofadoption of the EU 6th Research Framework Program.

FP6 funding for the derivation of new stem cells will only bemade available if proposals successfully pass a rigorous scientificpeer-review and an ethical review, for which this proposal sug-gests the criteria. The derivation of hESCs from supernumeraryembryos is only one element in the broader EU approach tostem cell research, which also includes funding for adult stemcells, training of researchers in this field, and so on.

At present, 9 of the 15 EU nations have banned hESCresearch, but the EU adopts a supportive attitude to somemember states that are reluctant to adopt liberal hESC cellpolicies – particularly the Catholic countries of southern



Europe, such as Italy. The text says they should be allowed notonly to ban the use of such techniques, but also to prohibitimports of cells or tissues derived via methods or from sourcesthat offend national sensitivities. hESC issues are mixed upwith cloning, as some members seek ‘for ethical reasons, andfor reasons connected with the high risks of a medical natureconnected with human cloning’, an EU-wide ban on the useof tissues and cells of hybrids derived from germ cells ortotipotent cells of human and animal origin.

Even though there is no EU consensus as to whether and inwhat circumstances hESCs may be processed, it does clearlystate that the processing of adult stem cells and of stem cellsfrom the umbilical cord is legal and ethically non-controver-sial in all the member states. It also urges that alternative solu-tions to the use of ES cells should be specifically promoted bythe EU and that obstacles to the processing of adult stem cellsand the umbilical cord should be removed.

6.5 DenmarkDenmark moved into hESC work following the establishmentin 2002 of a national stem cell research network, the DanskCentre for Stamcelleforskning, which was already fundingadult stem cell projects. The new legislation does not permitsomatic cell NT. The law is formulated in such a way that itdoes not mention NT, but implicitly bans such activity. It alsoforbids commercialisation of the research. The legislation isadministered on a regional basis throughout Denmark.

In September 2003, a team of researchers based at the Univer-sity of Southern Denmark in Odense was the first group in Den-mark to receive permission to carry out hESC research,following a change in the country’s legislation. The Clinic forMolecular Endocrinology at the Odense University Hospital willdevelop its own hESC lines based on a combination of proprie-tary protocols and data published by other groups. The clinicplans to implement a fully human system in the coming monthsand aims to develop multiple lines using a variety of protocols.

6.6 FrancePreviously, French researchers were not authorised to work onhESCs. While waiting for the legislative decision, importation oftwo lines of hESCs was authorised provisionally in 2002. On9th July 2004, the French Parliament adopted a new bioethicslaw that allows hESC research within strict parameters. Research-ers will be able to import hESCs. Research on supernumeraryfrozen embryos resulting from IVF will be authorised within5 years. At present, investigations are underway to determine theexact number of embryos available in storage across France, asthe estimated number varies between 100,000 – 200,000. Thenew French law allows parents to select one embryo amongseveral to produce an offspring that is best matched to a sib-ling suffering from an incurable genetic disorder. The new lawalso states: ‘research can be authorised on the embryo and onembryo cells when deemed to lead to major therapeuticprogress and if this cannot be done by alternative, equally effi-cient, methods.’ In order to legislate matters relating to

embryology and reproduction, as well as human genetics andgrafting, a new ‘national agency for biomedicine’ is to be createdand is expected to be operational by 1st January 2005 [101].

6.7 GermanyAt present, German law only allows research with hESC linesthat are imported from overseas and were created before 1st Jan-uary 2002. Every research project is peer-reviewed by a nationalauthority, the Robert Koch Institute, and has to be considered‘high ranking’ in order to get approval. On 13th September2004, many of the hopes for relaxation of restrictions on hESCresearch were shattered when the National Ethics Councildecided to maintain the ban on NT. This is considered to bemore of a political than an ethical recommendation [102].

6.8 IndiaIndia is ahead of most countries in hESC research and it hasan adequate infrastructure for research in this field. Ten of theseventy-eight hESC lines were developed in India. There is nospecific legislative enactment in this area in India. Stem celltransplants for tissue regeneration have been performed onpatients, particularly corneal grafting. Observations on theIndian scene are:

• hESC lines from frozen embryos were procured with‘informed donor consent’ for research and were free of cost.

