Human Genome Research Project --- "Choosing genes for future children: the regulatory implications of preimplantation genetic diagnosis" [2006] NZLFRRp 1

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R E G U L AT I N G P R E I M P L A N TAT I O N G E N E T I C D I AG N O S I S

Choosing genes for future children: the regulatory implications of preimplantation genetic diagnosis/Human Genome Research Project. Dunedin, N.Z.: Human Genome Research Project, 2006.

Early in my tenure as President of the Law Commission, Lynda Hagen and then Trustees of the New Zealand Law Foundation called to discuss the possibility of a major project centred on the Human Genome Research and its core unifying factor for all humanity. Their object was awesome. Their determination was inspirational. The credentials of those they proposed to involve were impressive. Although firmly based in New Zealand and engaging locally, the concept envisaged international as well as interdisciplinary collaboration.

Because of the size and scope of the exercise, the Trustees responsibly first undertook a thorough and comprehensive assessment of the idea following which the commitment to the three-year project was made.

The concept at its inception was, and always will be, visionary. It deals with issues which are evolving and emerging by the day. Its concern is not merely with the advances made by science, but the implications, at all levels and in all aspects of human endeavour, of those changes.

I have been fortunate to be one of those invited to be part of an ongoing Advisory Review Committee. From time to time, we receive reports on what is being achieved, offer suggestions from the experience of our varied backgrounds and are available as a general sounding board.

As was the case with the original brief, the Review Committee has remained committed to the demand that this project must add value to what is being done elsewhere around the world but remain reflective of the particular environment within this country.

Although it is early days, we are persuaded that the confidence which the Law Foundation placed in the principal investigator, Professor Mark Henaghan, and the extraordinarily impressive team that he has built up around him, has been well placed. We have seen the difficulties of embarking on a task which breaks new ground, the frustrations of finding that extensive work which has been undertaken is being replicated elsewhere and the demand of ensuring that anything produced must stand up to rigorous peer analysis but at the same time be capable of being understood and evaluated by any informed reader.

I am reminded of the words by Thomas Jefferson which appear across the gate of the University of Virginia “For here we are not afraid to follow truth wherever it may lead.” It is in that spirit that this professional, responsible and sensitive inquiry is being undertaken. There are no hidden agendas. There are no preconceptions. There are issues which impinge upon everyone of us within the community that demand serious and thoughtful consideration.

New Zealand cannot divorce itself from global advances. Barriers of time and space are history. As a society we must understand what is being achieved abroad and be prepared for its implications for good and ill within our own country.

This project is an important vehicle to extend our knowledge and understanding and to help prepare us for whatever the future will demand. There are seldom right or wrong responses in any absolute sense. Judgment will need to be made, balance achieved and mutual respect fostered. The work of our researchers can assist significantly in providing the data and possibilities for responsible and responsive decisions to be taken.

This three-year research project is groundbreaking for New Zealand and it has the potential to touch the lives of every New Zealander. The New Zealand Law Foundation is delighted to have been the catalyst for such important research and to see the publication of the first report from the project.

At the start of the new millennium, the Law Foundation took the initiative to explore significant areas where it appeared that the development of the law may well be lagging behind developments in technological advancement.

After extensive analysis, the Law Foundation identified an urgent need to research the law relating to biotechnology and more particularly reproductive technologies.

Scientific advances around the world had resulted in rapid progress in gene technologies. New and fundamental questions were being raised about the essence of life, humans and human nature. The ability to alter the building blocks of life was being acquired and developed in an environment of uncertainty in relation to ethics and law. The Law Foundation recognised that while the science supporting biotechnology was well developed, the pace of change often rendered current law and regulation inapplicable or irrelevant and denied communities the opportunity to debate and research the consequences of that science.

The Law Foundation saw the opportunity to assist the nation to navigate through this potential minefield by commissioning this independent, international study – The Human Genome Research Project, Te Kaupapa Rangahau Ira Tängata: Law, Ethics and Policy for the Future.

This research is an important step towards ensuring the law in New Zealand is well positioned to meet the legal and ethical challenges arising from gene biotechnology. It is crucial that the debate is well informed. The Human Genome Research Project will assist that process.

These challenges are international and the Law Foundation is convinced that a global, inter-disciplinary approach is required. While the project will determine the effect of rapid advancement in gene technologies on New Zealand law, the debate must be wider to include scientific, medical, ethical, cultural, economic and philosophical perspectives.

The Law Foundation chose the Otago Law Faculty under the leadership of Professor Mark Henaghan to head this research in New Zealand, and linked it with recognised national and international leaders in these fields to enhance the focus and add the expertise necessary for a project of this kind. While the focus is New Zealand, the findings will have relevance to other legal systems.

An important aspect of the project is that it is independent. This will no doubt add weight to the findings and recommendations.

Finally, it is important to acknowledge the efforts of two Law Foundation personnel. The first is past Chair Gray Cameron for his leadership at the inception of this project.

The second is Executive Director Lynda Hagen. Lynda’s vision identified New Zealand’s need for this project. Her determination ensured the Foundation Board also understood this need. Her dedication to this project has been outstanding and the Board is truly grateful to Lynda for her exceptional efforts in ensuring this project reached fruition.

“[T]he human genome underlies the fundamental unity of all members of the human family, as well as the recognition of their inherent dignity and diversity. In a symbolic sense, it is the heritage of humanity.”

The New Zealand Law Foundation Trustees and their Executive Director, Lynda Hagen, had the vision that the emergence of genetic technologies in medicine would pose new challenges for current and future regulatory frameworks, and that thoughtful, strategic and balanced scholarly work by a team of scholars would help inform policy and the law for New Zealand both now and into the future.

That vision led to the creation of the Human Genome Research Project, Te Kaupapa Rangahau Ira Tängata: Law Ethics and Policy for the Future, based at the University of Otago and sponsored by the New Zealand Law Foundation.

The goal is to discuss options for legal, ethical and regulatory policy that will be adopted not only in New Zealand but internationally. Policy development and law reform need to address new knowledge and the implications resulting from advances in genetic technology that can be complex and made more challenging by a number of factors, for example: the speed of discoveries in new understandings and applications; the plurality of opinions, attitudes and perceptions; the importance for scientists and clinicians to conduct research and undertake innovations; market pressures and consumer demands coupled with an increasing degree of global connectedness; and evolving social expectations and norms.

To encourage wide-ranging analysis and reflection as much as possible, the Project has been designed to be interdisciplinary and international. In comparison with international initiatives in this area, this project is unique in having such a full array of perspectives – all focusing on the same issues at the same time.

The Principal Investigator of the Project is Professor Mark Henaghan, Dean of the Law Faculty at the University of Otago.

Richman Wee, formerly of the Health Research Council of New Zealand, manages the Project.

The Project has an Advisory Review Committee (ARC) which is coordinated by Dr Bruce Scoggins, CEO of the Health Research Council of New Zealand. ARC members comprise:

The Project has contact with the Ministry of Health, the Advisory Committee for Assisted Reproductive Technology (ACART) and the Ethics Committee for Assisted Reproductive Technology (ECART) set up under the Human Assisted Reproductive Technology Act 2004, the National Screening Unit, and the Bioethics Council.

The direction of the Project emerged from a three-month scoping exercise that was undertaken in the summer of 2003: The Regulatory Implications of the Human Genome Project for New Zealand, Phase 1, involving Professor Mark Henaghan, Professor Donald Evans, Dr Tony Merriman, Dr Ian Morison, Bevan Tipene-Matua, James Dann, Katie Elkin, Claire Gallop, Matthew Gillett, Mereana White, and discussions with ARC.

In 2004, Dana Wensley was funded by the New Zealand Law Foundation and prepared a report on the Acceptable Limits of Reproductive Genetics: A Discussion of Ethical Principles and Regulatory Mechanisms of Control (July 2004). The aim of the report was to identify commonly held ethical principles and legal mechanisms for control that have been developed in other jurisdictions. Dana Wensley’s report showed the dichotomy between the fundamental right of reproductive freedom and society’s interest in ensuring that technology is not used in a manner that is unacceptable or which may cause harm to society in general is not as simple as it seems. Our views about how far the right to reproductive autonomy extends are coloured by our views of how private uses of genetic technology affect society in general. The report touched on a few of the wider implications of genetic decision-making, such as the effect on the family, the parent-child relationship and the community of people with disabilities. That report was written just before New Zealand passed the Human Assisted Reproductive Technology Act 2004 (the HART Act).

In 2005, Kirsty Dobbs, a summer research scholar on the Project, produced a background paper on comparative legal approaches for preimplantation genetic diagnosis.

This first major report from the Project, after six months of a fully assembled team of researchers working together, critiques and communicates a wide range of issues and concerns about PGD from a variety of perspectives. This report will be built on in other reports that will follow as a result of ongoing work arising from the Project. In the spirit of open inquiry and thinking we will, if necessary, revise and adjust the findings of this report in subsequent reports in the light of further reflection, insight and research.

Preimplantation genetic diagnosis (PGD) is publicly funded in New Zealand from 2006. PGD poses a range of issues that have ongoing significance for other later emerging applications of genetic technologies arising from the sequencing of the human genome. The idea of the ‘designer baby’ is the most publicly proclaimed outcome of new developments in genetic medicine.

Professor Gareth Jones cites the following as examples of how the public imaginations and fears are fed.1 The first is from a hoax website:

Thank you for considering GenoChoice to plan the future well-being of you and your family. My name is Dr Elizabeth Preatner, a prenatal geneticist and embryologist here at GenoChoice. Using our state-of-the-art technologies, you can quite possibly ensure that your child’s life may be free of such diseases as cancer, Alzheimer’s, and heart disease – as well as conditions like obesity, aggression, and dyslexia. And you can even specifically choose genes that may determine favorable characteristics in your child”.2

“We are at a turning point in history. For millenniums our technologies ... have been aimed at modifying our environment. Now, for the first time, our technologies are increasingly aimed inward – at altering our minds, memories, metabolisms, personalities, and progeny. This is not some science fiction future. Inexorable increases in ingenuity are opening vistas, especially in what we may call GRIN – genetic, robotic, information and non – technologies”.3

Professor Jones also cites the German philosopher, Jurgen Habermas, who views PGD as being:

“based on a judgment of the quality of a human being and therefore expresses a desire for genetic optimisation. An act that in the end leads to the selection of a healthier organism issues from the same attitude as a eugenic praxis”.

Professor Jones argues persuasively that distinctions between medical therapy and enhancement, normality and abnormality, health and disability, are not clearly defined. They change over time and between societies – “all of us, when compared with our forebears, are enhanced”. He emphasises that “what is lacking from so much debate in this area is a lack of what is or is not scientifically feasible ... there are differences of kind between PGD and designing the perfect baby”.

The title of our report: Choosing Genes For Future Children – Regulating and Preimplantation Genetic Diagnosis has been carefully selected We want the report to be accurate about what is being done. It is possible, using PGD, to choose that a baby will not have genes for a particular genetic disorder.

There is no societal unanimity on the answers to the ethical and moral questions that are raised by the use of PGD. When artificial insemination was first possible, a Royal Commission was set up in the United Kingdom to see whether it should be made a criminal offence. Now the technology is widespread throughout the world. Our society places high value on individual choice and autonomy, yet there are times when individual choice and autonomy are perceived to harm the community as a whole – at which point that is reached is rarely a matter of common agreement.

