Cloning and Embryonic Stem Cell Technologies

Cloning and Embryonic Stem Cell Technologies Associate Professor Julian Savulescu Director, Ethics Unit, The Murdoch Childrens Research Institute Melb...
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Cloning and Embryonic Stem Cell Technologies Associate Professor Julian Savulescu Director, Ethics Unit, The Murdoch Childrens Research Institute Melbourne

And Bioethics Programme Centre for the Study of Health and Society University of Melbourne Email: [email protected] Fax:-61-3-9348 1391 Funding: Murdoch Childrens Research Institute

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ABSTRACT Every day, people die because there are insufficient tissues available for transplantation. The development of cloning and embryonic stem cell line technologies offer real hope for developing better sources of tissues for transplantation. Moreover, these new technologies may mean that damaged tissue (after a stroke or heart attack, for example) can be replaced with normal functioning tissue rather than scar tissue. Research into “therapeutic cloning” and the development of embryonic stem cell lines is illegal in several states in Australia. It is time to review that legislation to allow destructive embryo research. I argue that at least research should be allowed on spare embryos from assisted reproduction. I argue that it is only one moral view (of several plausible candidates) of the status of the embryo which precludes producing embryos for research. I argue that this view is mistaken and so it morally permissible to produce embryos for research into therapeutic cloning. ACKNOWLEDGEMENTS Alan Trounson, Jeff McMahan, Bob Williamson, David McCarthy, Edgar Dahl, Peter Singer, Lynn Gillam and Ainsley Newson. INTRODUCTION There have been two recent scientific advances that hold great hope for producing new, abundant and better sources of human tissues for transplantation.

1. Establishment of Human Embryonic Stem Cell Lines Stem cells have the ability to mature into different mature cell types. Totipotent stem cells are cells with the potential to form a complete human being if placed in a uterus. They are early embryos. Pluripotent stem cells are very immature stem cells with the potential to develop into any of the mature cell types in the adult (liver, lung, skin, blood, etc), but cannot by themselves form a complete human being if placed in a uterus. Recently, human embryonic stem (ES) cell lines have been established for the first time. 1 Embryonic stem cells are cells obtained from the inner cell mass of the blastocyst or preimplantation embryo. At this stage, the embryo is a microscopic ball of around 100-200 cells, and is only a few days old. ES cells are pluripotent. Embryonic stem cells from mice have been directed to differentiate into vascular endothelium, myocardial and skeletal tissue, haemopoietic precursors and neurons. 2 Clinical applications include haemopoietic repopulation (“bone marrow transplant”) and treatment of neurodegenerative disease, diabetes, spinal cord injury 3 , as well as the screening of drugs. 4 Haemopoietic repopulation now has a role in treatment of haematological malignancy, storage disorders and rheumatoid arthritis. Researchers at the Monash Institute of Reproduction and Development have differentiated ES cells into nerve cells 5 and elsewhere trials of the use of similar cells in the treatment of stroke are underway. 6 Animal research has suggested that such grafts can reverse cognitive and motor deficits. 7 ES cells could be used to reduce immunological rejection by: (i) banking of many ES cell lines representing the major histocompatibility complex (MHC) alleles to increase the chances of MHC matching; (ii) genetic alteration of MHC genes to reduce rejection; (iii) introducing the recipient’s MHC genes through transgenesis and gene targetting.3 2

ES cells could also be vectors for gene therapy in the treatment of genetic disease. A gene could be inserted and tissue grown without genetic abnormality, which could be transferred to the patient.