• In contrast to the public in western countries, most lay peo-ple in India are not aware of the hESC research or its con-troversial nature. Therefore, there is no public outcryagainst hESC research in India.

• There is no bar on the use of embryos and aborted fetusesin an overpopulated country, which does not have a banon abortion.

• Human cloning is not allowed.• India does not allow export of biological material, particularly

that derived from human embryos, for research.

6.9 IsraelIsraeli scientists have moved to the forefront of hESC researchand were key players in the landmark isolation of hESCs in1998. Technion in Haifa has 4 of the 78 approved hESC lines.There is broad public support for hESC cell research in Israel.In the Jewish tradition, the primary importance of saving livesand helping suffering patients can take precedence over thefears generated by modern genetic and reproductive research [9].

However, the State of Israel has strict regulations concern-ing hESC lines. In 2001, the Bioethics committee of theIsrael National Academy of Sciences and Humanities recom-mended to authorise donation for research of supernumeraryhuman embryos from IVF, when parents declare these to beno longer destined for implantation and give free, informedand explicit consent. Regulations include: separation of themedical teams involved in the IVF treatment and in the stemcell research, no buying or selling of preimplantationembryos, no in vitro culturing of human embryos beyond

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2 weeks and no creation of embryos for research purposes.Israel has a 5-year renewable Law on Prohibition of GeneticIntervention, first adopted in 1999 and renewed in 2004,which prohibits genetic manipulation of reproductive cellsand human reproductive cloning (specifically the implanta-tion of cloned embryos in utero). In line with the law, theBioethics committee considers it ethically permissible toexperiment with technologies such as NT to produce hESCs.Proposed research protocols on hESC production of any typehave to be approved by the National Helsinki Committee forGenetic Research in Humans.

6.10 JapanThe Japanese Parliament banned human cloning in 2000. In2001, the Council for Science and Technology Policy pub-lished the ‘Guidelines for Derivation and Utilization ofhESCs’. The council voted in July 2004 to adopt policy rec-ommendations that would permit limited cloning of humanembryos for stem cell research in Japan. Some issues are stillunder discussion. Points worth noting about hESC cellresearch in Japan are:

• The published hESC guidelines cover embryos youngerthan 14 days.

• Tissues from the dead fetus (including aborted fetuses)after the age of 4 months are used under the frame of theAnatomical Act.

• Kyoto University and Shinshu University are producinghESCs.

• Derivation and utilisation of hESCs will be limited tobasic research for the present, and clinical application shallnot be carried out until specific criteria other than theguidelines have been established.

6.11 The NetherlandsImportant points of the ‘Law on Embryos’, which has beenpassed by the Dutch Parliament, are:

• Research on ‘spare’ IVF embryos for developing hESCtherapy is allowed.

• NT is temporarily, but not definitely, prohibited.• In view of the fact that the Christian Democrats play a cen-

tral role in the new coalition in the Netherlands, it isunlikely that the ban on creating embryos for research ingeneral and NT in particular will be lifted soon.

6.12 SingaporeSingapore has modelled its hESC regulations after the UK. InSingapore’s multi-religious society, some groups have raisedobjections, but they are free to not participate in any hESCproject. The government has appointed a panel of experts onphilosophy, science and law to study ethical and moral ques-tions regarding biotechnology research in general. In Novem-ber 2003, Singapore unveiled plans for a US$287 millionstem cell research centre. The current status of ethical aspectsof hESC research in Singapore is as follows:

• Scientists are allowed to make new stem cell lines fromspare human embryos from fertility clinics.

• The Singapore government will allow the cloning ofhuman embryos for certain research projects with ‘strongscientific merit’ or ‘potential medical benefit.’ Scientistscan keep the cloned embryos alive for up to 14 days toextract the stem cells.

• Singapore hopes that the guidelines will allow local firmsto take a leading role in stem cell research that could leadto both profits and cures for disease. It will also attractscientists from other countries.

