THE SINGAPORE APPROACH TO HUMAN STEM CELL RESEARCH, THERAPEUTIC AND REPRODUCTIVE CLONING

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1 Blackwell Publishing Ltd.Oxford, UK and Malden, USABIOTBioethics Blackwell Publishing Ltd ArticlesTHE SINGAPORE APPROACH CATHERINE TAY SWEE KIAN AND TIEN SIM LENG Bioethics ISSN (print); (online) Volume 19 Number THE SINGAPORE APPROACH TO HUMAN STEM CELL RESEARCH, THERAPEUTIC AND REPRODUCTIVE CLONING CATHERINE TAY SWEE KIAN AND TIEN SIM LENG ABSTRACT With the controversial ethical issues on the creation of human embryos through cloning for therapeutic research, which holds more promise for medical breakthroughs that the world could ever imagine and the acknowledgement by many scientists that this biotechnology may not lead in the near future to therapies; this country report discusses the approach Singapore takes on human stem cell research, interjected with the authors own arguments and suggestions especially on research compensation injuries, an often neglected important issue. International comparative viewpoints taken by the major countries in the world are also included in the appendix. INTRODUCTION On December 2000, the Bioethics Advisory Committee (BAC) was appointed by the Singapore Cabinet to examine the scientific, ethical, legal, and social issues arising from biomedical research and development in Singapore and to recommend policies to the Ministerial Committee for Life Sciences. The BAC s fundamental approach is to balance two ethical commitments to advance human life by curing diseases and to protect human life. In the process, an extensive consultation process was carried out to understand the concerns and sentiments of the local community, the interest groups, the religious and professional organizations. A study of the positions adopted internationally was done, with, 9600 Garsington Road, Oxford OX4 2DQ, UK and 350 Main Street, Malden, MA 02148, USA.

2 THE SINGAPORE APPROACH 291 the BAC also receiving invaluable advice and information from local experts and members of the BAC constituted International Panel of Experts. The BAC recognizes that their recommendations will have a considerable impact in Singapore and internationally. It supports Singapore s continued drive to excel in biomedical research and development, while remaining responsible to mankind and the people. However, it is submitted that technological advance will always outpace laws and we will have to continue educating ourselves. The BAC report focuses on the ethical issues of whether human stem cell research, reproductive and therapeutic cloning should be allowed and to what extent, while acknowledging that the position taken on these ethical issues will create the foundation for the necessary laws and regulations. Currently, Singapore has no comprehensive legal framework for research on human embryos. But there are guidelines, namely the Guidelines for Private Healthcare Institutions Providing Assisted Reproduction Services (Regulation 4 of the Private Hospitals and Medical Clinics Regulations). These guidelines provide for the use of human embryos below 14 days that were created through IVF techniques, but which are not used in assisted reproduction treatments is permissible, provided stringent regulatory stipulations are met. The BAC adopts two broad ethical guiding principles accepted by most responsible societies, namely that, the results of biotechnology must be just and sustainable as a conceptual framework to formulate its recommendations. Just refers to the obligation to respect the common good of fair sharing of the costs and benefits. Sustainable refers to an obligation to respect the needs of the generations as yet unborn. The BAC recognizes the potential benefits of human stem cell research leading to treatment and therapy and the study of human cell biology. This is in line with the medical ethical principles, which include the concepts of beneficence and non-maleficence, that of encouraging the pursuits of social benefits while avoiding harms. The BAC believes that its recommendations would lead to just and sustainable results. The results would be just, in that research with potential therapeutic benefits to mankind will proceed. The results would be sustainable, as such research has little genetic impact on future generations with the ban in reproductive cloning. Public policies would create the necessary foundation for laws and regulations which must be based on a considered weighing and balancing of the spectrum of views held by the various sectors,

