1. Medical Ethics Year 2 1 The Ethics of Genetics Lecture 1 January 20th 2010 Dr. Ruth Pilkington

2. 2Medical Ethics Year 2 Following the announcement of the mapping and sequencing of the first draft of the human genome in 2000, it was predicted that this would bring about ‘a new understanding of genetic contributions to human disease and the developments of rational strategies for minimizing or preventing disease phenotypes altogether...’ (Collins 1999)

3. 3Medical Ethics Year 2 Other factors come into play e.g. Penetrance (the % of people with the gene that develop the corresponding feature), low or no penetrance, ‘forme fruste’, may still pass on to next generation and cause a full disease phenotype (i.e. appears to ‘skip a generation’) Expressivity (the extent to which the gene is expressed in the person) Sex-limited (affected by hormones, e.g. male pattern baldness) Chromosomal inactivation (X chromosome) Genomic imprinting (one parental allele expressed only) Codominance (e.g. blood type) The belief that there is direct causal connection between genotype and disease phenotype was exaggerated

4. 4Medical Ethics Year 2 Monogenic Only a small number of diseases Polygenic Number of gene mutations, e.g. cancer Multifactorial Most diseases

5. 5Medical Ethics Year 2 Monogenic disorders Single gene mutation / Rarely complete penetrance Monogenic Autosomal dominant (e.g. Huntington’s Dx) Autosomal recessive (e.g Cystic fibrosis) X-linked (e.g Haemophilia, Duchenne’s Musc. Dystrophy)

6. 6Medical Ethics Year 2 Hence, there is ambiguity in the genetic component in most diseases. Having a mutation does not necessarily mean that one will develop the disease associated with it.

7. Medical Ethics Year 2 7 Genetic Testing & Screening

8. 8Medical Ethics Year 2 Genetic Testing / Screening Genetic testing –for individuals who are known to be at increased risk of having a genetic disorder with a familial mode of inheritance. Genetic screening –to test members of a particular population for a disorder for which there may be no family history or other evidence of its presence.

9. 9Medical Ethics Year 2 Genetic Testing / Screening 1 Purpose - To prevent harm to people who would develop genetic diseases during their lives, e.g. causing people to exist with these diseases can harm them by defeating their interest, once they exist, in living without pain, suffering, and limited opportunities, relief of anxiety, etc. Purpose - To prevent harm to people who would develop genetic diseases during their lives, e.g. causing people to exist with these diseases can harm them by defeating their interest, once they exist, in living without pain, suffering, and limited opportunities, relief of anxiety, etc.  Dangers – A predisposition to a disease is no guarantee that one will develop that disease (in the case of non- monogenic disease).  Dangers – Insurers or employers might discriminate against individuals on the basis of the genetic information. 1 Glannon, Biomedical Ethics, OUP

10. 10Medical Ethics Year 2 Considerations of Harm ‘New knowledge about the risk of genetic transmission of diseases and other harmful conditions will give individuals both the opportunities and the responsibility to choose whether to transmit such harms to their offspring or to risk doing so.’ 1 1 Buchanan, Brock, Daniels & Wikler, From chance to choice, Cambridge, p.204

11. 11Medical Ethics Year 2 Considerations of Harm For the individual : What actions and interventions are morally required to prevent harm? and What actions and interventions are morally permissible to prevent harm?

12. 12Medical Ethics Year 2 Considerations of Harm Is there a role for Society? Education... Is there a role for the law? Legal measures...

13. 13Medical Ethics Year 2 Huntington’s Disease Monogenic disease / Autosomal dominant Monogenic disease / Autosomal dominant 50% of offspring affected 50% of offspring affected Severe debilitating disease with onset usu. 30’s – 40’s. Irreversible motor and cognitive degeneration. Ultimately fatal. Severe debilitating disease with onset usu. 30’s – 40’s. Irreversible motor and cognitive degeneration. Ultimately fatal. Virtually 100% penetrance hence people with the Huntington's mutation are at very high risk of developing the disease and the consequent physical and psychological risk. Virtually 100% penetrance hence people with the Huntington's mutation are at very high risk of developing the disease and the consequent physical and psychological risk.