6.13 South KoreaA legislation was introduced in 2002 that allowed research onsurplus embryos, but prohibited reproductive cloning. Bioethicscommittees were empowered to allow NT. In December 2003,the South Korean parliament voted to authorise the cloning ofhuman embryos. In February 2004, South Korean scientistswere the first to successfully produce embryonic stem cells bycloning [10]. These will be used for research and for potentialapplications in human therapeutics. The scientists stress that allthe research was in the laboratory, in vitro. No embryo wasimplanted in a woman. The women who provided unfertilisedeggs that were needed to start the cloning process were not paid.There was no advertising for egg donors and no payments. The16 women who donated the 242 eggs were found through per-sonal contacts. The investigators selected 176 eggs that were in adevelopmental stage that made success seem most likely. Tostart the cloning, the team removed the genetic material fromthe eggs and replaced it with genetic material obtained fromcumulus cells, the adult cells that cling to eggs. The purpose ofcreating stem cells this way would be to study how genes causedisease. Another potential use is to grow replacement tissuesthat are identical to the patient’s own cells for the treatment ofdiseases. The research was financed by the government of SouthKorea, where cloning to create a baby is illegal.

6.14 SpainSpanish authorities approved the use of embryonic stem cells forresearch on 25th July 2003, but stressed at the same time thatonly embryos left over from fertilisation treatment may be used,and then only with the parents’ consent. This opens the way forthe use of 35,000 surplus embryos that are at present in coldstorage facilities of human fertilisation clinics throughout thecountry. The Spanish government recognises that the purposeof embryos is a reproductive one, but when this is not possible,alternatives may be considered. Ethical misuse and profiting willbe avoided, as the parents must give consent. In the last fewyears, Spain has moved from a position where there was in effecta ban on stem cell research that uses hESCs to a position wherea stem cell bank would be fully operational in 2004.

6.15 SwedenIn Sweden, research on fertilised eggs has been permitted since1991. The Act (1991:115) concerning research on fertilised



eggs was introduced to regulate research focused on improvingtechniques for IVF. Research is only permitted in the first14 days after fertilisation; after this, the egg must be destroyed.A fertilised egg that has been subject to research may not beimplanted in a woman’s body. Genetic changes that can beinherited are not allowed. The Swedish Government has pro-posed the following amendments and clarifications withregards to stem cell research in current legislation, which willcome into force in January 2005 [11]:

• Research on fertilised eggs will continue to be permitted,but it will come under the provisions of the Act on EthicalReview of Research involving Humans (2003:460), whichentered into force on 1st January 2004, and is aimed atprotecting the individual.

• Reproductive cloning is banned.• Until now, research has been done on surplus eggs after

IVF and the consent of the couples receiving treatment isrequired. In the case of research on somatic cell NT, awoman has to donate an unfertilised egg and anotherindividual has to donate a human cell. Here, too, donorconsent will be required.

Swedish institutions account for almost a third of the78 embryonic stem cell lines worldwide. Clinical trials forstem cell therapies are anticipated before the year 2008.

6.16 SwitzerlandA law in Switzerland regulating hESC research was approvedby the Swiss Parliament in December 2003. It would allowhESCs to be extracted for research purposes from embryos atthe trophoblast stage left over from IVF, but only under strictconditions. In a referendum in November 2004, 66% of thevoters backed the new law, which will take effect in March2005. Several conditions, which have already been in forcesince 2002, include the following:

• Patents on embryos, organs, cells or cell lines are forbidden,but procedures for obtaining and using hESCs are patentable.

• Written permission from the parents, given freely after theembryo is determined to be superfluous, is required.

• Permission to be given to obtain hESCs for projects thatcannot be conducted by other means or with adult stem cells.

• Import of hESC lines is allowed provided the Swiss ethicalguidelines are met during the process of developing these.

• NT is not allowed.

6.17 United KingdomThe UK has the world’s most liberal hESC policy. The UK per-mits research on embryos up to 14 days old for medical pur-poses. The 14-day boundary for research on human embryoswas established because there is no suggestion at that stage of anervous system and the embryo is not aware or conscious. In2002, the Human Fertilisation and Embryology Authority(HFEA), based on a House of Lords report, gave licenses totwo groups for research on embryonic stem cells derived from

human embryos: the Centre for Genome Research (Universityof Edinburgh) and Guy’s Hospital, London.

In April 2003, the European parliament took the first stepstowards the introduction of a union-wide ban on embryonicstem cell research that could mean the end of various researchprojects now under way in the UK. Because the EU hadreached no decision as of June 2003, the HFEA of the UKauthorised the Roslin Institute to derive new human embry-onic stem cells from donated excess embryos created as aresult of IVF treatment.