The Hippocratic Oath, which states “I will follow treatments which according to my ability and judgment I consider for the benefit of my patients and abstain from whatever is harmful”, does not provide all the answers to the complexities of the issues that PGD raise. The concepts of “benefit” and “harm” are not neutral and depend very much on the perspective of whoever is looking at them.

It would be too simplistic if the choice were between either opting for a broad-brush approach of greatest caution reinforced by State control until such time as we have foreseen and tested all the possible risks and concerns of the use of PGD, or an ultra-liberal approach of non- interference until it is clearly proven there are risks and harms that everyone agrees upon.

In the past, both such approaches have led to negative consequences in particular contexts. For example, in the 1930s in the United States of America, over 20,000 people who the United States government believed were “undesirables” were sterilised against their will as a precaution against them having children. The case of Buck v Bell 4 in 1924 concerned three generations: a mother Emma Buck, her daughter Carrie Buck, and a granddaughter Vivian Buck who lived in a “colony for epileptics and feeble-minded” in Virginia. Emma Buck’s sister Doris was also part of the case. They were all deemed to be mentally defective by an IQ test (the Binet test). Vivian was only seven months old at the time of “testing” but was reported to have a “look” about her which was not quite “normal”. This was sufficient evidence to convince Justice Oliver Wendell Holmes in the United States Supreme Court to declare “three generations of imbeciles are enough”.

Doris and Carrie were duly sterilised. The upshot of the 1924 decision in Buck v Bell was that by 1931, 27 other States enacted sterilisation laws to prevent the “undesirable classes” from reproducing. The laws provided for the compulsory sterilisation of certain classes of people thought to be insane, feeble-minded or epileptic, habitual criminals and moral perverts. Vivian, Carrie Buck’s daughter, went through second grade at high school where her teachers reported her to be very bright. Doris Buck was never told the real nature of the operation; simply that it had been for a burst appendix. David Galton5 says that when Doris Buck learned the truth she said: “I broke down and cried. My husband and me wanted children desperately. We were crazy about them. I never knew what they’d done to me.” The individual is harmed in the mistaken belief the State will benefit.

At a similar time in the United States, in 1932,6 the individual unregulated choices of medical researchers had a massive impact on 400 African-Americans who had signs of syphilis in the infamous Tuskegee Syphilis Study. The 400 African-American research subjects were observed for 40 years to see how syphilis progressed in them. They did not know the nature of the experiment nor were they told after 1945 that penicillin could treat their condition. By 1955,

one-third of the research subjects were dead from syphilis. In the 1970s, this public health scandal was brought to light when medical papers were published about the experiment. A civil rights action was filed against the United States Public Health Service and was settled out of court for more than US$9 million. It took until President Clinton’s presidency for an apology to be issued on behalf of the US Government to the surviving victims. The freedom of the researchers to research as they saw fit led to cruel and inhumane harm to the subjects of the research.

In New Zealand, in 1987, the Committee of Inquiry into Allegations Concerning the Treatment of Cervical Cancer at National Women’s Hospital and into Other Related Matters (the Cartwright Inquiry) found that an experimental research programme conducted by Dr Green in the 1960s and 1970s at the National Women’s Hospital in Auckland resulted in inadequate treatment for many women.7 The research involved withholding conventional treatment from patients with carcinoma in situ of the cervix in order to study the natural course of the disease. About 40 of the women patients eventually developed invasive cancer.

The best way to develop good regulatory policy is to consider as many viewpoints as possible in a fair and even-handed manner. The final decision to regulate or not is for the government to consider, decide and act. Our task is to present the viewpoints and regulatory options with compassion and to analyse them as best we can without bias. Our hope is that the tone of this report will, at the very least, enable readers to empathise with interests and concerns that go against their own interests and concerns. For a community to work through potentially deeply divisive issues, it is crucial that an attitude of seeing the concerns of others in their best light is cultivated. This is not the same as giving up one’s own values and committing to the values and beliefs that give a particular concern force. Dr Anthony T Kronman has said:

“Only the person who has surveyed, with sympathetic detachment, the conflicting interpretations that different members of his community offer of its goals is in a position to say whether his own preliminary views should be revised and to make an informed choice among the alternatives before him”.8

There is an incommensurable diversity of human goods and no overriding objective criterion to definitively rank them. If there are no rational grounds for insisting that one view of the good is superior to those of others, then forced suppression of a particular belief or practice leads to the loss of something humanly valuable.

The investigators and researchers working on this Project do not represent any particular political party, religion, belief or government policy. They are all independent and diverse thinkers who bring to the Project a spirit of open inquiry and empathy for different viewpoints and dispassionate (as is humanly possible) analysis.

PGD was developed as an alternative to prenatal diagnosis for couples who were at risk of passing inherited diseases to their children. With prenatal testing utilising chorionic villus sampling (CVS) or amniocentesis, diagnosis is undertaken when pregnancy is already established. If the foetus is affected then parents may consider whether to continue with the pregnancy or to terminate it. Hence, when compared with prenatal diagnosis, PGD substantially minimises or avoids the need for termination.

Research in the UK on PGD began in the mid-1980s to help couples who wished to have diagnosis for inherited disease before embryo implantation instead of during pregnancy. Preimplantation testing techniques were not new then but had been carried out on non- human embryos since 1968 and were used routinely in the context of animal husbandry to breed animals of the preferred sex.9

The first successful human pregnancies using PGD were reported in 1990 for various X-linked or sex-linked disorders (where males, not females are affected) with the selection of female embryos for implantation. This was followed by the report in 1992 of a live birth after utilising PGD selection against cystic fibrosis, which is an autosomal disease where both copies of a gene are non-functional.10

By 2000, PGD had been used in the UK to test for a range of disorders caused by a single gene,

e.g. beta-thalassaemia, sickle cell anaemia and muscular dystrophy, and for chromosomal abnormalities, e.g. Down, Turners and Edwards syndromes.11

PGD involves the creation of embryos, embryo biopsy, analysis of one or two biopsied cells, and transfer of unaffected embryo(s) to establish pregnancy. PGD incorporates the use of IVF technology as part of the process.

Embryos are created by injecting a single sperm into each oocyte to achieve fertilisation. This technique, intracytoplasmic sperm injection (ICSI), is used in the majority of cycles of PGD, to avoid contaminating sperm interfering with the PCR analysis.

After fertilisation, embryos are cultured and then embryo biopsy carried out. This involves taking one or two cells from an embryo, two to four days after fertilisation. In some instances, polar body biopsy, involving the analysis of polar body cells resulting from oocyte development, is used. The polar bodies give an indication of the genetic composition of the egg. Polar body biopsies are used in countries where embryo biopsy is prohibited.

Single cell diagnosis is then performed using the polymerase chain reaction (PCR) or fluorescent in situ hybridisation (FISH), depending on the disorder being diagnosed.

PCR is the exponential amplification of a specific region of DNA and is used to analyse small changes in DNA in a single gene. Each new mutation requires the development of a new PCR test. In addition, because it is such a sensitive technique and because the target is so small, contamination has to be carefully avoided. A technique called whole genome amplification (WGA) is a way of increasing the amount of template for the PCR reaction from just one copy of the genome to many. PCR is also hampered by a phenomenon known as ‘allele dropout’ (ADO) or ‘preferential amplification’ which happens when an allele being examined fails to

amplify. In a carrier, for example, only the normal or only the affected allele is amplified rather than both alleles equally. Analysis of areas either side of the mutation (also using PCR) control for this phenomenon.

FISH is used to analyse chromosome numbers and gross abnormalities and for sex selection mainly for X-linked disorders. It can easily be used for non-medical sex selection, the use of which is illegal in NZ currently.

PGD started with the purpose of identifying embryos that have the genetic mutations for serious, life threatening conditions. PGD can also be used to help women with a history of recurrent miscarriages or of advanced maternal age to reduce the rate of miscarriage. Embryos are biopsied and screened for changes in chromosomal numbers (aneuploidy12) and only those embryos with a normal number of chromosomes are transferred. This is by far the most common use of the technology according to recent figures13 but this use of the technology is not publicly funded in New Zealand. On the basis of what is presently known in terms of the science and technological ability, screening for aneuploidy is not sufficiently determinative of a guaranteed outcome.

PGD has subsequently been used to select a tissue-matched or HLA compatible embryo for the purpose of having a child who will be a match for an existing sick sibling for a stem cell transplant from the umbilical cord.

In 1997, a PGD consortium was formed as part of the European Society of Human Reproduction and Embryology (ESHRE) to undertake long-term study of the efficacy and clinical outcomes of PGD. The ESHRE PGD Consortium started collating data from 25 centres (increasing to 66 centres by 2005) from Europe and six other countries and on referrals, cycles, pregnancies and babies born after PGD. Reports have been published in 1999, 2000, 2002 and 2005, covering data up to 2002.14

Recognising variations in local or national regulations and specific laboratory practices, and acknowledging that differences will remain with regard to the ways in which PGD is practised, the ESHRE PGD Consortium recently provided guidelines in the hope that higher quality overall and standardisation of PGD can be achieved by building consensus opinion within the PGD community on best practices based on available evidence.15

A study of the past 12 years of data from the world’s three largest PGD centres, comprising 4748 PGD attempts and 754 successful pregnancies, led to the conclusion that PGD is safe.16

PGD is not yet a widely used procedure but seems likely to become more popular both as people become aware of its availability and as the number of conditions for which testing is available expands. New Zealand is unique amongst countries offering PGD services, given its commitment to funding the full cost of up to two cycles of IVF/PGD for people who use PGD to test for serious inherited genetic disorders. This funding includes the costs of the IVF treatment that must accompany PGD.17 While the embryo biopsy can now be performed in New Zealand, many of the tests are conducted on a contracted-out basis at Monash IVF in Australia. Monash IVF is contracted to provide tests for five major conditions18 and also offers aneuploidy screening – any testing beyond these can be done on a case-by-case basis.

The question of whether or not New Zealand develops a full capability for this technology is likely to be dependent on the actual and projected uptake by the population. PGD is a highly specialised technique and requires skilled personnel. Staff competence and skill maintenance will be vital to the provision of this service in order to maximise safety and efficiency, yet New Zealand has challenges to overcome, for example, in terms of offering competitive and attractive remuneration by comparison with other countries. It has been noted, for instance, that “New Zealand has traditionally had difficulty recruiting and retaining geneticists, mainly because of professional isolation.”19

Mäori are the tangata whenua – the indigenous people of New Zealand. The Treaty of Waitangi 1840, a treaty signed between Mäori chiefs and representatives of the British government, and the principles of the Treaty create and continue to re-create the unique relationship between the Crown and Mäori in New Zealand.20 Mäori concerns about PGD hinge partly on the concern that the principles of the Treaty may have been undermined by the Human Assisted Reproductive Technology Act 2004 (the HART Act) and the Guidelines on Pre-implantation Genetic Diagnosis (the Guidelines) in that neither the legislation nor the Guidelines make express reference to the Treaty of Waitangi, nor do they provide sufficiently adequate account of the ethical basis for how culturally-based decisions may be undertaken or implemented consistent with tikanga Mäori.