14. 14Medical Ethics Year 2 Huntington’s Disease Considerations of harm Unfortunately, by the time the symptoms appear, the affected individual has had children and so the gene and disease may already have passed on into the next generation Unfortunately, by the time the symptoms appear, the affected individual has had children and so the gene and disease may already have passed on into the next generation In spite of there being no treatment for the disease, there would be an obligation on an individual with a family history and early symptoms to test and so provide the information to children that they might make decisions and life choices based on this information while there is time. In spite of there being no treatment for the disease, there would be an obligation on an individual with a family history and early symptoms to test and so provide the information to children that they might make decisions and life choices based on this information while there is time. Thus testing for the prevention of harm, i.e. to allow the children make decisions about having children themselves and to allow prudential life choices to be made. Thus testing for the prevention of harm, i.e. to allow the children make decisions about having children themselves and to allow prudential life choices to be made. The point is to allow those at risk for the disease to make informed choices. The point is to allow those at risk for the disease to make informed choices. 1 Glannon, Biomedical Ethics, OUP

15. 15Medical Ethics Year 2 Familial Breast Cancer Considerations of harm BRCA1 and BRCA2 gene mutations BRCA1 and BRCA2 gene mutations Significantly high risk of breast (up to 85%) and ovarian (up to 60%) developing over a lifetime. Significantly high risk of breast (up to 85%) and ovarian (up to 60%) developing over a lifetime. Female and male offspring - 50% chance of inheriting Female and male offspring - 50% chance of inheriting A woman with a suggestive family history but without sisters or offspring – has no obligation to test except for prudential interests, e.g early mammography A woman with a suggestive family history but without sisters or offspring – has no obligation to test except for prudential interests, e.g early mammography A woman with breast cancer and a family or sisters – has on the other hand an obligation –to clarify the risk to her family A woman with breast cancer and a family or sisters – has on the other hand an obligation –to clarify the risk to her family However that obligation not as strong as the one in the case of Huntington's disease, because 50-85% vs. 100% However that obligation not as strong as the one in the case of Huntington's disease, because 50-85% vs. 100% 1 Glannon, Biomedical Ethics, OUP

16. Medical Ethics Year 2 16 Genetic Screening

17. 17Medical Ethics Year 2 Tay-Sachs Recessive disorder, hence parental carriage Recessive disorder, hence parental carriage c.f. Ashkenazi Jewish population Children born normal but develop degenerative neurological disease culminating in death by age 3 or 4 Children born normal but develop degenerative neurological disease culminating in death by age 3 or 4 Pre-conceptive genetic screening of an at risk population Pre-conceptive genetic screening of an at risk population Screening couples intending to conceive Screening couples intending to conceive 1 Glannon, Biomedical Ethics, OUP

18. 18Medical Ethics Year 2 Tay-Sachs Decrease in incidence since screening of Orthodox Jewish community since 1970s Decrease in incidence since screening of Orthodox Jewish community since 1970s Reduction due to carriers avoiding marriage, carrier couples undergoing prenatal testing and terminating affected foetuses or embryos, the use of donor gametes, and adoption Reduction due to carriers avoiding marriage, carrier couples undergoing prenatal testing and terminating affected foetuses or embryos, the use of donor gametes, and adoption Adolescent screening particularly. Prudential and moral implications – allows ample time to plan future in accord with their values. Enables them to prevent harm to children who would be born with Tay-Sachs. Adolescent screening particularly. Prudential and moral implications – allows ample time to plan future in accord with their values. Enables them to prevent harm to children who would be born with Tay-Sachs. 1 Glannon, Biomedical Ethics, OUP

19. 19Medical Ethics Year 2 Phenyketonuria (PKU) The most compelling case for genetic screening is for disorders that can be treated through non-genetic means, e.g. PKU The most compelling case for genetic screening is for disorders that can be treated through non-genetic means, e.g. PKU PKU recessive disorder, the body fails to metabolise the amino acid phenylalanine. Can lead to severe mental retardation in affected children. PKU recessive disorder, the body fails to metabolise the amino acid phenylalanine. Can lead to severe mental retardation in affected children. Special diet limiting the intake of phenylalanine avoids the condition hence neonatal screening. So prevents harm. Special diet limiting the intake of phenylalanine avoids the condition hence neonatal screening. So prevents harm. 1 Glannon, Biomedical Ethics, OUP

20. Medical Ethics Year 2 20 Genetic Testing

21. 21Medical Ethics Year 2 Genetic testing Of Note – Genetic testing differs from most other medical testing on a patient in that results may provide significant medical information not only for the patient but also for their genetically related relatives. Who owns this information?

