ISABEL BRITTON AND RACHEL MURTON

Linklaters, London

With the recent announcement by Advanced Cell Technology of the cloning of a human being¹, and the decision by the English High Court that human cloning was unregulated in the United Kingdom,² stem cell research has lurched into the public consciousness. The technology is developing quickly since the cloning of ‘Dolly’ the sheep by scientists in Edinburgh in February 1997. ³ Some governments have rushed to keep up with these technical developments, while others are still considering the possibilities. This article surveys the current situation and compares the approaches currently being taken.

What are Stem Cells and Where do they Come From?

Stem cells can be compared to floating voters – they have yet to make up their minds. They are unspecialised cells that can renew themselves indefinitely and develop into specialised, more mature cells. They have the potential to be useful in repairing or replacing damaged body parts, and the hope is that they could be the basis for future treatments of many diseases, including Alzheimer’s and Parkinson’s diseases, spinal cord injuries, multiple sclerosis and diabetes.

Stem cells can potentially be derived from several sources: first, from embryos while they are still microscopic clusters of cells; second, from foetal tissue, usually from aborted foetuses; and third, and perhaps with greater technical difficulty, from adult organs, for example from bone marrow during transplantation.

Possible sources of embryonic stem cells are embryos left over from fertility treatment that would otherwise be discarded, and specially created embryos. Embryos could be created using standard in vitro fertilisation (IVF) techniques, whereby a sperm cell and an egg cell are combined. Other methods are cloning techniques, such as cell nuclear replacement (where the nucleus of an adult cell is introduced into an unfertilised egg), and parthenogenesis (where an egg cell is activated into commencing development without being fertilised). A potential advantage of cloning is that it could avoid the recognition by the recipient’s immune system of the tissue developed from the stem cells as foreign, and rejection of the tissue. Once isolated, stem cells can be cultured and stored. As well as being potentially useful in treating disease (therapeutic cloning), cloned embryos could be implanted into a woman with a view to the birth of a child (reproductive cloning).

Human embryonic stem cells were successfully isolated and cultured from embryos in the United States in 1998. ⁴ These embryos were produced by IVF for clinical purposes, and donated for the research.

A recent publication by researchers from ACT ⁵ reports preliminary experiments on two means of making early-stage embryos: parthenogenesis and cell nuclear transfer. This sparked heated debate, with many religious groups and US political leaders denouncing the research. ⁶ ACT has said that it is pursuing this technology in order to develop life-saving therapies for a wide range of human disease conditions and not to create cloned human beings.

A number of other groups have claimed that they have already gone further than ACT in the field of human cloning. Other scientists are more sceptical, however, pointing out that the ACT embryos did not develop beyond the six-cell stage ⁷ and that these groups have a long way to go before human cloning will have been achieved.

These areas of activity raise several ethical issues, centred on the acceptability of creating a human embryo with the intention of using it solely for research purposes, and on the acceptability of cloning as such. A key consideration is how viable as an alternative source of stem cells adult cells are. Increasingly, use of adult stem cells to produce a narrower range of tissue types seems to be a possibility. ⁸

The Legislative Response

As these technological milestones have been announced, governments have, with varying degrees of alacrity, begun to impose regulation. Many developed countries have now drawn up legislation or codes, or signed up to Conventions, regulating the creation and use of embryonic stem cells. Some regimes have already been shown to be lagging behind the technology.

The response of many governments to reproductive cloning is a complete ban. Approaches to therapeutic cloning vary quite widely. The United States presidency and various European bodies and institutions are taking a restrictive approach to embryonic stem cells, while the United Kingdom has passed relatively permissive legislation. We discuss these developments country by country.

The United States

US regulation falls into two main areas; control of federal funds for research, and the broader question of regulation of the activities themselves.

Following an announcement by President Bush on 9 August 2001, United States federal funds became available for stem cell research on embryonic cell lines already in existence. ⁹ Before that, more liberal National Institutes of Health Guidelines had recommended that funds were to be available for the creation and use of stem cells from spare IVF embryos. ¹⁰ The 64 embryonic cell lines

identified by US officials as already being in existence, and therefore a suitable subject for federally funded research, were generated by various institutes in the United States, Sweden, Australia, India, and Israel.