The HART Act does, however, state that the needs, values and beliefs of Mäori should be considered and treated with respect, and that the different ethical spiritual and cultural perspectives in society should be considered and treated with respect.

Cultural values that underpin a Mäori way of being and the place of Mäori in the universe are established by virtue of their whakapapa (genetic inheritance). The authority of a group to make collective decisions about the best interest of its members, individual autonomy, or self-governance, is based on the ability of a group to govern themselves. Ultimately, Mäori acknowledge that an individual has a right to use PGD, but the collective asserts its authority to protect its whakapapa – as a taonga under Article II of the Treaty of Waitangi.

A pioneering study of ethical, spiritual, cultural and social issues pertaining to pre-birth genetic testing from a Mäori perspective was carried out by the Mäori research team collaborating with this project. The study involved in-depth interviews with a range of Mäori participants. No single Mäori view on the potential risks and benefits of pre-birth genetic testing is offered although strong patterns of agreement on aspects of the potential risks and benefits emerged. There was general agreement that PGD has the potential to do more good than harm for Mäori communities. There was also general agreement and concern that Mäori may not have equity of access to PGD. The most pressing concern for Mäori is working at the balance between individual and collective rights to the use of PGD and creating an environment where this can happen.

A cultural decision-making framework based on tikanga Mäori to help with assessing the risks and benefits of PGD in a culturally appropriate way is proposed.21 The framework provides

a position for assessing a situation or event that challenges thinking and values, using key concepts (such as tapu, mauri, take, utu, whanautanga, manaakitanga, mana, tika and noa)22 relating to tikanga Mäori.

Respect for cultural priorities is an extremely important consideration in the regulation of genetic services in New Zealand. A role of any regulatory regime is therefore to support the expression of tikanga Mäori in the modern world, enabling the present generation of Mäori to reproduce according to the spiritual and philosophical understandings of their ancestors

The fact that embryos are specifically created for selection in the use of PGD entails their possible rejection. This, rather than the PGD activity itself, is thought by some to be objectionable as it is said to instrumentalise embryos. Equally, other arguments are used by opponents of PGD, for example that it may have negative effects on resultant children and that there may be risks to the child’s physical and/or emotional status. The emotional risks would be the hardest to quantify but some believe that the power of choice put into the hands of parents by PGD could alter the parent/child relationship fundamentally from one of unconditional love to one dictated by the realisation (or not) of specific ‘designer’ expectations.

There are a number of arguments against PGD. One of them is the ‘Playing God’ objection which is examined from the Christian viewpoints, and from the secular standpoint in terms of interfering with the natural order.

There is a plurality of Christian views of PGD ranging from the conservative proscriptive position to the modern facilitative position of engaging with God in His creative activity. The conservative view holds that to engage in PGD is to reject God’s image in His creation; it is to reject human life as a gift and transform it into a humanly designed product. Each of these undermines the dignity of human beings and their unconditional worth. This is, however, a minority view. The modern facilitative view is that people are seen as co-creators with God to realise the existence of a better world. On this basis PGD, is not ruled out per se but is limited to applications which are ‘good’. The challenge lies in identifying which applications are ‘good’.

A difficulty with the ‘Playing God’ objection is the level of uncertainty attaching to Christian views because of the wide range of views about God and the Christian moral order. These make the objection equivocal. Furthermore, the Christian justifications for intervening in human life in many areas, including modern medicine, to avoid agonies being suffered by people, make it inconsistent to avoid by means of PGD the intractable and unbearable suffering brought about by serious incurable genetic disorders.

Secular substitutes for the Playing God criticism of PGD take the form of claiming that it amounts to an unnatural intrusion into procreation and therefore is an invitation to risks such as reduction in biodiversity. This criticism is countered, first, by an appeal to the fact that interference in breeding over centuries has not had this effect and, second, that the small numbers involved in PGD could not produce such an effect. The claim that interference

with nature entailed by PGD would produce a slippery slope to eugenics is an empirical claim which lacks evidence in that other similar reproductive technological innovations have been successfully regulated by public consensus.

The conservative view of the embryo as having the full moral status of a person proscribes PGD. On the other hand, the liberal view that no moral status is accorded to the embryo or foetus places no barriers on what should be done to them. Between these views, the moderate view sees the developing embryo and foetus as growing in moral status throughout gestation and calls for limits to the use of PGD but not its proscription.

The wide and differing range of views held by the general public on the status of the embryo and foetus cannot be ignored. New Zealand legislation already permits abortion and PGD on limited grounds, and so does not reflect the conservative view of the foetus although the limits imposed might be construed as opposing a completely liberal view. There are no conclusive arguments, nor is there any crucial evidence, which can resolve the differences in views from various accounts of the status of the human embryo and foetus. The question of whether PGD should or should not be permitted is ultimately not usefully addressed by seeking an answer to the question of the status of the human embryo or foetus.

The moderate or ‘gradualist’ approach to the human embryo – an approach that sees the embryo as more than a mere collection of cells, but as less than a full person – is adopted in this report. This approach requires that the embryo of the human species is worthy of respect at all stages, but that certain interventions/treatments may be permissible at certain stages, with the limits of permissibility narrowing as the embryo/foetus nears maturity.

Selecting embryos on the basis of their genetic status is a matter of considerable concern for many people – particularly those speaking for the disability rights community. Attitudes vary as to whether or not the availability of PGD to screen out genetic conditions will result in disrespecting people with disabilities or whether this use of PGD sends out a eugenics signal. For some, it is inevitable that the ability to choose to discard affected embryos means that those currently living with the relevant condition are disrespected; that their lives are regarded as less worthy. There is a lack of empirical evidence to support one case or the other.

Proponents of PGD contend that it is the disability and not the disabled that we are seeking to avoid. On this argument, there need be no negative impact on those living with disability.

Equally, the eugenic argument is asserted strongly by some, while others would distinguish individual rights to make choices from the state-sponsored eugenic programmes which were in place in the United States and, most especially, Nazi Germany in the early parts of the 20th Century. For example, the House of Commons Select Committee on Science and Technology took issue with the negative connotations of the word ‘eugenics’, saying:

“If ensuring that your child is less likely to face a debilitating disease in the course of their life can be termed eugenics, we have no problems with its use: state programmes that impose a genetic blueprint are another matter. They should be outlawed as part of any regulation of assisted reproduction. Use of the word eugenics must not be used as an emotive term of abuse to obscure rational debate”.23

Discussions about these issues in New Zealand are emerging. The New Zealand Organisation for Rare Disorders is open to the use of emerging genetic technologies for parents to choose to avoid the birth of children with disabilities. For the Crippled Children’s Society, their focus has been to consider changing their constitution to emphasise that they celebrate the lives of people with disabilities.

The place of people with disabilities and the impact of clinical advance on their position is sometimes seen to be somewhat marginalised, and surely deserves special protection. New Zealand does not have a Disability Rights Commission (as, for example, the UK does) although it has a Minister for Disability and an Office for Disability Issues. Additionally, even with a number of statutes relevant in this area (the New Zealand Bill of Rights Act 1990, Human Rights Act 1993, and Health and Disability Commissioner Act 1994), New Zealand has no body directly responsible for issues that fall under the category of promoting good relations between people with disabilities and their communities.24

The bioethical analyses are informed by the Universal Declaration of Bioethics and Human Rights (UDBHR)25 which significantly focuses on the inter-relationship between bioethics and human rights, and helps shape thinking and reflection for both the process of developing policy and determining the content of policy. At the heart of the ethical analysis of PGD is the tension between, on one hand, individual freedom and privacy to make reproductive choices and, on the other hand, social solidarity and responsibility to ensure that human dignity is not eroded or undermined.

The assessment of legislative frameworks in this report is based on principles which are most likely to enable regulatory initiatives to be accepted by the general public as legitimate. These principles require that the regulatory framework must be proportionate to the perceived harms or risks posed to justify the imposition of regulatory limits. Regulators should have clear lines of accountability, in particular, their decisions must be justified and be subject to public scrutiny. There should be accessible, fair and effective complaints and appeals processes. Consistency in administering the regulation and in the regulation itself, and transparency in terms of what the regulatory objective is, and the legal obligations of those being regulated are essential. Finally, regulation must be precisely targeted to achieve its objective.

In comparison to other regimes with similar regulatory structures, New Zealand is unique in that the HART Act establishes two statutory bodies with clear remits. New Zealand has therefore departed from the international trend of having one statutory authority that both creates and implements policy. Instead there are two bodies: an advisory committee which creates policy, and an ethics committee which assesses individual cases against the advisory committee’s guidelines. The main benefit of this structure is that focusing solely on policy increases the efficiency of the Advisory Committee’s policy-making process, both in terms of time and the expertise of those creating policy.

New Zealand is different from the jurisdictions used here as comparators in that it has essentially de-regulated some aspects of assisted reproduction. The UK Human Fertilisation and Embryology Authority26 is presently arguing for more rather than less inclusive regulation.

The mechanism governing ‘established procedures’ in the HART Act allows certain procedures to be carried out without external scrutiny and indicates to that extent a commitment to imposing only such regulatory restraint as is seen to be necessary. The fact that it is an offence to perform an established procedure unless the provider is certified under the Health and Disability Services (Safety) Act 2001 shows there is emphasis on ensuring that appropriate clinical standards are observed and patient safety is maintained. A further difference in the New Zealand legislation is that it has not adopted a licensing system. Instead, it has built on existing health and safety requirements, making certification under the Health and Disability Services (Safety) Act 2001 a statutory requirement and providing civil sanctions for non- compliance. There is no explicit provision allowing for conscientious objection within the regulatory framework for PGD that recognises circumstances where a segment of providers and the public may not wish to be involved because of, for example, religious or personal moral beliefs.27

There is as yet no provision for applicants to appear before the Ethics Committee when presenting their case (a right which has recently been made available in the United Kingdom). This may perhaps be an unfortunate omission, particularly as the Ethics Committee exercises the function of applying policy and making decisions affecting individual citizens coming before it. Allowing an explicit process that provides the opportunity for applicants to speak to their case would render decisions more transparent, and build more confidence and trust in the process. There is no right of appeal from a decision of the Ethics Committee – such a right exists in both the UK and the state of Victoria.

The report identifies issues of inconsistency in the legislation and policy development within the context of the legislation. The creation of a category of ‘established procedures’ reflected an apparent desire not to regulate unnecessarily, yet it is arguable that the outright ban on non- medical sex selection is unnecessarily rigid, particularly as public and other attitudes can and do shift rapidly. The ‘established procedures’ category is potentially broad enough to capture late-onset and susceptibility disorders, such as those involving BRCA1 and BRCA2 mutations which are transmitted in an autosomal dominant pattern in families. Carriers of the mutations have a 60% to 90% risk of developing breast cancer, compared with a 10% risk in the general population. This may not have been intended but the wording of ‘serious impairment’ is broad enough to cover this situation. The determination of ‘serious impairment’ under the ‘established procedures’ category is solely a medical one at present in New Zealand. By way of contrast in the UK, the determination is made in collaboration with the family who have a say into the decision about PGD use.

Selection of embryos with a genetic impairment seen in a parent is prohibited by the Guidelines. The implication of this, by contrast, is inconsistent with prenatal testing where parents can choose to continue with the pregnancy when aware of genetic impairment in a foetus.