22. 22Medical Ethics Year 2 Genetic testing Cases

23. 23Medical Ethics Year 2 Case 1 1 A couple, Anna and Colm attend a genetics clinic. Their newborn baby has been diagnosed with a severe & disabling autosomal recessive condition (it is likely that the child will die in the first year). Prenatal diagnosis may be possible in a future pregnancy. Autosomal Recessive condition, hence there is a 25% chance that a subsequent child could be affected. The carrier frequency of the recessive gene is 1 in 1000. 1 Adapted from Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

24. 24Medical Ethics Year 2 Case 1 1 Molecular analysis of blood samples shows that Colm is not the biological father. ? Should the geneticist disclose the finding of non- paternity to the parents? Should the geneticist disclose the finding of non- paternity to the parents? They did not seek information on paternity, however, it is of direct relevance to their understanding of the probability of an affected child in future pregnancies. 1 Adapted from Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

25. 25Medical Ethics Year 2 Case 1 1 ‘Options’ White lie’ to Colm and Truth to Anna (anecdotal evidence) 1 Adapted from Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

26. 26Medical Ethics Year 2 Case 1 1 Respect for Colm’s interests requires the truth. Doctors should not lie to their patients 1 Adapted from Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

27. 27Medical Ethics Year 2 Case 2 1 A woman whose mother has Huntington’s disease tests positive for the gene mutation, although she is not, as yet, symptomatic herself. During post test counselling, she reveals that she donated eggs to a private fertility clinic 6 months previously. She refuses permission for the counsellor to contact the clinic because she is afraid she will get into trouble. 1 Adapted from Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

28. 28Medical Ethics Year 2 Case 2 1 ? Should the doctor breach the patient’s confidentiality here. 1 Adapted from Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

29. 29Medical Ethics Year 2 Case 2 1 Professional guidelines do not suggest that doctors should break confidentiality because a patient may have broken the law; However here a child may be born with a very serious genetic condition. 1 Adapted from Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

30. 30Medical Ethics Year 2 Case 3 1 Ciara has a child (4 ) just diagnosed with Duchenne’s Muscular Dystrophy (DMD), a severe, progressive muscle-wasting disease assoc. with a life expectancy of 20-30 years. Ciara is a carrier of this X-linked condition, hence risk of 50% of male children will be affected. Niamh, Ciara’s sister is 10 weeks pregnant. She doesn’t know of her nephew’s diagnosis or the risk to her own child. Ciara has told her geneticist that she does not want the information given to her sister, as she fears she will terminate her pregnancy, which Ciara believes to be wrong. 1 Adapted, Parker & Lucassen (1994), as quoted in Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

31. 31Medical Ethics Year 2 Case 3 1 Should the geneticist respect Ciara's wishes and keep the genetic testing confidential? or Should the information from Ciara be used to test Niamh and her foetus and provide Niamh with the information she may require to make informed reproductive choices? 1 Adapted, Parker & Lucassen (1994), as quoted in Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

32. 32Medical Ethics Year 2 Case 3 1 Personal Account Model Consider if harm to Niamh and her foetus is sufficiently severe to justify a breach of confidentiality- 1. Would termination of the pregnancy be a greater harm. 2. Would the harm of having DMD and not preventing it be worse. 3. Existing with DMD vs. not existing at all Adapted, Parker & Lucassen (1994), as quoted in Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

33. 33Medical Ethics Year 2 Case 3 1 Joint Account / Property Model Analogous to asking a bank manger not to reveal information about a joint account to fellow account holders. Genetic information belongs not just to one person, but to families. The presumption then is that genetic information is to be shared with family members, unless there is very good reason to exclude them from knowing. 1 Parker & Lucassen (1994), as quoted in Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

34. Medical Ethics Year 2 34 Genetic Testing of Children

35. 35Medical Ethics Year 2 Genetic testing and Children For Beneficial in making lifestyle or career choices Beneficial in making lifestyle or career choices Self-knowledge promotes autonomous decision making Self-knowledge promotes autonomous decision making Testing resolves uncertainty, thus reducing anxiety Testing resolves uncertainty, thus reducing anxiety Testing respects parental autonomy Testing respects parental autonomy Participation of child promotes development of autonomy Participation of child promotes development of autonomy Early testing promotes better psychological adjustment than later testing. Early testing promotes better psychological adjustment than later testing. Hope, Savulescu, Hendrik, Medical Ethics and Law (2008) Adapted from Savulescu (2001), as quoted in Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