The world’s first ES cell bank opened in the UK on19th May 2004, breaking new ground in one of the mostcontroversial areas of medical research. The bank is being runby the National Institute for Biological Standards and Con-trol (South Mimms, Hertfordshire), a government-fundedorganisation involved in quality assurance of research relatedto biological medicines. This ensures that there is a singlenational independent institute responsible for supplying stemcell lines. It aims to provide an international resource forstoring, characterising and supplying ethically approved,quality controlled stem cell lines for research and, ultimately,for treatment.

Cell banks already exist for many other types of stem celllines, but this is the first repository for stem cell lines of alltypes, derived originally from embryonic, fetal and adult tis-sues. These will be developed to supply well-characterised celllines both for basic research and clinical applications underappropriate and accredited quality systems. Its store of celllines is expected to number tens of thousands. The bank putsthe UK into conflict with pro-life campaigners and with theUS. The bank, in Hertfordshire, southern England, will befunded by the Medical Research Council and the Biotechnol-ogy and Biological Sciences Research Council. The bank willensure that researchers can explore the enormous potential ofthis exciting science for the future benefit of patients. Thebank’s first two stem cell lines were developed separately byresearchers at King’s College London and the Centre for Lifein Newcastle, northern England. The bank will operateaccording to strict principles of governance laid down by asteering committee. A management committee, with repre-sentatives from research, healthcare, regulatory bodies and thepublic, will oversee its work. The bank will grow cells undercontrolled conditions, ensuring good quality material forresearchers. The bank will handle and store cells under GoodManufacturing Practice conditions, which meet those requiredfor human medicines, so that the cells could eventually beused for therapeutic purposes.

In June 2004, a team at Newcastle University (Newcastleupon Tyne, UK) requested the HFEA for a license to createembryos from which hESCs would be harvested for medicalresearch. The researchers hope eventually to create insulin-producing cells that can be transplanted into diabeticpatients. In August 2004, the license was granted, but the sci-entists may use NT only for purposes of extracting hESCs formedical research.

Jain


6.18 United Nations, cloning and nuclear transferOn 19th November 2004, the United Nations’ (UN) diplo-mats abandoned contentious efforts to draft a treaty thatwould outlaw human cloning and will likely settle for a weakerdeclaration that would not seek a comprehensive ban on clon-ing and NT. This is relevant to NT, which is still referred to as‘therapeutic cloning’ in the UN discussions and is thusincluded in the broad category of cloning. All 191 UN mem-ber nations are clearly against reproductive cloning that couldbe used to make human beings, but are divided on the issue ofNT. The first proposal, from Costa Rica, also supported by theUS, recommends a complete ban on both reproductive clon-ing and NT. A second resolution, put forward by Belgium andco-sponsored by the UK, Denmark, Japan and South Korea,would leave the decision on NT up to individual govern-ments. Because NT is approved in some countries, there is noway that these countries can sign up to the complete ban. Inaddition to the UK, China, South Korea and Japan all havelegislation allowing carefully regulated NT, so would beunable to sign up to legislation banning all forms of cloning.The Costa Rican proposal for a total ban had 62 backers,while the Belgian proposal for a partial ban had 22 supporters,mostly European countries. If the Belgian proposal is success-ful, the US and others would still be free to ban all humancloning, but countries that see the promise offered by NT canstill carry out research on hESCs.

The UN General Assembly is now considering a non-bind-ing declaration to ban reproductive cloning and adapt legisla-tion to respect ‘human dignity’. The latest proposal,submitted by Italy, is due for discussion in February 2005.

7. Expert opinion, conclusions and suggestions for improvement

This review shows the diversity of viewpoints on the ethicsof hESC research in various countries. It is unlikely that a

universal agreement can be reached on this topic. Evenwithin the EU, there is no accord for the guidelines tohESC research. It is hoped that the new International StemCell Forum [103], which is aimed at standardising the regula-tions and research, will be able to bring some harmony intothis diversity.