3 292 CATHERINE TAY SWEE KIAN AND TIEN SIM LENG Singapore being a multi-racial, multi-religious, and pluralistic society. 1 RECOMMENDATIONS OF THE SINGAPORE BIOETHICS ADVISORY COMMITTEE The recommendations include the following. a. Adult stem cells It is ethically acceptable to derive and use stem cells from adult tissues. 2 The BAC recommends that research on adult stem cells be permitted, subject to securing the informed consent of the tissue donor. b. Cadaveric foetal tissues The BAC recommends that research involving the derivation and use of stem cell from cadaveric foetal tissue be allowed, subject to the securing of informed consent from the tissue donor. 3 This is closely linked to the ethical acceptability of abortion. Further the decision to donate the cadaveric foetal tissue should be made independently of the decision to abort. c. Embryonic stem cells As the use of embryonic stem (ES) cells raised the most ethical debates with differing views on the status of human embryo, it must be balanced with the ethical use of embryo research, which has tremendous potential benefits to mankind. The BAC adopts the position that a human embryo has a special status as a potential human being, but it does not have the same status as a living child or adult. But such respect is not absolute and must be weighed against the benefits arising from the proposed research. 1 The National Council of Churches of Singapore, The Catholic Medical Guild of Singapore, the Sikh Advisory Committee, and the Singapore Hospice Association have strong contentions that a human life begins from the moment of conception. Others such as the Majlis Ugama Islam Singapura held the view that a human life does not begin until some time after conception. The Buddhist Federation in Singapore supports research on the view that it is ethically irresponsible to deny the progress of scientific research that would benefit mankind. 2 Adult stem cell research is also widely supported in many jurisdictions, including the United States of America and the United Kingdom. 3 Abortion is allowed by the Termination of Pregnancies Act (Cap. 324).

4 THE SINGAPORE APPROACH 293 The BAC supports ES cell research subject to stringent regulations and recommends that such research be permissible only where there is strong scientific merit in and potential medical benefit from such research. It also recommends that where permitted, ES cells should be drawn firstly from, existing ES cell lines, originating from ES cells derived from embryo less than 14 days old. 4 Secondly, surplus human embryo created for fertility treatment less than 14 days old. 5 Currently in Singapore, existing ES cell lines are a ready source for ES cells without requiring further sacrifice of embryos. ES cells can be obtained justifiably from surplus embryos. It is not seen as disrespecting these embryos, but rather as enabling them to serve a greater good by being used for research which is an act of greater respect for these embryos. However, the BAC recognizes the limitations faced in research limited to just using existing ES cell lines. There are concerns from the scientific community of the possible immunological rejections at the stage of clinical applications because of the limited number of existing ES cell lines. It is submitted that with genes limited to a few donors in existing ES cells, there may be widespread propagation of gene mutation due to recessive genes. In fact scientific evidence points to the necessity for an alternative source of ES cells. d. Creation of human embryo specifically for research The BAC acknowledges that the creation of embryos through therapeutic cloning does offer an opportunity to derive stem cells which are immunologically compatible with the person being treated, thereby avoiding the problem of rejection. Therapeutic cloning also enables scientists to study the mechanism of reprogramming adult cells to behave like embryonic stem cells again. In the future, it may be possible for adult stem cells to be able to be reprogrammed to behave like embryonic stem cells, which would thus potentially remove the use of embryos to derive ES 4 Before the 14 day mark, the cells of the embryo are as yet undifferentiated into tissues and there is no organized development. In the United States, federal funding of research with ES cells derived from approved existing ES cell lines is allowed. The Singapore BAC believes that the level of respect and protection increases as the embryo develops. In embryology, before 5 days, the embryo is a mass of undifferentiated cells. On day 14 the primitive streak appears, thereby signaling the onset of cell differentiation and organ formation including the development of the nervous system. 5 See Singapore Guidelines for Private Healthcare Institutions Providing Assisted Reproduction Services and Regulation 4 of the Private Hospitals and Medical Clinics Regulations.