36. 36Medical Ethics Year 2 Genetic testing and Children Against Fails to respect the child’s later autonomy to decide whether to have testing or not, and violates the future adult's ‘right not to know.’ Fails to respect the child’s later autonomy to decide whether to have testing or not, and violates the future adult's ‘right not to know.’ Breaches child’s confidentialty, as parents will know the result. Breaches child’s confidentialty, as parents will know the result. Testing may disturb family dynamics and thus harm child and involve stigma, discrimination, development of low self esteem, depression and anxiety. Testing may disturb family dynamics and thus harm child and involve stigma, discrimination, development of low self esteem, depression and anxiety. Parents may develop a sense of guilt. Parents may develop a sense of guilt. Hope, Savulescu, Hendrik, Medical Ethics and Law (2008) Adapted from Savulescu (2001), as quoted in Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

37. 37Medical Ethics Year 2 Genetic testing and Children Most strongly advise against testing children for a disease in which surveillance, or pre-emptive or definitive medical treatment, is not available in childhood. Inc. UK Clinical Genetics Soc.(1994), Am. Soc. For Human Genetics (1995), Human Genetics Soc. Of Australia (2005)

38. 38Medical Ethics Year 2 Incompetent Adults Testing may amount to battery in law.

39. Medical Ethics Year 2 39 Genetic Counselling

40. 40Medical Ethics Year 2 Genetic Counselling ‘The process by which patients and their relatives at risk of a disorder that may be hereditary are advised of the consequences of the disorder, the probability of developing and transmitting it and of the way in which this may be prevented or ameliorated.’ 1 1 Harper (1988), as quoted in Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

41. 41Medical Ethics Year 2 Non-directive Counselling is the ideal In response to the coercive practices of eugenics in the early 20 th century. To distance clinical genetics from those eugenic practices. Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

42. 42Medical Ethics Year 2 Non-directive Counselling Arguments for Reduces risk of coercion Reduces risk of coercion Patient is best placed to make decisions about genetic testing Patient is best placed to make decisions about genetic testing Patient’s values (not the counsellor’s) are most important Patient’s values (not the counsellor’s) are most important Promotes active autonomous decision-making. Promotes active autonomous decision-making. Hope, Savulescu, Hendrik, Medical Ethics and Law (2008) Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

43. 43Medical Ethics Year 2 Non-directive Counselling Arguments against Not possible, because there will always be an inherent bias in presenting the information. Not possible, because there will always be an inherent bias in presenting the information. Patients may want and need advice and direction Patients may want and need advice and direction Denies patients moral dialogue about their choices Denies patients moral dialogue about their choices Allows ‘wrong’ decision making without discussion Allows ‘wrong’ decision making without discussion No place left for persuasion No place left for persuasion Inconsistent with other areas of clinical practice where advice is given. Inconsistent with other areas of clinical practice where advice is given. Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

44. 44Medical Ethics Year 2 Non-directive Counselling However is the non-directive approach always the correct one?

45. 45Medical Ethics Year 2 Non-directive Counselling Séan’s Case 1 Séan’s father died from bowel cancer at a young age. He had a diagnosis of familial adenomatous polyposis coli, a disease which involves the development of multiple bowel polyps. These lesions have a high risk over a lifetime of becoming cancerous. Surveillance colonoscopy and polyp removal is the treatment of choice. A prophylactic colectomy may be indicated. 1 Adapted from Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

46. 46Medical Ethics Year 2 Non-directive Counselling Séan’s Case 1 Séan’s genetic counsellor explains these disease facts to him and that there is a 50% chance of his having inherited the gene for the disease. However Séan decides that he will neither have a genetic test nor a colonoscopy. The counsellor finishes by ensuring that Séan has understood the key facts. Two years later Séan develops bowel cancer and dies. 1 Adapted from Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

47. Medical Ethics Year 2 47 Genetic Information & The Law

48. 48Medical Ethics Year 2 Clinical Practice Pre-existing common law applies, as does legislation regarding consent and confidentiality regarding the use and disclosure of medical information, unless specific legislation has been put in place. International Instruments, e.g. Universal Declaration on the Human Genome and Human Rights (UNESCO, 1997), Convention for the Protection of human rights and dignity of the Human Being with regard to the application of Biology and Medicine (Council of Europe, 1997), Human Tissue Act, 2004 (UK)– non-consensual analysis of human DNA is an offence.