2. Cloning On February 24, 1997, Scottish scientists announced that they had cloned Dolly the sheep using nuclear transfer. This involves taking the nucleus of a mature somatic cell and transferring it to the cytoplasm of an egg to create a totipotent stem cell –or early embryo - capable of producing a clone of the entire individual from which it was derived. 8 9 If nuclear transfer could be applied to human cells, cloning could be used to produce tissues by producing a totipotent stem cell. This totipotent cell could be used to produce ES cell lines. This has been called “therapeutic cloning” which has been distinguished from cloning to produce a live born offspring (“reproductive cloning”). If the blastocyst from which the ES cells were derived was cloned from a mature cell from the potential recipient of the transplanted tissue, there would be no tissue incompatibility because the cells would be the person’s own. Significance of Therapeutic Cloning Therapeutic cloning could be used in the following way. Imagine a child develops leukemia. She will die without a bone marrow transplant. No compatible donor can be found. We could use therapeutic cloning to take one of her healthy skin cells and turn it into healthy bone marrow. And because it would be her own bone marrow, she would never need any drugs to prevent rejection. Therapeutic cloning is important for 5 reasons: 1. There is a shortage of tissue for transplantation. As few as 5% of the organs needed ever becoming available, with the discrepancy between the number of potential recipients and donor organs increasing by approximately 10-15% each year in the US. 10 2. There are problems with compatibility of transplanted tissue requiring immunosuppressive therapy with serious side effects. Cloned tissue would be compatible without the infectious risks of xenotransplants. 3. The role of transplantation could be expanded to include common diseases like heart attack and stroke. After a stroke, the dead part of the brain is replaced by scar tissue. It may be possible in the future to use therapeutic cloning to give stroke victims new brain tissue. 4. This technology may be a cost-efficient means of preventing disability and morbidity, and promoting distributive justice. 5. It would facilitate the development of biotechnology in Australia. Restrictions on biotechnology reduce competition and diversity as large companies such as Geron Corporation patent and monopolise new technology. In addition, talented scientists in Australia may go off-shore.

Research in Australia ES cell technology has been described as the most significant development since recombinant DNA.4 Laws regulating ES cell research vary. At the most permissive end, the UK Human Fertilisation and Embryology Act 1990 allows the destruction of embryos until 14 days from any of these three sources. 3

At the other end, in August, 2001, President Bush approved the use of Federal funds only to experiment on ES cell lines which were in existence at that time. These allegedly number about 60, though they may be as few as 30. New ES cells cannot be created from any these three sources using Federal funds in the US, though there are no laws on embryo research which does not use Federal funds. In 2002, the Council of Australian Governments agreed that the Commonwealth, States and Territories would introduce legislation that would ban cloning and the production of human embryos by either cloning or IVF for research. However, it would allow the use of embryos which were excess to IVF requirements as of April 5 for research. The derivation of ES cells from an embryo requires the destruction of that embryo. Embryos used to produce ES cells can come from three sources: (1) embryos created specifically for research by in vitro fertilisation (IVF); (2) embryos which were created for the treatment of infertility but are no longer required (“spare” embryos); (3) embryos created by nuclear transfer (“therapeutic cloning”). Many people see that the use of spare embryos from IVF for this research which would otherwise be destroyed as the least contentious source of embryos. I have argued that, even if one believes the embryo is a person, it is acceptable: it is like taking organs from a brain dead child. 11 However, even the use of spare embryos is problematic to some.

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The Moral Status of the Embryo According to different moral views, the embryo or fetus has a significant moral status or a right to life at different times. 1. Conception 2. Day 14 3. 6 weeks (Judaism) 4. Quickening (around 18 weeks) 5. When consciousness begins (around 24 weeks) 6. Viability (currently around 22 weeks) 7. Birth 8. Sometime in the first year after birth Consider three of the most influential views.

1. The Conception View According to this view, from the point of conception a person exists with a full right to life. This is the present view of Catholic Church. It has been extended to include a totipotent stem cell produced 4

by cloning. It is only this view which grounds an opposition to destructive embryo research. On all other views, therapeutic cloning would be permissible. There are a number of problems with this view. It implies that abortion is like the murder of an innocent person. Nearly 100,000 abortions are performed every year, over 95% of which are for nonmedical reasons. According to this view, this is like mass murder on a scale similar to the seen in Nazi Germany. While many people are uneasy about abortion, they do not believe it is like murder. It implies that the destruction of a frozen embryo is like killing a person. Such destruction is requested regularly by couples and required by law in Victoria after five years if the embryo’s parents cannot be contacted. There are also logical problems with the view that an entity has a right to life from conception. Recent scientific research has revealed that sometimes two zygotes fuse after conception to produce one enduring entity (chimera). 12 13 The resulting chimera cannot be identical with both zygotes from which it was formed, because this would imply that the two different zygotes were identical with each other (a logical impossibility). If this is so, the chimera cannot have come into existence before the time of embryo fusion, which is some time after conception. The phenomenon of twinning also raises serious problems for the view that we begin to exist at conception. What happens when a zygote A divides into identical B and B* at day 2? When did B begin to exist? Was B identical with A? Both B and B* cannot be identical with A, because this would imply that the twins B and B* are identical to each other – that is, that they are both the same thing. This implies that B and B* came into existence when A divided on day 2, not at conception. Indeed, Dame Mary Warnock said: “the embryo hasn’t decided how many people it is going to be.” Thus the Warnock Committee in the United Kingdom influentially concluded that embryo experimentation was justifiable until 14 days after conception. At that point, cells have committed themselves to producing the placenta or the embryo proper (including the brain). Soon after, at around day 18-20, twinning ceases to be possible. To destroy a zygote prior to day 14 is like destroying an egg and a sperm that would have created an identifiable individual. It is not to kill that individual but to prevent one coming into existence. Destruction of the early embryo is in this way more like contraception than murder. Indeed, postcoital contraception (the morning after pill) results in the death of the preimplantation embryo. On the conception view, post-coital contraception is like murder. That is not plausible.