The Guidelines which set out the lawful parameters of PGD in conjunction with HLA tissue typing are problematic on several fronts. The Guidelines require that the planned treatment for the affected child will utilise only the cord blood of the future sibling. Yet medical procedures carried out on a child, such as bone marrow donation, do not come within the jurisdiction of the policy-making body under the HART Act 2004. In New Zealand, medical procedures carried out on a child are covered by other established healthcare law and principles.

The effect of the Guidelines is that an embryo may be tested for HLA compatibility as an add-on procedure if embryo biopsy is indicated to test for the presence of a genetic disorder in the prospective offspring. However, tissue typing may not be carried out as an additional procedure if the affected child is suffering from a non-genetically heritable condition, regardless of whether embryo biopsy is indicated to test for the presence of a familial single gene or familial chromosomal disorder in the embryo. It is unlikely this was an intended consequence by those responsible for the Guidelines. The anomaly may be easily rectified by requiring only that the affected child is suffering from a severe life-threatening condition. Regulating HLA tissue typing so narrowly is in tension with the minimal evidence of risk to the embryo, particularly when a wide range of PGD uses are already permitted as established procedures.

All of the policy formulated via and pursuant to the Act has been based purely on therapeutic applications of PGD technology. Although there has been an intention expressed by the Select Committee that PGD should not be used for selection of non-medical traits, this has not been expressly stated in the Act. While the prohibitions in Schedule One of the Act prohibit reproductive research, they do not prohibit the conduct of non-reproductive research which may be permitted should the Advisory Committee promulgate guidelines.28

The terms of reference provided by the Minister for the Advisory Committee evoke some concerns. Decisions of the Advisory Committee may be made by simple majority vote. This may be criticised by some but it is the robustness of the debate that is important. Understandably, perhaps, the members are restrained from publicly expressing any disagreement with policy decisions. It would increase transparency, and thereby promote public confidence in the legitimacy of the Committee and the process, if decisions of the Committee were accompanied by reasoned analysis of the decisions reached, including the scientific basis, the differing perspectives taken into account, the number of members in favour or against (or abstaining from) decisions that are made, and the opportunity for dissenting individual members to record and append their comments to the final decision of the Committee.

There are strong grounds to believe that the decision-making process of the Ethics Committee as set out in the Terms of Reference for ECART is ultra vires. The HART Act, in effect, requires the Ethics Committee to be subject to the Operational Standard for Ethics Committees (the Operational Standard). The Minister’s terms of reference permit decision-making on the grounds of a two-third majority, contrary to the Operational Standard which requires consensus decision-making. This leaves any decision made by them open to challenge by way of judicial review on the grounds of procedural invalidity. In addition, the Act requires that the Minister must ensure the committee complies in its composition with the Operational Standard which requires a minimum of 10 members. However, the Terms of Reference for the Ethics Committee provide only for 8 members as a minimum, and the committee is currently constituted with 8 members. It is possible, therefore, that ECART may be open to challenge as being not legally constituted under the Act.

It is a concern that, although the Advisory Committee has been given the mandate and duty to monitor the application and health outcomes of assisted reproductive procedures and research, a robust medium- or long-term monitoring system has not been put in place before, or at the same time as, PGD has been declared to be an established procedure.

There is little doubt that the HART Act 2004 was a necessary legislative initiative. The framework sets up affordable, efficient and responsive processes, and is supported in terms of health and safety aspects by other health law instruments. The success of the regulatory scheme, in terms of being seen as transparent, fair and legitimate, will be largely left to the Advisory Committee who will need to be on the constant look out for ‘fine-tuning’.

New Zealand’s bi-cultural identity necessitates consideration of issues emerging from the use of novel technology from at least two cultural perspectives. These may be harmonious or discordant depending on a multitude of factors, adding a level of complexity which may be less noticeable in mono-cultural societies. Social research which investigates perceptions, experiences and attitudes relating to assisted reproduction is vital to deliberation in applied ethics. Any ethical analysis and resultant policy which does not consider these would unlikely be effective or may lead to unintended consequences.

New Zealand is renowned for its thorough investigation of issues surrounding the implementation of novel technologies as was seen in the Royal Commission of Inquiry into Genetic Modification. There is, however, a comparative dearth of research investigating issues surrounding individual perceptions, experiences, and attitudes relating to new human assisted reproductive technologies.

Caution should be exercised before directly applying the findings or knowledge arising from research investigating public groups overseas to the New Zealand situation. The main concerns which have emerged from social research into PGD in other countries include, but are not limited to, its potential impact on the following: pre-natal life, children, people with disabilities, those involved in making reproductive decisions, women, men, communities, and family relationships.

The creation of fair and relevant criteria with which to evaluate public views is extremely difficult and has in the past resulted in the marginalising of relevant groups, such as children and people with disabilities. This, coupled with the consultation requirement built into the HART Act, highlights the importance of specific social and ethical research into assisted reproduction in New Zealand. Such research will greatly enhance the level of ethical debate and also the value and durability of policy and legislation in these areas.

When there are strongly held positions on either side of a debate such as there is on PGD, a common situation in a democracy is to go with the majority view. However, the meaning of democracy needs refinement and the following comment from H.L.A. Hart, the Oxford legal philosopher, gives us pause for reflection:

“It seems feasibly easy to believe that democratic principles entails acceptance of what may be termed moral populism: the view that the majority have a moral right to dictate how all should live ... The central mistake is a failure to distinguish the acceptable principle that political power is best entrusted to the majority from the unacceptable claim that what the majority do with that power is beyond criticism and must never be resisted. No one can be a democrat who does not accept the first of these, but no democrat need accept the second”.29

At present, PGD has the most dramatic impact on a small minority of families. Their voices and concerns can easily be lost. This report critiques majority positions which unjustifiably or inconsistently erode family choices.

(with thanks to Richman Wee and to all project members for their input into this chapter)

tHe science anD clinical utilisation oF Pre-BirtH genetic testing witH Particular Focus on PgD

Prebirth testing is used by parents and clinicians to determine the actual risk of a genetic abnormality or disorder affecting an embryo or fetus.

Prebirth genetic testing can be divided into pre- and post-implantation testing. Preimplantation genetic diagnosis (PGD) is used to analyse an embryo prior to its transfer into the uterus. Prenatal testing, in which amniocentesis or chorionic villus sampling (CVS) is used to obtain embryonic tissue, is used for an established pregnancy.

Prenatal testing is the older technique and is widely available in many countries. PGD was developed in the late 1980s and is offered only by a few, specialist organisations in mainly industrialised countries.

PGD is medically safer for the mother than prenatal testing and termination of affected pregnancies. It is possibly also psychologically safer although there are no data for this. In an Australian study, however, the majority of women who have had both prenatal testing and PGD would choose PGD for future pregnancy planning1.

The risks of fertility treatment (including ovarian hyperstimulation syndrome and increased multiple births) are additional risks that otherwise fertile parents face when using PGD. These risks must, however, be weighed against the risk of having a termination or an affected child.

PGD is particularly suitable for subfertile couples, who would use in vitro fertilisation (IVF) anyway.

Two main approaches are taken to genetic analysis in preimplantation embryos: molecular genetic analyses for many single gene disorders, and chromosomal analyses for translocations and aneuploidies (particularly when is there a history of miscarriage or late maternal age). Misdiagnosis rates appear to be low.

Current data suggest that PGD is a safe procedure for mother and child, with risks (such as congenital malformation) no greater than those for foundation technologies such as IVF and intracytoplasmic sperm injection (ICSI). There is a need for more reporting by clinics providing PGD services to enable monitoring of the technology, including for usage and for long-term follow-up of children born through PGD.

Preimplantation genetic screening (PGS) for chromosomal abnormalities can be used in combination with IVF, to increase implantation and live birth rates and to decrease miscarriage rates, but there are currently not enough data to recommend this use. Larger controlled trials and new technologies such as comparative genomic hybridisation may alter the reported success rate of this technique.

PGD is not a guarantee of a healthy baby. Misdiagnosis aside, it can only analyse embryos for specific genetic problems. Even aneuploidy screening currently tests a subset of chromosomes only, so that chromosomes outside the testing set may still be abnormal.

New Zealand does not currently have a full PGD service. Fertility Associates, the only organisation offering this technique, performs the embryo biopsy and the genetic analysis is contracted to Monash IVF (Australia). The first NZ PGD pregnancy (privately funded) is 16 weeks old2. The expecting mother has a five-year history of miscarriage.

NZ recently announced public funding of PGD for serious genetic disorders. Forty cycles per year will be funded (up to two cycles per couple) through District Health Boards.

As with many areas of reproduction, there is a wide range of strongly held opinions about the advantages and disadvantages of this technology.

The use of PGD in New Zealand, beyond serious genetic disorders, is limited by law, current scientific knowledge and by genetic principles. The actuality of enhanced “designer” babies is improbable although the degree of “seriousness” of many genetic traits will continue to be debated.

It would be very unusual indeed for a person not to be aware (at least to some degree) of genetics and heredity. Phrases such as “you have your mother’s eyes” or “they’re a chip off the old block” are age-old in our society. Traits that may be inherited include physical, behavioural and medical characteristics. There is a widespread appreciation that children will inherit various features from their parents and it is this fact that forms the basis of genetic testing.

The goal of this part of the report is to provide the scientific and clinical background to enable rational discussion of prebirth testing and its benefits, consequences and limitations. Other parts will discuss the legal, ethical and cultural aspects and implications of the analytical techniques outlined here.

This section includes an overview of genetics and the inheritance of genetic disorders and a review the current technologies used in clinical prenatal genetic testing, namely amniocentesis and chorionic villus sampling (CVS). The current extent and usage of preimplantation genetic diagnosis (PGD) internationally will be explored, followed by a summary of future technologies and the New Zealand situation. The report concludes with the current limitations of these technologies and analyses them with respect to concerns raised about positive selection and “designer” children.

This section is not a definitive review of every aspect of prebirth testing. The main issues are outlined and readers are referred to more specialised review articles for further detail in various areas. The format is a general overview at the beginning of each major section, followed by more detailed subsections. Some aspects of this section of the report have been generalised for the sake of conciseness, for example, references to couples and (prospective) parents in no way preclude application of the concept to single parent families, same sex relationships and surrogacy relationships.

Some birth defects are heritable, others have environmental causes and others are random developmental errors. There are currently at least 1228 specific genetic disorders tested for in clinical and research laboratories worldwide4 and there are an estimated 3500 to 5500 inherited disorders5.

“Every year an estimated 7.9 million children - 6 percent of the total births worldwide

- are born with a serious birth defect of genetic or partially genetic origin.”6

There are also genetic problems that prevent the formation of a viable embryo or that cause a fetus to spontaneously abort before term. The attempt, on the part of both clinicians and parents, to minimise preventable deaths and suffering and to increase reproductive options for parents, has driven the development of prebirth testing.

Prebirth testing is currently used for many purposes. The three principal uses are:

Before prebirth testing, the options available to couples at risk of passing a genetic disorder to their children were:

Prebirth genetic testing in the form of amniocentesis has been in use since the mid-1950s. It was originally developed to screen pregnancies for fetal sex, where there was a risk of serious X-linked disease such as haemophilia7. As only male children are affected, cytogenetic techniques (to look at chromosomes) could be used to determine the sex of the fetus and male pregnancies could be terminated. Whilst no affected children would be born, half the terminated male pregnancies were unaffected and half the females born were carriers, at risk of passing the disease to their male offspring.