49. 49Medical Ethics Year 2 The Law and Genetic Information The traditional confidentiality approach – is medical confidentiality absolute? The traditional confidentiality approach – is medical confidentiality absolute? A human rights approach c.f. Article 8(2) of Human Rights Act would justify breaching confidentialty??? A human rights approach c.f. Article 8(2) of Human Rights Act would justify breaching confidentialty??? A property approach e.g. Data Protection Act, FOI A property approach e.g. Data Protection Act, FOI GMC standard - a breach of confidentiality is justified only ‘ where failure to do so may expose the patient or others to risk of death or serious harm’ GMC standard - a breach of confidentiality is justified only ‘ where failure to do so may expose the patient or others to risk of death or serious harm’ Where possible gain the patient’s consent to inform relatives. Where possible gain the patient’s consent to inform relatives. Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

50. 50Medical Ethics Year 2 Clinical Practice 1. Consent 2. Confidentiality 3. Communication Uncertainty of much of information / Realistic expectations / Avoidance of exaggeration of genetic risk

51. 51Medical Ethics Year 2 Genetic Information Non Discrimination Act (GINA) 2008 The Genetic Information Non-discrimination Act of 2008 (GINA) A law in the US designed to prohibit the improper use of genetic information in health insurance and employment. It prohibits group health plans and health insurers from denying coverage to a healthy individual or charging that person higher premiums based solely on a genetic predisposition to developing a disease in the future. The legislation also bars employers from using individuals’ genetic information when making hiring, firing, job placement, or promotion decisions. A law in the US designed to prohibit the improper use of genetic information in health insurance and employment. It prohibits group health plans and health insurers from denying coverage to a healthy individual or charging that person higher premiums based solely on a genetic predisposition to developing a disease in the future. The legislation also bars employers from using individuals’ genetic information when making hiring, firing, job placement, or promotion decisions. ? The "first major new civil rights bill of the new century" (Senator Ted Kennedy) ? The "first major new civil rights bill of the new century" (Senator Ted Kennedy)

52. Medical Ethics Year 2 52 Eugenics

53. 53Medical Ethics Year 2 ‘ Eugenics casts a long shadow over contemporary genetics.’ 1 1 Wikler (1999)

54. 54Medical Ethics Year 2 Eugenics Francis Galton, cousin of Darwin coined the term and launched the movement, based on selective breeding and applying the theories of natural selection to the human population. Francis Galton, cousin of Darwin coined the term and launched the movement, based on selective breeding and applying the theories of natural selection to the human population. Eugenics [Greek] ‘Good Creation’ Eugenics [Greek] ‘Good Creation’ ‘The use of science to improve the human genome’ ‘The use of science to improve the human genome’ Extremely popular among scientists, doctors, leaders of society (1880s – 1945). Extremely popular among scientists, doctors, leaders of society (1880s – 1945).

55. 55Medical Ethics Year 2 Eugenics Galton believed that the talented and favoured of society should be encouraged to have many children (positive eugenics) and those with ‘less to offer’ should be discouraged from reproducing (negative eugenics). Strong eugenics movements in many countries, inc. US, Canada, UK, Germany. Galton believed that the talented and favoured of society should be encouraged to have many children (positive eugenics) and those with ‘less to offer’ should be discouraged from reproducing (negative eugenics). Strong eugenics movements in many countries, inc. US, Canada, UK, Germany. Adopted by the Nazis, imposed sterilisation and mass murder; fell into disrepute from 1945. Adopted by the Nazis, imposed sterilisation and mass murder; fell into disrepute from 1945.

56. 56Medical Ethics Year 2 Eugenics Now an offensive concept, but ‘is clinical genetics simply eugenics under a different name?’ 1 Positive and Negative eugenics are distinct practices motivated by distinct aims. 1 Wikler, JME 1999

57. 57Medical Ethics Year 2 Negative Eugenics 1 ? Forms of negative eugenics - genetic testing and screening, PIGD, gene therapy Thus the aim of negative eugenics is to prevent or limit / control disease 1 Glannon, Biomedical Ethics, OUP

58. 58Medical Ethics Year 2 Positive Eugenics 1 An example of positive eugenics might be genetic enhancement i.e. improving normal traits and capacities 1 Glannon, Biomedical Ethics, OUP

59. 59Medical Ethics Year 2 Eugenics 1 ‘If there is a decisive reason and thus an obligation to prevent or control diseases, then we are obligated to practice negative eugenics.’ ‘If there is no decisive reason and thus no obligation to improve normal capacities, then there is no obligation to practice positive eugenics.’ Indeed should positive eugenics be prohibited? 1 Glannon, Biomedical Ethics, OUP

60. Medical Ethics Year 2 60 Gene Therapy

61. 61Medical Ethics Year 2 Gene Therapy Gene therapy is in its infancy. Options – germline and somatic.