5 294 CATHERINE TAY SWEE KIAN AND TIEN SIM LENG cells. To date, ES cell research is developing rapidly and there is scientific evidence that supports the need to use research embryos. In February 2003, Singapore ES Cell International has paved the way for stem cell treatment that offers hope for diabetic patients, as its scientists have the means to develop insulinproducing cells for patients. There is, therefore, an intense need to respond effectively to such scientific advances and discoveries. In the final analysis, the BAC weighed the need to protect the human embryo against the scientific value of research embryos and the potential benefits to be reaped from such research, and recommends that the creation of human embryo specifically for research can only be justified where there is strong scientific merit, potential medical benefit from such research, there is no acceptable alternative, and carried out on a highly selective caseby-case basis, with the specific approval from a proposed statutory body. Further, only embryos less than 14 days old should be used for the derivation of ES cells. It is submitted that whatever regulations are made here should be flexible enough to respond effectively and efficiently to advances in science, in order to facilitate deserving and worthy research and not hinder it. e. Reproductive cloning The BAC views that the creation of a human being by any cell nuclear replacement techniques or any other method should be prohibited as the public policy reasons are over-whelmingly against it. The strict prohibition of any implantation of embryo (created by cloning technique) into a womb should allay any fears in the cloning of a whole human being. f. Informed consent The BAC recommends that there must be informed consent from the donors of surplus human embryos, gametes, or cells when deriving and using ES cells. In obtaining such consent, the information given to the donors must not only be comprehensive but there must not be any financial, therapeutic, or other benefits or inducements for the donors or any coercion or undue influence for the donation. But the donor is not precluded from receiving treatments or therapies that may be subsequently developed. A set of regulations and guidelines on obtaining informed consent from the donor is crucially necessary.

6 g. Donated materials THE SINGAPORE APPROACH 295 The BAC recommends that there should be laws banning the commerce and sale of donated materials, especially surplus embryos. Further, researchers should be permitted to gain commercially from the products of research, as well as from treatments and therapies developed from the donated materials. h. Legislative framework and regulatory body The BAC recommends that the United Kingdom model be adopted as a basic model, subject to the necessary modification being made for Singapore, as well as refinements found in other regulatory systems in other countries. 6 It recommends a regime where there should be a statutory body to license, audit, control, and monitor all human stem cell research conducted in Singapore, together with a comprehensive legislative framework and guidelines. The management of the statutory body should be vested in a board, with the Chairman of the Board not being directly involved in stem cell research. The members of such a board should be multidisciplinary including members of the public. It is submitted that we must avert the dangers of having one person on the board managing related positions, as the pool of persons in this area is small. The BAC recommends the appropriate body should assess whether the research is delivering the anticipated benefits, and highlight any unforeseen concerns that may arise. The permissible areas of human stem cell research should increase knowledge on serious illnesses and the development of the embryo, or enable such knowledge to be applied in finding new treatments and cures. In granting licenses, the body must review the research proposals and its protocols carefully, ensuring that the above requirements are met. Stringent conditions; including conditions on derivation, storage, and use of research materials; should be attached to such licenses. The body should be empowered to impose sanctions, including criminal penalties on pain of noncompliance with the regulations and law. It is submitted that any proposed criminal sanctions should not be too harsh, but do need to strike a careful balance, as the legal framework may lead to scientists leaving to conduct their research in other more permissive countries in the world. 6 In the United Kingdom, research with human embryo is subject to license issued by the Human Fertilisation and Embryology Authority.

7 296 CATHERINE TAY SWEE KIAN AND TIEN SIM LENG There should be regulations and guidelines on obtaining informed consent from donors and commerce and sale of research materials. There should also be laws providing that no one shall be under a duty to participate in any manner of research on human stem cells (if permitted by law) to which he has a conscientious objection. With diverse views on the ethics of human stem cell research, the BAC envisaged that on moral or religious grounds, a segment of the research community and the public may not wish to be involved in such research. Such objections are legitimate, as Singapore is a multi-religious and pluralistic society. The BAC would not challenge or reconcile disagreements held from personal, moral, or religious convictions. The BAC believes that given an individual s beliefs, he should be allowed to make an informed choice on whether to participate in such research. But it is submitted that one should ethically question, If an individual strongly objects to human stem cell research in the first place, why should he gain from the new treatments and cures that may be subsequently developed? It is only logical that the argument follows through that one would not want to benefit the new cures and treatments subsequently developed from the human stem cell research, which was opposed right from the start. SINGAPORE LEGISLATION The whole of the BAC s recommendations was accepted by the Singapore Cabinet with the passing of the Regulation of Biomedical Research Bill in November This Bill seeks to regulate the conduct of biomedical research and ban certain types of research. However, Singapore decided to adopt a step-by-step approach to the regulation of human stem cell research and cloning. She started with the more pressing issue of human reproductive cloning by enacting the Human Cloning and Other Prohibited Practices Act Separate laws will subsequently be developed for human embryonic stem cell research and human tissue research. Section 5 of the Human Cloning and Other Prohibited Practices Act specifically prohibits the implantation of a human embryo clone in the body of a human or an animal. Further, it is not a defense to this criminal offence that the human embryo clone could not have survived. However, therapeutic cloning of human embryos for research is allowed under special circumstances. Section 7 bans the implantation in a woman of any human embryo created by the process other than fertilization of a human egg by