Genetic testing technologies have advanced in scope, accuracy and safety since the 1950s. Newer prenatal techniques, such as chorionic villus sampling, enable testing to be carried out earlier in the pregnancy. Genetic testing is, for the most part, much more precise than the first amniocentesis and sex selection protocols. Families with single gene disorders can now be tested directly for their specific disorder, for example, for the haemophilia mutations instead of for male and female sex.

Prenatal testing and screening is an option that many parents choose to access. If a test is positive for a genetic abnormality, prospective parents can choose to terminate the pregnancy. A few conditions can be treated or mitigated in utero8. Other parents use the information to plan for the birth of the affected child, emotionally and practically. They can, for example, make financial, work and care arrangements. This information also allows medical and support services to be accessed early for the benefit of both the child and the parents.

A recent development in prebirth testing is preimplantation genetic diagnosis (PGD). This is performed before the embryo even implants to form a pregnancy. In vitro fertilisation (IVF) embryos that are tested and found to be free of the disorder or abnormality are transferred to the uterus. This is considered by many (including parents who choose to use it) to be preferable to genetic testing and the possibility of termination, once a pregnancy is established. This preference is particularly marked in women who have had a previous termination9.

Women who have a history of implantation or IVF failure and miscarriage also increasingly use PGD. The aim is to improve the chance of a full term pregnancy and live birth by screening for chromosome abnormalities. It also has the potential to decrease the chance of miscarriage. This is now the most common use of the PGD technique internationally10.

PGD has been used for social sex selection although this is relatively rare. It is thought that this is predominantly for “family balancing” in Western countries. In areas of the world where there is a marked preference for male children, ultrasound diagnosis is the usual technique to identify gender, as it is quick, cheap and portable. Prenatal diagnosis is less commonly used and PGD is rarely available for any use in such countries.

Newer and more controversial uses of PGD include tissue matching of an embryo to that of a sick sibling. The potential outcome is that the umbilical cord blood from the tissue-matched pregnancy will serve as a source of stem cells for a transplant-based cure for the affected sibling.

To understand the rest of this science and clinical section, it is useful to have a short introduction to normal genetics and inheritance, and the language used to describe some genetic concepts.

The hereditary material in nearly all living organisms is deoxyribonucleic acid or DNA. DNA is held in a cellular structure called the nucleus. The DNA contained in one cell is called the genome and each cell in the body has one copy of the genome. The functional part of the genome is structures called genes. Genes are the blueprint from which proteins are made, via an intermediate of ribonucleic acid or RNA. A few genes code for a functional RNA instead of a protein, but references to genes in this report will be made in the context of protein production.

The term gene describes a block of DNA that contains the actual code for an eventual protein product as well as the signals that control when, how much, in what type of cells the protein is produced and where in the cells the specific protein is transported to. Long strands of DNA containing many genes are packaged in structures called chromosomes. There are approximately 25 000 genes in the human genome.

Humans normally have two copies each of 22 chromosomes called autosomes, a total of 44 autosomes. These vary in size and structure, chromosome 1 being the largest and chromosome 22 the smallest. In addition, humans have two sex chromosomes: two X chromosomes in females (denoted XX) or one X and one Y chromosome (XY) in male. In total, the human genome contains 46 chromosomes.

At fertilisation, the male contributes one copy of each pair of his chromosomes to the embryo (in the form of sperm) and one copy of each chromosome is supplied by the female egg or ovum. The sex chromosomes are also paired so the female will contribute one of her two X chromosomes and the male either an X or a Y chromosome. This extends to genes, in that one copy of each gene will be maternal and one will be paternal.

Since one set of chromosomes is inherited from each parent, there are two copies of every chromosome, and thus every gene, in each cell (except genes on sex chromosomes in males). Any change to this chromosomal set is known as aneuploidy. This concept will be expanded later in the document.

The human genome is full of variation, so the genes contributed by each parent will not necessarily have identical DNA sequences. This normal variation is also known as polymorphism and is caused by changes (mutations) accumulated in the DNA sequence over many generations. Gene variants are known as alleles. One gene many have a few or many alleles in a population, however an individual can only ever have two alleles per gene (unless there is an aneuploidy). An individual with two different alleles is heterozygous at that gene, whereas if two identical alleles are present, they are homozygous for that gene.

A new mutation could have a beneficial effect, no effect or a detrimental effect on the protein product. Most variation in the alleles of genes is essentially neutral to the purpose of a gene, i.e. the functions of the synthesised proteins are unaffected. Occasionally a change or mutation in an allele will be in a crucial functional part of the gene or protein. A negative mutation could change the protein blueprint so that the protein produced is unable to function normally, or prevent the protein from being produced at all.

When a mutation is pathogenic (causing disease) reference is often made to “the gene for” a disease, particularly in the media. This is inaccurate, since the role of all genes is to ensure normal development and health. What is being referred to is the fact that one allele (or both) of the gene has been damaged and no longer fulfils its (their) usual function. This results in the disease symptoms or a phenotype. Reference would be more correctly made to “the damaged gene that causes” a disorder or “the gene mutation for” a disorder.

There are a number of different types of genetic disease. Disorders and abnormalities can result when the function of a gene and/or protein is affected negatively by mutation. Another cause is an abnormal cell division where chromosomes are unevenly divided between daughter cells, which results in cells having the wrong number of chromosomes. This, in turn, results in the wrong amount of protein being expressed in various tissues, which can have surprisingly large effects on development.

A person with genetically different types of cells in their bodies is known as a mosaic. This is not unusual in humans. All females are in fact mosaic, through a process where only one X chromosome is used in each cell. The other X chromosome is “turned off” early in development, but which X chromosome is on and which is off is a random process. Mosaicism also arises through a mutation early in development. The cell with the mutation continues to divide, as do all the other cells in the embryo or fetus, resulting in a mixture of cells, some with the new mutation and some without.

A molecular mutation is a change in the DNA sequence. This can be caused by a number of different types of “errors”. Errors include mismatches during the replication of DNA and chromosomes and during DNA repair after environmental insults, such as UV light. Different types of mutations cause different results in the function of the protein. Some are “silent” and have no effect, a few have a positive effect; this report will focus on those changes that have a negative effect on the function of the protein.

The best way to describe the different types of mutations is to use a sentence as an analogy. Genes have three letter words in their sentence: the three letters are nucleotides and the words are amino acid building blocks that make up protein. The effect of some changes on the sentence is shown in Table 1. In the missense example, an E is changed to a Q. You will probably deduce the meaning (function) of the sentence if the word is not too important,

e.g. “THE” as below. It is more difficult if a more important word, say “FLY’ is mutated to “SLY”. In the nonsense example, a full stop (also a three letter code in genes) is moved from the end of the “sentence” to the middle, altering the meaning or removing meaning entirely. The expanding mutation is the mechanism for triplet expansion disorders such as Huntington disease and Fragile X. They show anticipation, where the damaged allele produces earlier onset of symptoms in each subsequent generation through more and more expansion of the triplet.

These gene “sentences” illustrate the effects of various types of molecular mutation on the meaning (or function) of the sentence. The site of the change or the actual change is underlined. (Modified from Lewis, 200311).

normal allele	THE ONE BIG FLY HAD ONE RED EYE.
Missense	THQ ONE BIG FLY HAD ONE RED EYE.
nonsense	THE ONE BIG.
Frameshift	THE ONE QBI GFL YHA DON ERE DEY EFU LLS TOP.
Deletion	THE ONE BIG HAD ONE RED EYE.
insertion	THE ONE BIG WET FLY HAD ONE RED EYE.
Duplication	THE ONE BIG FLY FLY HAD ONE RED EYE.
expanding mutation generation 1	THE ONE BIG FLY HAD ONE RED EYE.
generation 2	THE ONE BIG FLY FLY FLY HAD ONE RED EYE.
generation 3	THE ONE BIG FLY FLY FLY FLY FLY HAD ONE RED EYE.

Larger deletions, insertions and inversions occur and are usually described in the context of chromosomes and chromosome structure rather than a molecular sequence.

An aneuploidy is a change in the expected number of chromosomes resulting in an unbalanced chromosome complement.

“An estimated 10-30% of fertilized human eggs have the “wrong” number of chromosomes, with most of these being either trisomic or monosomic [for one or more chromosomes]. This has profound clinical consequences: approximately one-third of all miscarriages are aneuploid, which makes it the leading known cause of pregnancy loss and, among conceptions that survive to term, aneuploidy is the leading genetic cause of developmental disabilities and mental retardation.”12

Monosomy is an aneuploidy in which there is one chromosome instead of two. Monosomic embryos usually die early in the pregnancy. The principal pathological exception is Turner syndrome, where a female has just one X chromosome (X0).

Trisomy describes the presence of three copies of a particular chromosome instead of two. These are usually embryo-lethal, occasional exceptions being trisomy 21, 18 or 13. Whilst the majority of trisomy 21, 18 and 13 embryos spontaneously abort, these of all the autosomal trisomies are most likely to survive to term. Trisomy 21 results in Down syndrome, trisomy

18 is Edward’s syndrome and trisomy 13 is Patau syndrome. The average survival for trisomy 13 is 8.5 days and the average for trisomy 18 is 6 days13. There are also sex chromosome trisomies: XXX is triple X syndrome, XXY is Klinefelter’s syndrome and XYY is XYY or Jacob’s syndrome.

There are, additionally, many examples of partial aneuploidies in which portions of a chromosome are duplicated or are missing. These are less likely to be lethal as fewer genes are affected than if a whole chromosome is involved. Partial monosomy can result from a deletion of a portion of a chromosome, e.g. cri-du-chat syndrome results from a small deletion near one end of chromosome 5. Often partial aneuploidies result from translocations.

A translocation is where a portion of a chromosome has been cut or broken off and reattached to another chromosome. A balanced translocation is where portions from two different chromosomes are swapped. A Robertsonian translocation is where (one part of) a chromosome is fused to another chromosome. Whilst a translocation does not usually result in aneuploidy in the person who carries it, they can result in aneuploid embryos when that carrier reproduces.

There is an increase in the risk of having an aneuploid child with increasing maternal age14. Recent data have indicated, however, that it is not only older women who have a high rate of aneuploid embryos; in younger women, embryos have a 40-50% rate of chromosomal number errors15. There has also recently been wide variation reported in percentage of aneuploid eggs from women less than 30 years, with individual rates from 29% to 83%16.

Classical genetics is the description of inheritance, first quantified by Gregor Mendel at the end of the nineteenth century. This section will describe the principal modes of classical genetics or inheritance. For further information, consult a good biology or genetics text.

“Non-disease” genetic traits as well as disorders can be “simple”, in that they are caused by a change in only one gene. Within a gene, different changes (mutations) or alleles can cause the same trait. In cystic fibrosis for example, there are many alleles each with different mutations (throughout the CFTR gene) but if the mutation is in any crucial area in the gene, it has the potential to cause cystic fibrosis.

Normal traits and disorders can also be complicated (often called “complex”). In type I diabetes, for example, alleles of many different genes contribute to diabetes susceptibility, as do environmental effects. It is much more difficult to predict the likelihood of type one diabetes by looking at genetics. This will be discussed more fully at the end of this section.