US scientists have expressed concern that limiting funding in this way impedes research, particularly since some of the ‘approved’ cell lines are poorly characterised and may have been tainted by interaction with mouse cells. ¹¹ In addition, there have been disputes over the ownership of the ‘gold standard for stem cells’ produced by the University of Wisconsin, which could affect their availability to researchers, although some access provisions have been agreed for NIH-funded researchers. ¹²

Separately from the funding issue, the regulation of embryonic stem cell research is being actively considered by the US Government. On 31 July 2001, the House of Representatives voted for a broad ban on human cloning that would prohibit cloning for research purposes as well as for reproduction. ¹³ The Bill, which would impose heavy financial penalties and terms of imprisonment on those who generate cloned embryos, would affect both privately funded and NIH-supported research. It has now been referred to the Democrat-controlled Senate, which is expected to consider it early in 2002. ¹⁴ President Bush’s administration has expressed hopes that ACT’s announcement will encourage the Senate to pass the Bill. ¹⁵ However, a competing Bill, rejected by the House but also to be considered by the Senate, would ban only reproductive cloning, allowing cell nuclear transfer for researching new therapies. ¹⁶

The United Kingdom

The United Kingdom has had regulation in this area for some time. The creation of embryos for certain limited research purposes was made legal under the Human Fertilisation and Embryology Act 1990 (the ‘HFEA’). The subsequent Human Fertilisation and Embryology (Research Purposes) Regulations 2001 extended the permitted use of the embryo to include research to improve the understanding of treatment of serious noncongenital diseases. ¹⁷ Although legal, such activities are tightly regulated by the Human Fertilisation and Embryology Authority set up under the HFEA. A licence is required for each project, and there are criminal sanctions for failure to comply. Cloning using a fertilised egg is banned completely.

It had always been assumed that the creation of embryos using cell nuclear replacement was covered by the HFEA. The English High Court recently held, however, that such cell nuclear replacement techniques are not caught by the HFEA at all, because the definition of ‘embryo’ assumes that fertilisation has occurred. ¹⁸ The case was brought by the Pro-Life Alliance, an organisation campaigning for absolute respect for innocent human life, to clarify the law.

Following the court’s judgment on 26 November 2001, an Italian fertility specialist, Dr Severino Antinori, said that he would start a reproductive cloning programme in Britain. ¹⁹ In response, the UK Government has rushed through Parliament new legislation to close the loophole. ²⁰ The Human Reproductive Cloning Act 2001 makes it an offence to ‘place in a woman a human embryo which has been created by a method other than by fertilisation’. But UK legislation will still permit controlled therapeutic cloning to find cures for serious diseases. ²¹

European Union

The European debate is fragmented, with many disparate institutions and other bodies having their say. A number of European states have signed up to a Convention controlling this area. The European Union itself currently does not regulate the field of stem cell research, but the European Parliament has suggested that it should.

The European Convention on Human Rights and Biomedicine²² (the ‘ECHRB’) prohibits the creation of human embryos for research purposes and requires adequate protection of embryos where countries allow in vitro research. An Additional Protocol ²³ prohibits any intervention seeking to create a human being genetically identical to another. There are nearly 30 signatories to the ECHRB, including France, Italy and The Netherlands. ²⁴ But only those countries that are signatories to the ECHRB are bound by it.

This initiative is distinct from the European Union which does not currently regulate human stem cell research. The European Commission has announced that it has no intention of doing so on the basis that there is a diversity of views among Member States that should be respected. ²⁵