The vast majority of scientists involved in stem cellresearch favour the freedom to work on hESCs. In an idealscenario, scientists should not be restricted in their researchon NT, even though in some cases the non-embryonicsources may be adequate. Study of hESCs would provideimportant insights into the pathomechanisms of many dis-eases and will facilitate drug discovery. hESC research shouldcontinue along with the development of technologies fornon-embryonic stem cells. There is considerable interest inthe application of non-embryonic stem cells, particularlythose derived from the UCB.

There are still some ethical concerns about hESCs thatneed to be resolved. The ethical debate in the US has becometangled with politics. However, public opinion remains themost important driving force for further development. It ispredicted that research in hESCs will continue, althoughunder strict guidelines. At present, the countries with themost favourable environment for hESC research are the UK,Singapore, Sweden, Australia, India, Israel and China. Areview of the international scene indicates that hESC researchwill continue and that the countries with more liberal policieshave better prospects of making breakthroughs comparedwith countries with restrictions.

Numerous studies during the past few years have shown theversatility of hESCs in differentiating into a variety of bodytissues and repairing damage to various organs. Study ofhESCs is providing important insights into the pathomecha-nisms of many diseases and will facilitate drug discovery. Inany decision-making process, the benefits of hESC researchare expected to outweigh the ethical concerns.

BibliographyPapers of special note have been highlighted as of considerable interest (••) to readers.

1. JAIN KK: Ethical and regulatory aspects of embryonic stem cell research. Expert Opin. Biol. Ther. (2002) 2(8):819-826.

•• State of stem cell research and ethics in 2002 with relation to major religions.

2. JAIN KK: Cell Therapy: Technologies, Markets and Companies. Jain PharmaBiotech Publications, Basel, Switzerland (2005):1-465.

•• An exhaustive and constantly updated review of technologies and ethics of cell therapy, including stem cells.

3. LIM JW, BODNAR A: Proteome analysis of conditioned medium from mouse embryonic fibroblast feeder layers which support the growth of human embryonic stem cells. Proteomics (2002) 2:1187-1203.

4. BURGIO GR, GLUCKMAN E, LOCATELLI F: Ethical reappraisal of 15 years of cord-blood transplantation. Lancet (2003) 361:250-252.

•• Excellent review of stem cells fromcord blood.

5. ANONYMOUS: GEN Poll. Genet. Eng. News (2004) 24(7):1.

6. COWAN CA, KLIMANSKAYA I, MCMAHON J et al.: Derivation of embryonic stem-cell lines from human

blastocysts. N. Engl. J. Med. (2004) 350:1353-1356.

•• The first non-NIH-funded ESC line developed in the US.

7. SLABBERT M: Cloning and stem cell research: a critical overview of the present legislative regime in Australia and the way forward. J. Law Med. (2003) 10:514-530.

8. ETHICS COMMITTEE OF THE CHINESE NATIONAL HUMAN GENOME CENTER AT SHANGHAI: Ethical guidelines for human embryonic stem cell research. Kennedy Inst. Ethics J. (2004) 14:47-54.

9. REVEL M: Human reproductive cloning, embryo stem cells and germline gene



intervention: an Israeli perspective.Med. Law (2003) 22:701-732.

10. HWANG WS, RYU YJ, PARK JH et al.: Evidence of a pluripotent human embryonic stem cell line derived from a cloned blastocyst. Science (2004)303:1669-1674.

•• First human cloning for deriving ESCs.

11. MINISTRY OF HEALTH AND SOCIAL AFFAIRS: Stem Cell Research. Article 2003/04:148, Government Offices, Stockholm, Sweden. Vol. 9: June (2004).

Websites101. http://www.biomedcentral.com/news/20040

715/01BRAHIC C: France allows stem cell work. The Scientist 15 July 2004.

102. http://www.biomedcentral.com/news/20040914/04/KIENZLEN G: Germany advised on cloning. The Scientist 14 September 2004.

103. http://www.stemcellforum.org/ International Stem Cell Forum website.

AffiliationProf. Dr med. KK Jain FRACS, FFPMJain PharmaBiotech, Blaesiring 7, CH-4057 Basel, SwitzerlandTel: +41 61 692 4461; Fax: +41 61 692 4461;E-mail: [email protected]

ethical and regulatory aspects of embryonic stem cell research

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