Having two copies (or alleles) of a gene that are not identical introduces issues of dominant and recessive alleles. These are relative terms; some alleles may produce a protein that works more or less efficiently than another. A dominant allele is one whose product masks the effect of the other. A recessive allele is one whose effect is masked by the other. The combination of alleles is known as genotype.

The effect of the gene itself is called the phenotype. This is the physical manifestation of the genotype in a person.

As the description implies, an autosomal recessive effect is from a gene on one of the autosomes (non-sex chromosomes) and this effect is masked by (an)other alleles. A non-pathogenic example of this (at an oversimplified level) is human eye colour17. The blue eye phenotype is recessive to the brown eye phenotype. If a person has a blue allele and a brown allele of the eye colour gene, their eyes will be brown. Only when a person has two blue alleles will their eyes be the less common blue phenotype.

Recessive alleles are often impaired in function or have no function at all. A number of types of mutation can cause this but essentially, a crucial part of the protein product is changed so that it functions poorly or not at all, or in more extreme cases, no protein product is produced. In the (non-pathogenic) eye colour example, two blue eye alleles result in minimal pigment in the iris. This changes the behaviour of light in the iris (compared to more the intense pigment of brown eyes) resulting in a blue colour18.

Many rare disorders are recessive. One functional allele can often compensate for another damaged allele. Two impaired or non-functional alleles must be inherited for the disease to manifest as a phenotype or physical effect. This implies that both parents have a recessive damaged allele for that gene. They are called carriers. These carriers of a recessive damaged allele will not have symptoms of the disorder. They will, however, provided they mate with another carrier, have a one in four chance of having an affected child and a one in two chance of having a carrier child (like themselves).

Autosomal recessive disorders usually appear unexpectedly in families and an affected child is often the first indication of any genetic issues in the family. The rarity of these disorders is because the damaged alleles are infrequent in a population. The chance of two people, each with a damaged allele (carriers), reproducing together is low. Additionally, there is only a one in four chance that their children will inherit a damaged allele from each of them.

The frequency of the mutant alleles varies between the different diseases and between different populations. Consequently, there are different frequencies of different disorders within populations. Mutated cystic fibrosis alleles are actually common in populations of European descent: approximately one in 23 people are carriers and approximately one in 2000 live births are affected19. This frequency is lower in other populations, for example there are 1 in 150 carriers amongst Asian Americans. Hereditary haemochromatosis is even more common, one in seven New Zealanders being carriers. For other disorders, the mutated alleles are much less frequent. Phenylketonuria, for example, occurs in one in 30 000 European children yet in one in 2600 amongst Turks20.

Children with closely related parents (e.g. cousins or uncle/niece) or children from small or isolated reproductive populations (e.g. Ashkenazi Jews) are more likely to have recessive disorders. Consanguinity and inbreeding in a family increases the risk of a recessive disorder because both parents can inherit the same damaged allele from a common ancestor.

Examples of more common autosomal recessive disorders include cystic fibrosis, beta- thalassaemia, spinal muscular atrophy (SMA) and phenylketonuria (PKU).

Autosomal dominant disorder alleles mask the physical effect of other alleles. Reversing the eye colour example above, the brown eye phenotype is dominant to blue eyes; one brown eye allele allows pigment to accumulate which masks the effect of a blue eye allele. If there is a copy of a brown eye allele present, then that person will have brown eyes. In this way, many “wild type” or “normal” alleles are dominant to damaged alleles.

Autosomal dominant disorders run in families and there is usually an awareness of it amongst family members. As only one copy of an allele is needed for a disorder to develop, the disorder can be passed directly from parent to child. An affected parent has a 50% chance of passing on the damaged allele. It is this allele that causes the disorder, because of toxicity, a new function, or altered protein levels22.

Homozygotes, with two dominant damaged alleles, often die in utero and/or abort, or are very severely affected by the disorder.

Examples of autosomal dominant disorders are Huntington disease, achondroplasia (although approximately 85% of these are new mutations rather than hereditary23) and Marfan syndrome.

Sex-linked disorders are virtually always associated with the X chromosome. There are few genes on the Y chromosome. One of the rare examples of a Y chromosome disorder is infertility caused by small deletions. Obviously this was not often transmitted to sons in the past, but with the development of IVF techniques such as intracytoplasmic sperm injection (ICSI), there are now generations of families with these microdeletions.

Females have two X chromosomes and the probability of being homozygous for a recessive disordersuch as colour-blindness is low (as it is forautosomal recessive disorders). Consequently, X chromosome recessive disorders are rare in females. Carrier females, however, can pass their damaged allele to their sons who are vulnerable because they only have one X chromosome. If the one and only allele is damaged in a male, there is no other copy to compensate for the loss of function and as a result, that male will develop the associated disorder.

There is a complication to this simple explanation. In females, one X chromosome in each cell is essentially randomly shut down. This means that females have only one or the other X chromosome functioning in each cell and are a random mixture (mosaic) for the X chromosomes in each cell in their bodies24. In X-linked disorders, usually there is enough protein produced by a “normal” allele to compensate for the protein that is non-functional or not produced from the damaged allele.

Dominant X-linked disorders are equivalent to dominant autosomal disorders in females because only one damaged allele is required for the phenotype, but the phenotype is usually less severe in females than in males or dominant autosomal disorders. This is because the dominant (mutant) allele will be active in approximately half the cells, whereas in the rest the normal allele will be functioning.

Examples of X-linked disorders include Haemophilia A and B, Duchenne muscular dystrophy (DMD), colour blindness and Fragile X syndrome (in which females are also affected but usually to a lesser extent than males).

The mitochondrion is an organelle within the cell that generates energy. There may be tens of thousands of mitochondria per cell, depending on the energy needs of the tissue. They have their own small genome (distinct from the genome in the nucleus). For various reasons, the mitochondrial genome is more vulnerable to mutational damage27. The other interesting characteristic of mitochondria is that they replicate clonally, largely independent of cell division. Any mitochondria with (or without) a mutation can replicate itself, and in some cases, this replication will be faster than that of other mitochondria.

Mitochondria are only maternally inherited in mammals; paternal mitochondria from the sperm are destroyed at fertilisation. Eggs do not receive all the mitochondria from the progenitor cell during development; a number of the mitochondria are “sampled” by the egg. Inheritance of mitochondrial disease is unpredictable and it appears to be chance whether a small or large proportion (if any) of the mitochondria that are sampled by the egg are damaged or non-functional.

The presence of mitochondrial disease depends on the proportion of damaged mitochondria in each cell and tissue. Disease symptoms are exhibited once this mutation “load” reaches a certain threshold, usually in high energy demand tissues.

The above examples of single gene disorders are in fact exceptions, and most traits are multifactorial. Even single gene disorders are not always as simple as they first appear.

Many normal traits and disorders are the result of two or more genes acting together. For some traits the genes contribute roughly equally, whilst for other traits one gene has the predominant effect with many other genes contributing smaller effects. Examples of polygenic (multigene) traits include height, type I diabetes and heart disease and many behavioural traits such as depression, schizophrenia, risk taking etc.

Environment is also much more likely to influence these sorts of traits. Height and heart disease susceptibility, for example, will vary depending on childhood diet as well as genes.

The environment also influences single gene disorders. Smoking will exacerbate cystic fibrosis (autosomal recessive). Phenylketonuria (autosomal recessive) causes serious mental retardation

as a result of abnormal processing of an amino acid, but if this substance, phenylalanine, is removed from the diet then symptoms may never develop28.

Stress or exercise may precipitate a heart attack and death in someone with a rare single gene heart disorder (e.g. Catecholaminergic Polymorphic VT).

The number of confounding factors makes phenotype prediction complicated in multifactorial traits, as it is difficult to account for all the modifier-gene and environmental-factor combinations. PGD has been reserved for the simpler single gene disorders because there is (for the most part) a direct link between the genotype and the phenotype. It is also technically easier to test one gene than it is to test two or more.

Multigene and environment effects cause two phenomena called penetrance and expressivity. It can be said that penetrance is the light switch for phenotype and expressivity is the dimmer on the phenotypic light switch.

Penetrance is the probability of the appearance of the disease phenotype in a population. The two options for penetrance are phenotype or no phenotype. In Huntington disease, it can be said that 100% of people with a particular Huntington gene mutation will develop Huntington disease and that it is therefore fully penetrant. Some cancer predispositions, such as familial adenomatous polyposis (FAP) are also fully penetrant; in other disorders and predispositions the penetrance is lower, e.g. familial gastric cancer has a 70% penetrance and (only) seven in ten carriers will go on to develop gastric cancer in their lifetime29.

Expressivity is the degree to which the phenotype is expressed in a population. This assumes that there is a phenotype and that there is variation in the medical severity of the phenotype. If a single gene disorder has absolutely no modifying factors, then the same disease allele(s) in two different people should have the same effect, e.g. in achondroplasia. Many disorders are highly variable and the severity of the disorder is different, even between siblings where you might expect there to be a similar genetic basis for the disorder. Phenylketonuria (PKU) is a good example, where the severity of mental retardation, even amongst siblings, can vary30.

Expressivity and penetrance are also confounded by the fact that different alleles of a gene (with different mutations) have differing levels of functionality that may give rise to variation in the severity of symptoms. In cystic fibrosis, for example, different mutations of CFTR are associated with different severities of disease, ranging from mild to fatal phenotypes.

Prenatal genetic testing is the genetic analysis of a fetus before birth and is used when there is thought to be an increased risk of disease or abnormality in the fetus. This could be either a specific known risk such as a familial disease, or a less defined risk. The most common prenatal genetic analysis is for chromosomal number abnormalities (aneuploidies), which result from a random meiotic error.

There are two main methods used for obtaining fetal tissue for genetic analysis: amniocentesis and chorionic villus sampling (CVS). Other methods, such as direct sampling of the umbilical cord blood or fetal tissue, have been trialled, but these are not used routinely for genetic testing, because of the risk to the fetus.

Methods for non-invasive sampling of fetal cells are under development and include purifying fetal cells, DNA or RNA from the maternal bloodstream or from cervical washes. These methods are still experimental and are not yet (entirely) reliable, yet they offer important advantages over amniocentesis and CVS, including earlier diagnosis and substantially less potential for fetal damage or miscarriage. Research to increase the reliability of these techniques is ongoing.

Sampling of fetal cells and genetic testing is the method for obtaining a definitive answer to a specific prenatal question. This is useful in pregnancies where there is a high risk of a fetus being affected, e.g. in families with single gene disorders. In other situations, such as cytogenetic screening for aneuploidy in younger women, evidence clearly shows that it is safer to use a combination of indirect markers of aneuploidy (including biochemical blood markers)3233. Abnormal results from non-invasive screening can be followed up using direct sampling (with the attendant risk of miscarriage) and genetic testing.

Four independent groups first published the successful use of amniocentesis in 1955-195634. These were also the first successful reports of prenatal genetic testing. The initial use was sex determination of the fetus using X-chromosome structures (Barr bodies) found only in females. The application was for X-linked diseases; parents could choose to terminate male pregnancies (with a 50% chance of being affected), and female pregnancies could be continued in the knowledge that they were unaffected but that 50% were carriers.