62. 62Medical Ethics Year 2 Gene Therapy Somatic Uses genetic methods to treat disease in an individual. Thus the treatment only affects the targeted individual. Uses genetic methods to treat disease in an individual. Thus the treatment only affects the targeted individual. Aims to cure disease in the same way as other disease treatment. Aims to cure disease in the same way as other disease treatment. Risks as with all new therapies. Risks as with all new therapies. However ?future potential of enhancement of human characteristics. However ?future potential of enhancement of human characteristics.

63. 63Medical Ethics Year 2 Gene Therapy Germline The therapeutic intervention affects the targeted individual, but also future generations by genetic changes to the germline cells. Thus risks such as cancer inducing genes, etc. may affect future generations,...

64. Medical Ethics Year 2 64 Cloning

65. 65Medical Ethics Year 2 Cloning Therapeutic To harvest ES cells for therapy Reproductive To produce a new human being Controversy as to whether therapeutic cloning should be allowed / However most agree reproductive cloning should be prohibited

66. 66Medical Ethics Year 2 Cloning A cloned cell has a genome that is a near-identical copy of the genome of its parent or ‘progenitor’ cell. A cloned cell has a genome that is a near-identical copy of the genome of its parent or ‘progenitor’ cell. The 5 day old embryo is called a blastocyst and embryonic stem (ES) cells can be derived from this and grown on in culture to produce ES cell lines. These cells are totipotent and have the ability to regenerate tissue. Hence the potential to cure or alleviate diseases such as Parkinson’s, diabetes, heart disease, etc. The 5 day old embryo is called a blastocyst and embryonic stem (ES) cells can be derived from this and grown on in culture to produce ES cell lines. These cells are totipotent and have the ability to regenerate tissue. Hence the potential to cure or alleviate diseases such as Parkinson’s, diabetes, heart disease, etc. 2 methods of genome cloning – Fission vs. Fusion 2 methods of genome cloning – Fission vs. Fusion

67. 67Medical Ethics Year 2 Therapeutic Cloning Research in this area remains one of the most dynamic in genetics with massive potential both scientific and commercial. 2004 fraudulent claim by Korean scientist, Woo Suk Hwang that his team had successfully cloned a human embryo and derived a ES cell line from it.

68. 68Medical Ethics Year 2 Cloning Cloning by fission Blastocyst division Twinning is induced in the blastocyst by the application of heat or mechanical stress. Splits in two, and the two halves continue to grow into complete embryos. Max. two identical embryos.

69. 69Medical Ethics Year 2 Cloning Cloning by fission Blastomere separation The coating of an early embryo (blastocyst) is removed and the cells (blastomeres) are placed in a solution that separates them. Each of these blastomeres is undifferentiated and can grow into an embryo. This technique can produce eight embryos at most, but can be repeated on each new embryo to produce a larger number.

70. 70Medical Ethics Year 2 Cloning Cloning by fusion (SCNT) Fusion is achieved through the process of somatic cell nuclear transfer (SCNT). The nucleus is removed from a somatic cell and implanted into the cytoplasm of a denucleated egg. The egg reprograms the somatic cell’s DNA to a totipotent state, so that a complete embryo can be grown out of this cell. A theoretically endless number of clones can be created from the same individual in this way. SCNT is the only method currently available that might be used to clone existing or pre-existing people. Enucleated Egg Somatic cell

71. 71Medical Ethics Year 2 Therapeutic Cloning Centres on the concept of stem cells. Stem cells have the ability to develop into different mature cell types. Totipotent stem cells have the potential to form a complete animal if placed in a uterus. They are early embryos. Pluripotent stem cells are immature with the potential to develop into any of the mature cell types in the adult but cannot form a complete animal if placed in a uterus. This is regenerative medicine – ‘The holy grail’ of medicine.