The European Parliament has taken a more restrictive position, expressing opposition to the creation of embryos for research purposes and calling for the European Union to take control in this area. The European Parliament’s Temporary Committee on Human Genetics (‘the EP Committee’) was set up following a number of controversial developments, including the birth of the cloned sheep, ‘Dolly’. ²⁶ The Committee’s role is to report on developments in human genetics, to identify the implications of these developments, and to make appropriate recommendations to guide the European Parliament’s decision-making. In their recent report on ‘The Ethical, Legal, Economic and Social Implications of Human Genetics’, ²⁷ the EP Committee called for the European Commission and Member States to work towards an international ban on human cloning, both reproductive and therapeutic. In addition, it endorsed the opinion of the European Group on Ethics in Science and New Technologies²⁸ that no European Union funding should be available for the creation of embryos (whether by IVF or cloning methods) for the purpose of harvesting stem cells. In addition to the objections to using embryos as such, there are concerns that therapeutic cloning techniques are immature and present many possible risks. Instead, research projects that use adult stem cells should be treated as a priority for European Union funding. ²⁹

ACT’s recent announcement of human cloning prompted a statement from the European Commission. Research Commissioner Philippe Busquin emphasised the urgency and importance with which a European stance on research involving embryonic stem cells is required. He said that Community funds would not be available for reproductive cloning, or research into embryo stem cells, if it led to production of human embryos purely for the purposes of research or stem cell production. In order to strike an acceptable balance between the risks of abuse and the interest of researching and developing treatments for disease, he said that he would authorise, under strictly controlled conditions, the use of embryos already in existence for this purpose. He agreed with the European Group on Ethics’ position that other sources of human stem cells allow for a vast scope of research and that creating human embryos for research is premature. ³⁰ The possibilities, priorities and difficulties for stem cell research were debated on 18 and 19 December 2001 at a conference organised by the Commission through its Life Sciences High Level Group, entitled ‘Stem cells: therapies for the future?’. ³¹ The Council of Europe has reaffirmed its strong opposition to cloning and has called for the United States to support this position. ³²

Other voices recommend a move away from the relatively restrictive approach to embryonic stem cell research adopted at the European level. For example, the High Level Expert Group of the European Science Foundation ³³ is reported to take the view that it is ‘essential to proceed with research on stem cells derived from embryos, foetal tissue and adults in parallel’. ³⁴ There is also some evidence that the EP Committee’s approach may soften with time; at a conference on ‘Life Sciences and Biotechnology – a Strategic Vision’ held in Brussels on 27 and 28 September 2001, the chair of the EP Committee, Luxembourg MEP Robert Goebbels, is reported as saying that ‘only research ending in human cloning [presumably ‘reproductive cloning’] should be prohibited at EU level.’ ³⁵

Other European states ³⁶

At present the legislation in other EU countries, where it exists, tends to follow a more restrictive line than that taken by the United Kingdom. Of course, where the nation concerned is a signatory to it, the ECHRB (see Note 22 above) establishes the framework. In France, for example, cloning, although apparently initially authorised for therapeutic purposes, is now banned. Draft legislation, expected to be considered by the French Cabinet and Parliament in 2002, would allow research only on frozen embryos left over from IVF treatment. ³⁷ Germany seems likely to follow France, but at the moment the creation and use of human embryonic stem cells (however obtained) is essentially banned. Italian law bans all experimentation whose direct or indirect objective is the cloning of humans or animals. ³⁸

In The Netherlands draft legislation which would ban the creation of human embryos for scientific research, but allow the use of embryos left over from IVF treatment, ³⁹ is expected to be voted on shortly. However, The Netherlands is also said to be considering the option of allowing the creation of human embryonic stem cells for research purposes using the somatic cell nuclear transfer technique.

Sweden currently lacks legislation controlling stem cell research. The Swedish Research Council has recently produced guidelines recommending a ban on implantation of cloned embryos in the womb, but supporting the use of cell nuclear transfer for therapeutic purposes. Legislation is expected to be introduced in 2002. ⁴⁰

Outside the European Union, the Swiss National Science Foundation has recently approved funding of a Geneva-based project using human embryonic stem cells imported from the United States. A legal analysis was undertaken to ensure the work would not contravene Swiss law (Switzerland being a signatory to the ECHRB). ⁴¹ Russia has introduced a five-year moratorium on human cloning. ⁴²