8 THE SINGAPORE APPROACH 297 a human sperm, for a period of more than 14 days. It is an offence for any person to develop any human embryo outside a woman body for more than 14 days. Section 9 forbids any person to remove any human embryo from a woman body to collect a viable human embryo. It is also an offence to place any prohibited embryo in the body of a woman. This Act also bans the importation and exportation of human embryo clones. It also prohibits the commercial trading in human eggs, human sperms and human embryos. The criminal penalties for contravening the Human Cloning and Other Prohibited Practices Act are a maximum fine of $100,000 or a maximum ten years imprisonment or to both. CONCLUSION AND SUGGESTIONS We are reminded of the Hippocratic Oath and the fundamental concepts of beneficence and non-maleficence which apply in human stem cell research. Beneficial research should be carried out by weighing risks against benefits, as it is beneficence to do good, but harms and risks should be avoided (i.e. nonmaleficence). It is submitted that there should be regulations (on the development and use of human stem cells that will be used as biological products, or medical devices to treat or cure diseases) to end the current debate and monitor the conduct of clinical trials involving human experimentations closely. We should make progress and move ahead as it is ethically supported if we use the reasonable approach where benefits must outweigh the risks and even unreasonable objections, while allowing conscientious objectors to opt out. But the regulations needed to ensure responsible and professional and social control of stem cell research in Singapore must be justified as good laws stem from ethics. For an effective legal framework, the human stem cell research should be regulated and monitored in accordance with the relevant ethical considerations. Ethics goes beyond the Law! However, any proposed laws and regulations must be sufficiently flexible to allow for an adequate response to the scientific and biotechnological advances that are currently being developed at a very fast pace. It is of utmost importance to facilitate and not hinder worthy and deserving human stem cell research and therapeutic cloning, where there are tremendous potential curative cell-therapy treatments. Although there is no current evidence regarding which source of stem cells is the best for curing diseases, we should continue to strive in research using all sources to discover the truth. However, it may be prudent to set policies and institute measures to

9 298 CATHERINE TAY SWEE KIAN AND TIEN SIM LENG accelerate adult stem cell research over embryonic stem cells, so that in areas where adult stem cells are successful, the controversial embryonic stem cells may not be necessary. There should then be a strict overview of human stem cell research with adequate rules and guidelines relating to privacy, confidentiality, adequate counseling, and the securing of informed consent in order to prevent abuses and sufferings. But the penalties for breaching guidelines should not be too stringent, as researchers and scientists may be deterred and go to more permissive societies or countries to continue with their human stem cell research. It is submitted that compensation for research injuries be provided and incorporated into the informed consent forms 7 signed by the donors of human stem cells or by the human subjects in clinical research trials. It is only fair and ethical, to follow the argument through, to provide for research injuries compensation (whether for expected or unexpected risks) that may occur in human stem cell research. 8 Otherwise it is not displaying responsibility, but is a case of reaping the tremendous benefits of human stem cell research and not wanting to bear the predictive and unexpected risks that go along with the research. On the other hand, compensation for research injuries should not be too prohibitive so as to discourage research or put undue financial strain on the research grants. It should be covered by an appropriate insurance with a maximum cap on compensation. This is an area to be deliberated by the ethics committee to which the research paper is submitted. In the final analysis for the global world, it is submitted that there should be an international convention on bioethics and human stem cell research so that a consensus can be reached internationally with minimum standards and safeguards to be placed at national levels. 9 7 David Wendler. What research with stored samples teaches us about research with human subjects. Bioethics, 2002; 16: 1: See the Council for International Organisations of Medical Sciences (CIOMS) guidelines on International Ethical Guidelines for Biomedical Research Involving Human Subjects on compensation for research injuries, which is not found in other international guidelines or documents. 9 The French President Jacques Chirac indicated that he would lead an initiative in the UN Educational, Scientific and Cultural Organisation for an international convention on bioethics to prevent abuse of cloning research: The Straits Times, 25 February See Carlos M Romeo-Casabona et al. The Embryonic Stem Cell Research and Therapy: The need for a Common European Legal Framework. Bioethics 2002; 16: 2: See also George J. Annas, Lori B. Andrews & Rosario M. Isasi. et al. Protecting the Endangered Human: Toward an International Treaty Prohibiting Cloning and Inheritable Alterations. American Journal of Law and Medicine 2002; 28 No. 2 & 3:

10 THE SINGAPORE APPROACH 299 Appendix INTERNATIONAL PERSPECTIVES On the international scene, the tensions between the ethics of human stem cell research and the potential benefits to mankind are not spared, sparking off the great debate on human stem cell research. Internationally, theologians and scholars, even within the same faith, differ on the issue regarding the status of the human embryo. Different countries in the world adopt a variety of views. What is ethical to one country may not be an ethically accepted practice in another country, which serves to highlight the diversity in our global world. The Council of Europe s Convention on Human Rights and Biomedicine bans the creation of embryos for research purposes. A comparative study of selected countries reveals the diverse opinions on the ethical acceptability of human stem cell research and therapeutic and reproductive cloning. 1. The United States of America Privately funded human stem cell research projects are not subject to any control. But there is limited public funding for research on human embryonic stem cells obtained from existing human stem cell lines only. 10 Reproductive cloning is banned with federal funding. However, there is a voluntary moratorium in place for reproductive cloning. The US Human Cloning Prohibition Act of 2003, passed on 27 February 2003 prohibits cloning for medical research or to create pregnancy. Further it is a crime to receive or import a cloned human embryo or any product derived from a cloned human embryo, with fines of US$1 million and 10 years imprisonment United Kingdom Reproductive cloning is not expressly banned by the Human Fertilisation and Embryology Act of 1990, which allows for the 10 The US National Institute of Health has established a Human Embryonic Cell Registry to list human embryonic stem cells complying with the eligibility criteria for the granting of research funding. 11 The implications of the anti-importation provisions could deny American patients the benefits of SCNT-based regenerative medicines developed overseas and patients seeking foreign treatments that might result from embryonic stem cell research could be criminals.

11 300 CATHERINE TAY SWEE KIAN AND TIEN SIM LENG creation and use of human embryos up to 14 days old for research purposes including therapeutic cloning. And no distinction is made between embryos created by IVF, and those created by SCNT. All such research is regulated by licensing under strict conditions by the Human Fertilisation and Embryology Authority. The conduct of such research is further governed by guidelines issued by the UK Department of Health and professional bodies. The Nutfield Council on Bioethics while addressing ethical issues in human stem cell therapies, has recommended that research on human embryos be allowed for the purpose of developing tissue therapies from the derived ES cells. The Council also views that there would be no compelling reason to allow for the creation of additional embryos for ES cell research or therapy since there were enough donated embryos from IVF treatments. The Human Tissue Act of 1961 concerns stem cells derived from adult tissue while the stem cells derived from foetal tissue are governed by the Code of Practice on the Use of Foetuses and Foetal Material in research and treatment. 12 All such research proposals must be approved by a research ethics committee. 3. Japan Reproductive cloning is banned but cloning for certain limited purposes is allowed 13. There are guidelines governing therapeutic cloning, embryonic research, and stem cell research 14 and researchers must obtain individual consent before using stem cells for research purposes. Since July 2002, Japan established a human stem cell bank for regenerative medicine, which involves the use of cells, genes, and other biological building blocks to repair or replace tissues and organs damaged by ageing, illness, or injury. As regenerative medicine can involve embryonic stem cells as they can be grown to replace the heart, lungs, the nervous system, and other body parts, ethical issues do arise. To avoid such 12 The Polkinghorne Code of Practice, drawn up by the Polkinghorne Committee in 1989, required that informed consent as regards stem cell research and the subsequent use of the developed cell line must be obtained in writing from the donors of foetal material and embryos from which ES cells are derived as a safeguard to protect such donors who could be identified by DNA analysis. 13 The Japanese Human Cloning Regulation Act of 2000 bans the implantation of embryo created for research into the woman s womb. 14 Embryonic cells used in research can only be taken from those made for fertility treatment that would otherwise be discarded.