2. The 14 Day View Because of the problems that twinning raises, some philosophers have claimed that when the fertilised egg divides, there is nothing that continues to exist. 14 It is like an amoeba dividing. It ceases to exist and is replaced by two qualitatively identical amoebae. Similarly, when each of the daughter cells divides, it ceases to exist and is replaced by its own two qualitatively identical daughter cells. Again, there is nothing – no individual – that persists through these divisions. Only when the cells begin to be differentiated and to engage in co-ordinated activity do they together constitute an individual human being rather than human tissue.15 Jeff McMahan draws the following analogy. “Consider … an island on which there are people. Suppose these people are entirely unrelated: each came to the island independently of the others, each lives a solitary life with no communication or cooperation with the others, and each is even unaware of the existence of most of the others. These individuals do not together constitute an individual of any substantial sort. If, by contrast, various relations obtain among them – if, for example, they are related genealogically, speak the same language, accept the same moral and religious beliefs, follow the same customs, cooperate together in complex ways, and so on – then it is plausible to suppose that they together constitute a distinct individual: a nation, for example.” 15 5

3. The Consciousness View The view that it is morally permissible to experiment on embryos up until 14 days after conception is accepted in the United Kingdom, WA and SA. There are a number of objections to this view. The problem with the 14 day view is that it identifies us, what is fundamentally us, with facts about our body or physical organism. Yet we seem to be more than physical entities – we are minds, or conscious minds to be more precise. Thus, there is an emerging view that permanent unconsciousness is a state as bad as being dead. In the case of Tony Bland, the young man rendered permanently unconscious by the Hillsborough football disaster, withdrawal of artificial feeding and hydration was justified on the grounds that Bland had no interest in remaining alive. 15 To put it another way, Tony Bland’s mind was dead while his body lived. Another example which supports the view that we are conscious minds is that of conjoined twins. No one doubts that these are two separate individuals with one body. They are not one person split in two, but two persons joined. 15 A more extreme case is the hypothetical case of brain transplantation.15 Imagine that you have an identical twin, A. You have disseminated cancer and will die in one week. However, your brain is intact. A suffers a massive stroke and is brain dead. Brain transplantation has been developed. Surgeons offer to transplant your brain into A’s cranium. You accept. Most of us would consider that it is you who survives in A’s body. Thus we cannot be identical with our body or organism. If we are fundamentally conscious minds, we do not begin to exist at least until the structures are present which could support consciousness. The Royal College of Obstetricians and Gynaecologist’s Working Party produced a report on Fetal Awareness in 1997. It concluded that the structural development for ability to be conscious of pain is not present in the fetus before 26 weeks. Thus, the fetus does not achieve a moral status before 26 weeks. Which view of moral status should we accept? We need not settle this issue to decide whether therapeutic cloning and destructive embryo research are permissible. We need only decide if the Conception View is incorrect. If the Conception View is incorrect, then therapeutic cloning is permissible whichever alternative is accepted. I have argued that there are serious problems with the Conception View and much more plausible alternatives. Potentiality Another objection to using cloned cells and embryos is that they are potential persons. And it is wrong to kill a potential person. It is subject to a well known objection: potential X’s do not have the same rights as X’s. For example, potential doctors (medical students) do not have the same rights as doctors. Cloning, however, raises new problems with appeal to potentiality. Cloning shows us that somatic cells like skin cells have the potential to give rise to human beings. But we do not hesitate to kill or excise skin cells, even if they have this potential. They are not like complete human beings. A skin cell in a petri dish awaiting nuclear transfer is not morally different to a fertilised egg in the laboratory which requires microsurgical transfer to the uterus if it is to produce a baby. Both cells could produce a person, but both need human intervention to realise this potential. Hence, we are entitled to treat totipotent stem cells as we treat skin cells.