Japan

Japan’s Expert Panel on Bioethics, under the Cabinet Office’s Council for Science and Technology Policy, approved guidelines for research on embryonic stem cells on 1 August 2001. ⁴³ The guidelines are unlikely to be officially translated into English until next year, but they are said to give the go-ahead to the use in research of embryonic stem cells from embryos that would otherwise be discarded by fertility clinics. ⁴⁴ Japanese researchers have been quoted as saying that they believe that the guidelines may be relaxed to approve therapeutic cloning within the year, but at present human cloning is banned. Japanese scientists are particularly interested in using stem cell research to artificially produce human body parts because Japanese law strictly regulates organ transplants. ⁴⁵

Australia

Australia has been at the forefront of stem cell research ⁴⁶ and so has an incentive to permit research. A recent Australian House of Representatives Standing Committee report on human cloning ⁴⁷ found that Australian regulation was ‘unsatisfactory and outdated’. Different regimes apply in different parts of Australia, and to public and private research. The committee has recommended a ban on human reproductive cloning and on the creation of embryos for research purposes. Creation of embryos by cell nuclear transfer would be subject to a three-year moratorium, and then re-examined. It proposed a licensing regime for research on embryos made by IVF that would otherwise be discarded.

Summary

In summary, legislation concerning the extraction and use of stem cells from human embryos ranges from that of Germany, which currently bans such activities, to that of the United Kingdom, which allows the creation of embryos for

research by cell nuclear replacement as well as by standard IVF techniques. With other countries analysing the current situation, and in some cases considering the Donaldson Report ⁴⁸ on which much of the UK legislation was based, there is a possibility that some other nations will join the United Kingdom in permitting controlled therapeutic cloning. As with other areas in the biotechnology field, governments are grappling with the problem of scientific advances running ahead of the legislative process and reaching a consensus on the ethical principles on which such legislation is based.

© Linklaters & Alliance

1. Press release by Advanced Cell Technology, Inc., 25 November 2001, ‘Advanced Cell Technology Reports Publication of Results of Human Somatic Cell Nuclear Transfer and Parthenogenesis’. Full report: ‘Somatic Cell Nuclear Transfer in Humans: Pronuclear and Early Embryonic Development’, e-biomed: the journal of regenerative medicine, Vol: 2, pages 25 to 31, 25 November 2001.

2. R v Secretary of State for Health, ex parte Bruno Quintavalle (on behalf of Pro-Life Alliance) (Crane J, 15 November 2001).

3. ‘Scientists at the Roslin Institute publish scientific breakthrough: ability to clone sheep through transfer from somatic cells’, Roslin Institute Online News Release, 24 February 1997; Nature, 27 February 1997.

4. J. Thomson et al., ‘Embryonic Stem Cell Lines Derived from Human Blastocysts’, Science 6 November 1998, 282, 1145 to 1147.

5. See Note 1 above.

6. B. Williams, ‘Heated debate breaks out over cloning of human embryo’, Reuters on Excite News, 26 November 2001.

7. ‘Mavericks claim creation of many cloned embryos’, New Scientist, 27 November 2001.

8. P. Donovan and J. Gearhart, ‘The end of the beginning for pluripotent stem cells’ Nature, Vol. 414, 1 November 2001.

9. ‘US Details 64 Stem-Cell Lines Eligible for Funding’, Reuters, 27 August 2001, reporting on President Bush’s 9 August 2001 televised address.

10. National Institute of Health Guidelines for Research Using Human Pluripotent Stem Cells, effective 25 August 2000, 65 Fr 51976, corrected 21 November 2000, 65 Fr 69951.

11. ‘Health body admits stem cell supply problems’, Financial Times, 28 August 2001.

12. Ibid.; ‘Wisconsin Stem Cells Made available to NIH Researchers’; U.S. Medicine, 21 November 2001.

13. ‘House of Representatives Passes Legislation Banning Human Cloning’, Biospace.com, 31 July 2001.

14. ‘Cloning and the Law’, Scientific American, 24 November 2001.

15. ‘First human embryo brings concerned response’, Research DG, Cordis News, Brussels, 28 November 2001.

16. ‘Advanced Cell Technology’s success with human somatic cell nuclear transfer will reinvigorate the debate on human cloning’, Biospace.com, 28 November 2001.