12 THE SINGAPORE APPROACH 301 ethical concerns, Japan already has a stem cell bank for leukemia treatment using blood from the umbilical cords of newborn babies. The Bank will retrieve hemopoietic (blood) stem cells, neural stem cells, and other stem cells from collected cord blood and attempt to develop a technology to increase such stem cells for use in medical treatments. As a recipient may suffer an adverse reaction to an organ derived from another person s stem cells, Japan plans to collect 20,000 30,000 cord blood samples to create a system where 80% of citizens do not have adverse reactions. 4. Australia Human cloning is banned, and the deliberate creation of embryos for research purposes is prohibited. The Australian Health Ethics Committee recommends that a three year moratorium be imposed on the creation of embryos via SCNT, as there is currently no therapeutic purpose to be served as to date research has not identified any specific opportunities that warrant the deliberate formation of embryos. The use of surplus embryos from infertility treatments is allowed, subject to the approval by international ethics committee or national licensing body, and complying strictly with the guidelines. The Committee views that research using adult stem cells could be pursued since this source of stem cells is wholly accepted, even by those who oppose embryonic research. 5. Canada Currently, there are no guidelines on therapeutic and reproductive cloning, but a ban on cloning is expected with restrictions on embryonic research. The research using surplus embryos is allowed, subject to securing the donor s consent. Human stem cell research is allowed. 6. Israel The Prohibition of Genetic Intervention Law (Cloning Human Beings and Genetic Modifications of Reproductive Cells) bans reproductive cloning for five years from There are no guidelines for therapeutic cloning. Stem cell research and embryonic research are allowed. There is no legislation regulating stem cell research.

13 302 CATHERINE TAY SWEE KIAN AND TIEN SIM LENG 7. Italy Reproductive cloning is banned 15. The creation of embryos for research purposes and early splitting of embryos for therapeutic or research purposes is prohibited. Stem cell research is allowed. 8. Sweden Research using surplus embryos is permitted, subject to securing the donor s consent and if there is no acceptable alternative. 16 Reproductive cloning and therapeutic cloning are banned. Embryonic research and stem cell research are allowed. 9. Belgium Reproductive cloning, therapeutic cloning, and embryonic research are banned. There are no guidelines to date on stem cell research. Laws on genetic engineering prohibits the production, storage, and manipulation of human embryos for use as biological material Costa Rica The right to life is recognized from the moment of conception. 18 But, to date there are no guidelines regulating research. Reproductive cloning, therapeutic cloning, and embryonic research are not permitted. 11. Hungary Hungary has banned reproductive cloning, therapeutic cloning and embryonic research. The life of an unborn child is protected from its conception. 19 There are no guidelines on stem cell research. 12. Ireland In Ireland, the constitution expressly prohibits research being conducted on embryos. 20 The right to life of an unborn child is 15 The Italian National Committee on Bioethics opposes reproductive cloning (Opinion of 27 October 2000). 16 Law No. 1991:115 and Law No. 1982: Law No. 8974/ Law No of Law No. LXXIX of Article 40, paragraph 3 of the Constitution.

14 THE SINGAPORE APPROACH 303 equal to that of the mother. But there are no guidelines for stem cell research. Reproductive cloning, therapeutic cloning and embryonic research are not allowed. 13. Switzerland The Constitution prohibits medically assisted reproductive cloning for research purposes. 21 Reproductive cloning, therapeutic cloning and embryonic research are banned. There are no guidelines for stem cell research. 14. Peru Peru prohibits human cloning and the fertilization of human ova for purposes other than reproduction. 22 The right to life is recognized from the moment of conception. 23 Reproductive cloning, therapeutic cloning and embryonic research are not permitted. Catherine Tay Swee Kian Tien Sim Leng 32 Sunset View Singapore Article 19, 2c of the Constitution. 22 Law No Law No