Alternative Ways Forward A number of alternatives to embryo research have been proposed. Preliminary work has been done fusing human somatic DNA with enucleated cow eggs. 16 The organism stops developing before 6

organs start to form. That is, there will not be a mature organism. Work has begun developing ES cell lines from these blastocyst cells.1717 Another theoretical possibility is to insert trophoblast inhibitor genes into or knock out genes from cloned cells so that these cells will never form a placenta 18 . That is, they will be changed from totipotent to pluripotent stem cells. It may be possible to cause differentiated somatic cells to transform into pluripotent stem cells without a stage of totipotency. 19 It may also be possible to research dedifferentiation or reverse differentiation of mature somatic cells to turn them directly into immature stem cell forms without going through a stage of totipotency. Or it may be possible to use stem cells found in adults as a source of tissue. 20 Recently, neural stem cells have enticed to differentiate into blood cells in mice. 21 22 However, cloning and ES cell technology seem to offer more hope in the short term of yielding useful treatments. And, because every day that progess is delayed, someone else dies because the tissue they need is not available, there is a strong moral reason to support therapeutic cloning.

Two Issues There are two separate issues: 1. should embryos produced during IVF which would otherwise be discarded be available for research (with the consent of the couple who produced them)? 2. should we deliberately create embryos for use in research? The answer to the first question should be “yes.” There is no valid argument to defend the destruction of an embryo to no useful end when that embryo could be used in research which has the potential to save lives. Most sensible people would accept this. The use of “spare” or “excess” embryos in research is consistent with the current practice of using tissue from aborted fetuses in research and medical treatment. The answer to question 2 is more controversial. But in many ways, it is more important: the possibility of performing research into therapeutic cloning requires that we answer 2 in the affirmative. I believe there are good arguments to support deliberately creating embryos for research into therapeutic cloning. I have offered arguments to support the claim that at least the early human embryo does not have the same rights and interests as people, and that it is not as wrong to kill it as it is to kill a person. This is supported by the 14 day view and the consciousness view of moral status, and indeed all the views of moral status except the conception view held by the Catholic Church. There are other arguments that establish that there is something wrong with destroying embryos, such as a need to respect for human life in general. All of us (including me) feel there is something wrong with destroying a human embryo for no good reason. But when we weigh up the enormous potential good that is at stake, I believe that balance tips in favour of engaging in this research. John Harris points out that for every live birth, up to five embryos will miscarry. In attempting to have a child by natural conception, we (and presumably God who is omnipotent) implicitly accept that this loss is a price worth paying to produce a new life. 23 But if the loss of embryos is an acceptable price to pay to produce a new life, surely is it an acceptable price to pay to save an existing life? Previously, destruction of embryos was essentially only a part of IVF, which is relevant to a minority of the population. The advances from ES cell research are relevant to us all. We need to confront our inconsistent attitudes to the treatment of embryos. If we decide that destruction of embryos is too high a price to pay for this research, then we should be committed to stopping this “unethical” research outside Australia. We should also undertake never to use the products of this allegedly unethical research carried out in other countries. If it is wrong to do the research, it is wrong to 7

benefit from its products. That will mean forgoing treatments that may improve our lives radically. That, I suspect, is something few Australians would accept.

Conclusion Every day, people die because there are insufficient tissues available for transplantation. The development of cloning and ES cell line technologies offer real hope for developing new better sources of tissues for transplantation. We have a moral duty to engage in this research. The Nuffield Council on Bioethics’ Discussion Paper “Stem cell therapy: the ethical issues” 24 recommends amending UK legislation to allow research into ES cells on excess embryos produced from IVF (and leaves open the possibility of producing embryos specifically for research in the future) and research into therapeutic cloning. In Australia, around 1000 embryos from IVF are destroyed each year. Scientists cannot perform research on these embryos, even if the couple who produced them want that research to occur. Research should be allowed on excess embryos produced from IVF. I believe we should go further. Those states in Australia, such as Victoria, South Australia and Western Australian, which have legislation prohibiting therapeutic cloning and ES cell research should now review their legislation to allow this important research. The NHMRC should also adopt a facilitatory position on cloning and ES cell research. There are broader issues. Germ line gene therapy on embryos is not possible at present. It is currently proscribed by the NHMRC and illegal in some states. But it is only a matter of time before genetics progresses to the stage when genetic manipulation of the embryo to attempt to cure genetic disease and the genetic predisposition to disease is a reality. Will such research be possible? The answer depends on the approach we take to embryo experimentation in debate about cloning.

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