72. 72Medical Ethics Year 2 Therapeutic Cloning Hopes for 1. There is a shortage of tissue for transplantation 2. There are problems with the compatibility of tissue transplanted from one individual to another, requiring immunosuppressive drugs with severe side-effects. Whereas cloned tissue from an individual would be compatible. 3. The role of transplantation might be expanded to include heart attack and CVA 4. Cloning may prove cost-effective means of preventing disability and morbidity, and of promoting distributive justice. 5. Research into disease and drug testing using ESC lines in the lab. 6. Reduced need for animal experimentation.

73. 73Medical Ethics Year 2 Cloning by (SCNT) Possible future therapeutic application Enucleated Human or Animal Egg Skin cell from leukemic patient e.g. Leukaemia Derive ESC line Blood stem cells transferred post chemotx

74. 74Medical Ethics Year 2 Objections to Therapeutic Cloning 1 Objections to therapeutic cloning concern the morality of creating a human embryo with the intention of destroying it to harvest ES cells for research into future therapies. This it is argued that it amounts to destroying potential human life. In so far as the potential of an embryo to become a human being gives it the right to life, therapeutic cloning violates this life and thus should be prohibited. Does the embryo have the same moral status as a human being? 1 Glannon, Biomedical Ethics, OUP

75. 75Medical Ethics Year 2 Objections to Therapeutic Cloning 1 If an embryo has the same moral status as a person, then embryo research, in vitro fertilisation (IVF) and any termination of pregnancy is wrong. In natural conception, for every new life, 5 embryos die (Harris, 2000). We implicitly accept this is a price worth paying in naturally conceiving a child, then is it not a price worth paying to save an existing life. 1 Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

76. 76Medical Ethics Year 2 Objections to Therapeutic Cloning 1 A further objection to therapeutic cloning is the concern that in creating human embryos to destroy them represents a violation of the sanctity of life from conception and thus should be prohibited. The fact that therapeutic cloning blocks the embryo’s potential to become an actual person, thus their right to life is removed and so should be prohibited, even if therapeutic cloning would benefit those existing people, already alive, suffering from degenerative diseases, who would benefit from future ESC therapies. 1 Glannon, Biomedical Ethics, OUP

77. 77Medical Ethics Year 2 Objections to Therapeutic Cloning SCNT requires a supply of fresh human eggs (unless animal human hybrid research, using e.g. rabbit eggs, becomes acceptable). These must be provided by donation from women, who need to undergo arduous and sometimes painful ovarian stimulation and egg retrieval. Risk of OHSS. Egg donors may have restricted autonomy, perhaps due to poor economic circumstances, etc. As a new technology, will this be available only for the rich, while the egg supply may be provided by those less well off, perhaps in developing countries.

78. 78Medical Ethics Year 2 Support for Therapeutic Cloning 1 Others argue that an embryo is merely a clump of not integrated cells and cannot have interests and rights. Thus if an embryo cannot have interests or rights, it cannot be harmed or wronged by not becoming a person. Thus objections to therapeutic cloning rest on the absolute claim that embryos have a right to life which outweighs any potential benefit to existing people. But while embryos cannot suffer from or be harmed by not realizing their potential, existing people can suffer from and be harmed by disease. These existing people could benefit from treatments resulting from therapeutic cloning research. Embryos cannot be harmed or wronged by being created for this research. 1 Glannon, Biomedical Ethics, OUP

79. 79Medical Ethics Year 2 Support for Therapeutic Cloning 1 Sanctity of life If it is argued that embryos embody sanctity of life, then existing people also do. So it may be agreed that embryos and people have equal moral status. Yet in terms of suffering, embryos cannot suffer whereas existing people can suffer. The combination of sanctity and suffering vs. sanctity seems to carry more moral weight. If the suffering of existing people is morally worse than the creation and destruction of embryos then it follows, we should be more concerned about this. If embryos cannot be harmed, then therapeutic cloning should be permitted, i.e. we should do more for the needs of existing people than for the putative needs of merely potential people (embryos). 1 Glannon, Biomedical Ethics, OUP

80. 80Medical Ethics Year 2 Other options? Adult stem cells avoid this issue, but research has shown them not be ‘as plastic’ as ES cells, in terms of potential to generate as many cells types. In addition they are likely to be more immunogenic than ESC.