17. ‘UK to extend embryo stem-cell research’ and ‘UK government looks to expand research on embryos’, The Lancet, Vol. 356, articles dated 23 December 2000 and 25 November 2000. These articles consider the arguments debated and the vote which led to the change in legislation and the creation of The Human Fertilisation and Embryology (Research Purposes) Regulations 2001.

18. See Note 2 above.

19. ‘UK government acts to close legal loophole on human cloning’, Research DG, Cordis News, 20 November 2001.

20. ‘Brit Law Bans Human Cloning’, Reuters, 30 November 2001.

21. Department of Health press release, 16 November 2001, ‘Human cloning to be allowed’ and House of Commons website, ‘Summons Agenda 29 November 2001’; the text of, and explanatory notes to, the Human Reproductive Cloning Bill can also be found on the House of Commons website.

22. The Council of Europe Convention on Human Rights and Biomedicine, signed in Oviedo on 4 April 1997.

23. Additional Protocol prohibiting cloning of human beings, signed in Paris on 12 January 1998.

24. The current list of signatories is: Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Greece, Georgia, Hungary, Iceland, Italy, Latvia, Lithuania, Luxembourg, Moldova, The Netherlands, Norway, Poland, Portugal, Romania, San Marino, Slovakia, Slovenia, Spain, Sweden, Switzerland, former Yugoslav Republic of Macedonia, and Turkey.

25. ‘Philippe Busquin reacts to the UK parliament’s vote on therapeutic cloning’, European Commission Press Release IP/00/1501 of 20 December 2000.

26. See Note 3 above.

27. Published 8 November 2001, Report A5-0391/2001.

28. The European Group on Ethics in Science and New Technologies, an independent, pluralist and multidisciplinary body set up by the European Commission in December 1997.

29. EP Report, see Note 27 above; European Commission press release IP/01/1272 of 14 September 2001.

30. ‘Philippe Busquin takes part in debate on human genetics in European Parliament’, Biotechnology, 29 November 2001. The Commissioner’s entire speech is available as Speech/01/595; European Commission Press Release IP/01/1665, 27 November 2001.

31. Statement by Research Commissioner Philippe Busquin on cloning. Commission Press Release IP/01/1665, 27 November 2001.

32. ‘Council of Europe reiterates its ban on human cloning’, Council Press Release, Strasbourg, 26 November 2001.

33. The ESF is an association of national organisations responsible for the support of scientific research, established in 1974. Its aim is to promote science in Europe.

34. ‘Stem-cell research: drawing the line’, The Lancet, Vol. 358 No. 9277, 21 July 2001.

35. Cordis News, 1 October 2001, reporting on ‘Life Sciences and Biotechnology – a strategic view’, a conference held in Brussels on 27 and 28 September 2001.

36. See also Annex III to the EP Report, Note 27 above.

37. ‘French allow embryo research’, ERA News, January 2001.

38. ‘International opposition to cloning’, CNN.com, 29 August 2001.

39. ‘Netherlands bans cloning of human embryos for research’, BMJ 2000; 321:852 (7 October).

40. ‘Swedish Research Council guidelines support therapeutic cloning’, Research DG, Cordis News, Brussels, 4 December 2001.

41. ‘Swiss to use embryonic stem cells in research’, Research DG, Cordis News, 2 October 2001.

42. See Note 36 above.

43. ‘Research Guidelines Approved in Japan, US President Bush Okays Limited Funding’ Blood Weekly, 23 August 2001.

44. Ibid.

45. ‘US Stem Cell Plan in Line with World’, AP Online, 10 August 2001.

46. ‘Australia stops short of a ban on therapeutic cloning’, New Scientist, 29 September 2001.

47. ‘Human cloning: scientific, ethical and regulatory aspects of human cloning and stem cell research’, House of Representatives Standing Committee on Legal and Constitutional Affairs, August 2001.

48. The Donaldson Report on stem cell research, 26 August 2000: a report by a government advisory commission headed by Britain’s Chief Medical Officer Liam Donaldson which suggests that producing human embryonic stem cells for use in medical therapies be permitted.

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