The risk of a miscarriage caused by the amniocentesis procedure is approximately 0.5% above the natural risk at this stage in pregnancy35. It is possible, although rare, for the fetus to be injured in the procedure.

Amniocentesis testing occurs later in the pregnancy than CVS and is relatively late in a pregnancy if parents choose to terminate because of a detected abnormality. If one twin is found to have an abnormality then a selective termination is possible, leaving the healthy twin in place.

Maternal contamination of the fetal sample is a risk that must be accounted for. This is more likely if there is blood in the amniotic fluid sample. Contamination is easily detected if the fetus is male, due to the presence of the Y chromosome. Multiple cells are characterised to minimise the risk of misdiagnosis.

amniocentesis is the sampling of the fluid surrounded the fetus in utero, the amniotic fluid. a long needle is passed through the abdomen and uterus, into the amniotic sac. this is done using real-time ultrasonic monitoring to avoid the fetus. rarely, the needle is passed through the cervix. a sample of approx 10-20 ml of fluid is taken36 and Dna or cells that have naturally sloughed off the fetus into the fluid, are analysed. the most common test in new Zealand is for cytogenetic abnormalities. if there is the possibility of a familial disease, then this is specifically tested for, using the appropriate test.

this test can only be performed after the amniotic fluid appears at about 13 weeks, although it is almost universally performed at 15-20 weeks for safety reasons37. a higher incidence of club foot in early amniocentesis has been reported3839.

in twin pregnancies, provided there are two sacs, a small amount of dye is injected into the amniotic fluid of the first fetus to be sampled. this is used to distinguish the two separate pools of amniotic fluid, and the second amniotic sample should be clear of the dye. this procedure carries a higher risk of miscarriage40.

Chorionic villus sampling was apparently used for the first time in 1975, for fetal sex diagnosis and selection in Anshan, China.41.

The great advantage of CVS is timing. The biopsy is taken five weeks earlier than amniocentesis so test results are available earlier, allowing more time to make a decision if the results are abnormal. If the results are inconclusive, there is time to have an amniocentesis later in the pregnancy.

There are, however, a number of risks associated with CVS, over amniocentesis. There is a risk of about 0.5-1% that the sampling will cause a miscarriage, over and above the normal rate of miscarriage for this stage in the pregnancy. This risk is operator-dependent, with more experienced physicians having lower miscarriage rates, often equal to or slightly better than amniocentesis rates4243.

There is a higher rate of miscarriage of aneuploid fetuses up until approximately 12 weeks into the pregnancy. The implication of earlier testing is that a biopsy could be performed, only for the fetus to naturally abort.

Unlike amniocentesis, CVS cannot detect neural tube defects so additional biochemical and/or ultrasound screening may be necessary at 15-20 weeks44.

The placenta is known to tolerate aneuploidy better than the fetus and it is possible for a placenta to have a mosaic or mixed pattern of cells; some with 46 chromosomes and some aneuploid. Thus, there is a risk of misdiagnosis of the fetal chromosome complement (karyotype), since it is inferred from the placental karyotype. Estimates suggest that approximately 1% of samples are misdiagnosed45,46, potentially leading to an unnecessary termination. It has been noted, however, that placental mosaicism is associated with miscarriage47.

chorionic villus sampling is the biopsy of the embryonic portion of the placenta, the chorionic villi that extend from the chorion. after dissection away from the maternal tissue, the tissue is tested using molecular or cytogenetic techniques. this test is performed approximately 10-12 weeks into the pregnancy. Before ten weeks, there is an increased risk of damaging the fetus causing severe limb reduction deformities48.

there are two main routes for the biopsy: either a catheter is passed up through the cervix to suction a small sample of the placenta or, more commonly, a needle is passed through the abdomen and uterus to take a sample. real-time ultrasound is used to monitor and direct the needle or catheter. if the sampling procedure fails to obtain tissue, then a amniocentesis can be performed later.

Non-invasive fetal testing is an interesting new technology in prenatal genetic testing. As an alternative to amniocentesis or CVS, it has the great advantages of early detection and procedural safety for the fetus. It broadens the group of women to whom prenatal testing can be offered, including women at lower risk of aneuploidy.

Fetal material was identified in the maternal blood stream and other tissues in the late 1960s50 and has recently been identified in cervical mucus51. Different types of fetal cells as well as non-cellular DNA and RNA can be detected in the maternal samples.

The technical key is to isolate and/or identify low quantities of the fetal material from a background of maternal cells and/or DNA. This is comparatively straightforward in male pregnancies as the XY karyotype is easily distinguished from the maternal XX karyotype. This is obviously not the case in female fetuses, although the sex of the fetus can be inferred by the absence of XY cells or DNA. A maternal blood spot-based test is already marketed as a baby gender test for use as early as seven weeks of gestation52. The company, however, has very recently been sued over its claim of 99.9% accuracy after a number of misdiagnoses53.

Genetic disorders of paternal origin are detectable in a similar manner. PCR can be used to identify genetic markers inherited only from the father, from a mixture of maternal and fetal tissue. This method has been used to detect paternally inherited Rhesus D antigen (for rhesus incompatibility)5455 and thalassaemia alleles56. The reliability of this method of testing is variable though and it only analyses the paternal contribution. It may be that the maternally transmitted allele for, say, cystic fibrosis is functional and the fetus is only a carrier and not affected. Consequently, the decision to terminate an established pregnancy based solely on this incomplete information, can be a difficult one. In this situation, however, the couple would obtain a full prenatal diagnosis before making any decisions.

Any non-invasive diagnostic tests beyond those for sex and paternal contribution require the accurate identification of fetal material. Currently the technology is not reliable enough to be used in a clinical context:

“...while fetal cells are present in the maternal circulation, there is not a robust and reliable enough method currently available to isolate them for widespread clinical applications.”57

There is evidence that fetal cells and DNA in particular turn over quite quickly, yet cells of fetal origin can also be found in mothers of male pregnancies years after giving birth. This may confound testing and give rise to false positive results, although detection is variable and it is thought that these populations are very small58.

Fetal material is genetically analysed using molecular and/or cytogenetic techniques. There is a possibility of contamination of the fetal material by maternal cells during the tissue sampling. This is carefully controlled for by fetal sexing, testing of multiple cells and the use of suitable test controls.

Molecular methods are relatively straightforward. Fetal material is concentrated and DNA is extracted. The applicable test is then performed.

Older methods of prenatal cytogenetic analysis (developed in the late 1960s) involve growing the cells in culture and inducing the live cells to divide. Once the cells are dividing they can be stopped at the metaphase stage of cell division, where the chromosomes are condensed. A trained cytogeneticist can derive a lot of information about the chromosomes from these metaphases, including numbers of all the chromosomes and any major structural arrangements. Unfortunately, this method can take up to two weeks to perform.

The technique used more commonly is interphase FISH59, either alone or in combination with metaphase cytogenetic analysis. The chromosomes at the interphase stage are not dividing and are a tenth as condensed as they are at metaphase60 so cannot be visualised in the same manner. Chromosome-specific probes, with fluorescent molecules attached, bind to the chromosomes if they are present. In this way, one, two or three fluorescent spots are detected where the probe has bound to one (monosomy), two (“normal”) or three (triploidy) copies of the specific chromosome. If there is a known structural abnormality, then probes can be specifically designed to detect it. (See Fig. 6 for an example of interphase FISH on a single cell).

Much less detail is obtained from interphase FISH and not all the chromosomes are screened, as they are in metaphase analysis. Too many fluorescent signals in one cell can interfere with interpretation of the results, so the fluorescent probes used are confined to those for the most common aneuploidies in 10-20 weeks old fetuses (e.g. X, Y, 13, 18, and 21). Thus, although it is sensitive for abnormalities of the chromosomes, it will not detect as many different abnormalities as cytogenetic karyotyping. Results can, however, be obtained within a week, as the cells do not need to be cultured.

Variations on comparative genomic hybridisation (CGH) are the latest technologies under development for prenatal testing (and PGD). CGH is a technique that compares the number of chromosomes or parts of chromosomes to those of a “normal” sample. The test DNA from the fetal material is labelled with fluorescent molecules of one colour (e.g. green) and the “normal” (reference) DNA is labelled with fluorescent molecules of another colour (e.g. red). The relative amount fluorescence can detect whether the test DNA has the same number, more, or less of each chromosome compared to the normal sample.

To do this, equal total amounts (in nanograms) of the labelled test and normal DNA are bound (hybridised) to a metaphase spread of “normal” chromosomes. In trisomy 21 for example, the fetal test sample would have one and a half times as much green fluorescence as the red normal DNA on the metaphase chromosome 21. This is because it has three chromosomes 21 instead of two. All other chromosomes should have a one green to one red fluorescence ratio giving an orange colour. This fluorescence information is digitally acquired and analysed.

As this technique does not require cell culture, the testing takes approximately three days to perform. It cannot, however, detect balanced translocations or whole genome changes where there are fewer or more copies of all the chromosomes, as the ratios of test to normal DNA are constant63. Whole genome or “ploidy” changes tend not to form viable pregnancies.

This example of CGH on chromosome 1 shows a gain aneuploidy (trisomy) in the test sample in green and a loss aneuploidy (monosomy) in the test sample in red, compared to a normal DNA sample. The yellow areas are an equal signal from the green test DNA and the red normal DNA, indicating an equal amount of DNA (no aneuploidy). (Image sourced from Wells and Levy, 200364).

The most recent variation of CGH is where the fluorescently labelled test and normal DNA samples are hybridised to a microarray chip spotted with thousands of (characterised) fragments of DNA, representing all of the chromosomes. The microarray can be set up to screen for specific changes or for a whole genome screen. The information that can be discovered on chromosomal duplications and deletions using this technique is more detailed than any other technology, short of sequencing the whole genome. It can also be used to quickly screen for many other known mutations that might cause common disorders.

An example of an image obtained by CGH microarray. The yellow-green colour shows where the patient test sample has more copies than the “normal” DNA, the orange colour indicates an equal signal and the red is where there is more “normal DNA” than test DNA. (Imaged sourced from the Wellcome Trust Sanger Institute website65).

In the USA, a small number of commercial companies are now offering commercial microarray screening of fetal material from amniocentesis or CVS biopsy. The microarray chips are designed to simultaneously detect small deletions and insertions for a number of disorders, as well as larger segmental and whole chromosome aneuploidy. Baylor College of Medicine, in particular, is marketing a microarrray CGH with 850 known fragments of DNA (clones) to detect common and rare aneuploidies66,67.

Microarray technologies do have shortcomings. Reproducibility of results is a major issue and to control for this, two or three samples of each fragment of DNA are spotted in different places on to the microarray chips. The results from all of the replicate spots should be the same to be valid.

Natural human polymorphism introduces significant difficulties to using the technology, particularly for whole genome screening. The human genome is incredibly polymorphic and there are many deletions, insertions and inversions being discovered in populations, some of which are common and do not appear to cause disease68,69,70. This recent discovery of “large- scale” variation has implications for what is “normal” variation and for interpretation of results from these high density microarrays.

Microarray technologies and their implications will be further explored in Year Two of this research.

Review references: Braude et al, 200271; Sermon et al., 200472; Wells D, 200473.