81. 81Medical Ethics Year 2 Other options? Human-animal hybrids Cloning by SCNT An enucleated animal rather than human egg is used and the human somatic cell nuclear material is inserted into it, thus creating a hybrid. Animal (e.g. Rabbit) Enucleated Egg Human Somatic cell

82. 82Medical Ethics Year 2 Other Options? Human-Animal Hybrid / Chimera Technology Ethically these may be seen as unnatural and crossing a moral line, but with close regulation and destruction of the embryos following use, and an understanding that this is the creation of new biological tissue rather than new species would this be morally more acceptable? Risk of harm in future – Possibility of introducing new infections (zoonoses) into the human population.

83. 83Medical Ethics Year 2 The Slippery Slope Some would argue that while therapeutic cloning might be morally permissible, it should be prohibited as it could lead down the slippery slope to reproductive cloning, which would not be morally permissible. ‘? Throwing the baby out with the bath water’

84. 84Medical Ethics Year 2 Reproductive Cloning The production, by cloning, of an identical or near identical genetic copy of an existing person or a person who previously existed. [Agricultural industry - e.g. cattle have been cloned in this way using both fission and fusion.] The Human Reproductive Cloning Act (2001) UK - states that, ‘A person who places in a woman a human embryo which has been created otherwise than by fertilisation is guilty of an offence.’ Also an offence in many other countries and a number of international declarations forbid it.

85. 85Medical Ethics Year 2 Cloning Cloning by fission Blastocyst division Twinning is induced in the blastocyst by the application of heat or mechanical stress. Splits in two, and the two halves continue to grow into complete embryos. Max. 2 identical embryos.

86. 86Medical Ethics Year 2 Cloning Cloning by fission Blastomere separation The coating of an early embryo (blastocyst) is removed and the cells (blastomeres) are placed in a solution that separates them. Each of these blastomeres is undifferentiated and can grow into an embryo. This technique can produce 8 embryos at most, but can be repeated on each new embryo to produce a larger number.

87. 87Medical Ethics Year 2 Cloning Cloning by fusion (SCNT) Fusion is achieved through the process of somatic cell nuclear transfer (SCNT). The nucleus is removed from a somatic cell and implanted into the cytoplasm of a denucleated egg. The egg reprograms the somatic cell’s DNA to a totipotent state, so that a complete embryo can be grown out of this cell. A theoretically endless number of clones can be created from the same individual in this way. SCNT is the only method currently available that might be used to clone existing or pre-existing people. Enucleated Egg Somatic cell

88. 88Medical Ethics Year 2 Arguments made in favour of reproductive cloning 1 Reproductive cloning LibertyMedical reasons Freedom of scientific inquiry To achieve a sense of immortality Eugenic selection Treatment of infertility Replacement of a dead relative ‘Clonism’ – a new form of discrimination Clones are not the same person 1 Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

89. 89Medical Ethics Year 2 Arguments made against reproductive cloning 1 Reproductive cloning An affront to Human Dignity (But are twins an affront to human dignity?) Liable to abuse, e.g. evil dictator cloning armies or copies of self Instrumentalisation of human beings Clones will live in the shadow of the original person Allows eugenic selection But many current technologies could also be used for eugenics, e.g. PIGD Cloning would reduce genetic variation Right to genetic individuality Safety 1 Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

90. 90Medical Ethics Year 2 Reproductive Cloning Concerns about cloning violating human dignity are misguided because they concentrate too much on the biology of our entry into the world. We have human dignity because we are persons with autonomous desires, beliefs, and intentions that are not entirely functions of our biology. 1 Glannon, Biomedical Ethics, OUP

91. 91Medical Ethics Year 2 Reproductive Cloning 1 Safety Probably the strongest reason for banning it is that it would result in harm to the cloned child. c.f. ‘Dolly’ the sheep (b. 1996) aged at a faster rate than normal and needed to be euthanized. Thus risk of premature aging and disease (through mutations?). So perhaps the only valid reason to ban reproductive cloning is that it could result in physical harm to individuals who might be cloned. Hope, Savulescu, Hendrik, Medical Ethics and Law (2008) 1 Glannon, Biomedical Ethics, OUP, Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)

92. 92Medical Ethics Year 2 Reproductive Cloning 1 Cloning is in its infancy. If however, reproductive cloning and other forms of artificial reproduction were to become, in time, safer and more efficient than natural reproduction, would we have a moral duty to promote these over natural methods of reproduction? Hope, Savulescu, Hendrik, Medical Ethics and Law (2008) 1 Hope, Savulescu, Hendrik, Medical Ethics and Law (2008)