PGD is an alternative to traditional prenatal testing, in which the embryos are genetically characterised in some way so that healthy embryo(s) can be selectively transferred to the uterus. The three principal clinical uses for PGD are for selecting against serious single gene disorders, for aneuploidy screening because of late maternal age and for aneuploidy screening because of recurrent miscarriage and/or IVF and implantation failure.

PGD was first reported in humans in 1990, as an alternative to prenatal testing and termination of pregnancies with male fetuses for X-linked diseases74. Female embryos were identified and transferred to produce two pregnancies, both twin girls. Chorionic villus sampling (CVS) at ten weeks confirmed the genetic diagnosis. That study involved five couples and the investigators noted:

“All of the women had previous terminations of affected fetuses but most had difficulties in conceiving; each couple expressed a preference for this approach even though, in most cases, a specific diagnosis capable of distinguishing normal males and carrier females would be possible later in pregnancy.”75

PGD has advantages over prenatal testing in a number of situations, i.e. it is an option where potential parents have an objection to termination of pregnancy, have had the trauma of a previous termination, have a history of miscarriages or if they already have an affected child76.

Reasons for avoiding termination can include religious, moral and emotional objections, as well previous experience. In addition to psychological impact, the physical risks of termination include bleeding, infection, perforation of the uterus, cervical tear or failure of termination. Such complications may affect about 5-7% of terminations early in the second trimester77.

In a study of patient experiences of PGD, Lavery et al. found that of 20 patients who used both PGD and prenatal diagnosis (66% of whom had had a termination), 40% of patients found PGD less stressful, although 35% experienced more stress; of those couples who contemplated a further pregnancy 76% would choose PGD, 16% would opt for prenatal diagnosis, and 8% no tests at all78.

Evidence suggests that previous experience of prenatal screening and termination, subfertility and/or the existence of a severely affected child or relative, tends to make PGD more attractive than prenatal screening79,80,81,82. This not to say that there are not concerns around using the technology: Potential damage to the embryo, a low success rate and use of IVF (for fertile couples) have been raised in the same studies as negative aspects.

PGD can be used to select embryos on the basis of tissue type. The reasons for tissue typing range from blood group incompatibility, in which the maternal immune system threatens the life of the unmatched but otherwise healthy fetus, through to HLA tissue typing so a tissue- matched embryo can be transferred, (hopefully) for the benefit of a sick sibling.

Preimplantation genetic screening or PGS aims to decrease the rate of miscarriage and increase implantation and pregnancy rates by using testing to screen embryos for chromosomal abnormalities. Analysis has shown that most miscarriages are genetically aneuploid83 and that aneuploidy risk increases with increasing maternal age. Most major aneuploidies cause embryo death prior to or just after implantation, the occasional exceptions being trisomy 13, 18 and 21 and some sex chromosome aneuploidies.

Later maternal age may influence the choice to use PGD for another reason: time. Increasing maternal age, particularly after approximately 35 years is linked to increased risk of aneuploidy, lowering the chances of a successful natural full term pregnancy84. Older prospective parents also have a smaller window in which to conceive and generally take longer to conceive. If parents choose prenatal diagnosis (e.g. for a single gene disorder), they must first become pregnant before testing and then may decide to terminate one (or more) affected pregnancies. PGD, even with a low success rate (~10-30% per cycle), may be a faster way to have a healthy child because only ‘healthy looking’ embryos are transferred.

Recent data have indicated that it is not only older women that have a high rate of aneuploid embryos; embryos from younger women also have a 40-50% rate of chromosomal number errors. There is a wide variation in individual rates, however, from 29% to 83%85.

PGD is preimplantation genetic diagnosis. One or two individual cells (blastomeres) are removed from an eight-cell IVF embryo. This biopsy is not performed any earlier or later than the eight-cell stage without jeopardising either the viability of the embryo or the timeframe required to complete the tests. These cells are tested for genetic markers: either cytogenetic (chromosomes) or molecular (DNA sequence). These tests are the same as those used in prenatal testing. However, there is a limited amount of tissue available for testing. Cytogenetic techniques are predominantly used to look for chromosome number abnormalities (aneuploidies) such as Down syndrome, although they can be used for some specific genetic disorders and for sexing embryos. Molecular tests are used to look for specific, characterised, heritable genetic diseases and for HLA tissue typing. Once the test results are known, healthy- looking, diagnosed embryos are returned to the uterus or frozen for future use.

The main source of data on PGD is the European Society for Human Reproduction and Embryology (ESHRE) PGD consortium. Approximately 66 testing laboratories and clinics internationally now contribute to the ESHRE database annually86. ESHRE also issue regular guidelines on best practice for PGD87 and other reproductive technologies.

IVF is the first step in the PGD process. Eggs are recovered from the stimulated ovaries and placed into culture media. As eggs are very sensitive to the environment (chemical and temperature), conditions are very carefully controlled and any manipulations, for example examinations down a microscope are performed on equipment heated to 37˚C. The laboratory is kept at a higher temperature than usual and great care is taken to ensure that no volatile chemicals, such as cleaning chemicals, are used in the lab. The eggs are fertilised, either by the addition of sperm to the culture media, or by the injection of a single sperm into the cytoplasm of the egg.

The success rate of IVF varies from clinic to clinic and is also dependent on maternal age and the specific reason for subfertility, if relevant. The success rate is estimated to be less than 30% per embryo transferred89, yet this is not significantly different to the estimated natural fertility rate per cycle.

There are potential risks to women from the use of IVF. Ovarian hyperstimulation syndrome is a problem that may arise during the artificial stimulation of ovulation in IVF. In a recent study, approximately 2% of 2500 cycles resulted in the woman being treated for moderate to severe symptoms90. Death, however, is very rare: to date, only one death has been attributed to ovarian hyper-stimulation syndrome in the UK in approximately 500 000 stimulated cycles91. Other risks of IVF include an increased rate of ectopic and multiple pregnancies92.

ivF is in vitro fertilisation or fertilisation “in glass”. the egg and sperm are brought together for fertilisation in a plastic dish rather than in the fallopian tubes of the woman. ovulation is hyperstimulated by daily hormone injections to produce more than the usual one or two eggs per cycle. a comprehensive summary of this process can be found in cohen (2003)93. the eggs are extracted from the ovaries by passing a long needle through the vaginal wall into the ovarian follicles that hold each egg. ultrasound images guide the operator. the number of eggs retrieved ranges from zero to 20 or more.

the eggs that fertilise and start dividing are either returned to the uterus or frozen for future use. in some instances, in an attempt to increase the chance of implantation in women that have had difficulties, the embryos are cultured through to the blastocyst stage. some apparently healthy embryos will stop dividing before this stage in culture and it is thought that they might also do this in utero. embryos are transferred using ultrasound to guide embryo placement. a drug regimen continues for a number of weeks to maintain the uterine conditions for any embryos that implant.

ICSI was first reported in humans in 1992, as a treatment for male infertility95. The literature to date shows no or a slight increase in congenital abnormalities in children, compared to IVF alone. The risks of ICSI are discussed further in Section 7.5.2: Risks of Malformation.

ICSI is recommended96 and is the method of choice in PGD laboratories. ICSI avoids contamination of the single blastomeres by extraneous sperm, which may interfere with the test results. Excess sperm from natural fertilisation will generate their own test signals, which could confuse the results from the embryonic cells, particularly in molecular testing. During cytogenetic testing, any sperm present will light up with the fluorescent probes used. These sperm could overlay the blastomere, interfering with the interpretation of the fluorescent signal from the embryonic cell.

icsi (pronounced ick-see) is intracytoplasmic sperm injection. it was first used as a way for infertile men to father a child, as sperm motility is not necessary. sperm are collected, either naturally or by direct extraction from the testes. one sperm is taken up into a very fine syringe needle after the sperm is immobilised97. this both prevents damage to the egg and releases enzymes that are required for fertilisation. the whole sperm is injected into the cytoplasm (non-nuclear part) of the egg as the tail is also crucial for cell division98,99. icsi is now used in PgD to minimise contamination of the genetic testing process by excess sperm.

Once the embryo reaches the eight-cell stage of development, it is biopsied. This is the most common stage to perform the biopsy. The embryo is held by a very smooth and rounded pipette, under a gentle vacuum. This vacuum can be released at any time.

The outer shell of the embryo, the zona pellucida, is breached using either local acid application or, more and more commonly, a laser. The laser is considered quicker and more precise and less blastomeres are destroyed or damaged when compared to the acid method100,101. These observed effects apparently do not affect the implantation and pregnancy rates between the two methods.

One or two cells or blastomeres from the embryo are gently aspirated from the embryo using a (~40_m bore) pipette102. The small precise movements of the equipment are controlled mechanically. The cleavage stage biopsy (of eight cell embryos) is now approximately 99% efficient103.

The timing of the biopsy is crucial. Removal of blastomeres any earlier than six cells is now rare as many laboratories are now taking two blastomeres104. Any later than eight cells, the blastomeres are beginning to compact and are harder to biopsy. Sampling can be done later than eight cells, but there is a risk that the embryo will be damaged and it is more difficult to

complete the testing before the embryos need to be transferred to the uterus. The embryos are returned to the incubators to continue to develop, whilst testing is completed.

eggs (oocytes) and sperm (spermatozoon) are formed through a division process called meiosis. this has many aspects in common with normal cell division (mitosis), except that the number of chromosomes is halved, from diploid (two copies of each chromosome) to haploid (one copy of each chromosome). in males, one diploid cell will divide twice to produce four haploid sperm.

in females, the process is slightly more complicated. one diploid progenitor cell will divide twice to produce one large egg (with all the nutrients) and two or three tiny polar bodies. only the egg can be fertilised. the polar bodies are by-products and quickly degrade.

in females, meiosis starts in utero, when fetal ovaries start forming all the eggs for the future reproductive years. the progenitor cells start the first division, but are “arrested” before the completion and sit this way in the ovary until puberty. at ovulation, the first division is completed and the cell divides into the primary oocyte and the first polar body. the second division only happens at fertilisation, so the majority of eggs never fully mature. at fertilisation, the primary oocyte divides again into the egg and the second polar body. the first polar body may also divide again.

in PgD, both the first and second polar body can be used to deduce the genetics of the egg.

Fertilisation occurs when a whole sperm penetrates the egg. initially there are two pronuclei, one from the sperm and one from the egg. these fuse to form the true nucleus that contains two copies of each chromosome (including two sex chromosomes) and the cell starts dividing. each cell will divide to produce one “daughter” cell so that one cell becomes two, two become four etc.

the eight cell embryo is achieved at approximately three days after fertilisation. after this, the cells start acting more as a mass than as individual cells. the blastocyst stage is achieved at approximately five to six days. this stage marks the beginning of tissue differentiation with the formation of the inner cell mass (which becomes the fetus) and the trophectoderm (which partly becomes the placenta).

the embryo “hatches” at around day six when the trophectoderm extrudes through the zona pellucida shell surrounding the embryo, the first step in implantation into the uterus. in an attempt to increase implantation, embryos (from ivF) are occasionally artificially hatched before being returned to the uterus. embryos cannot be held in culture any longer than five or six days if they are to remain viable.

Fertilisation. The male and female pronuclei are visible, indicating fertilisation has taken place. Two Cell Embryo. The embryo has started to divide and a nucleus is visible in each cell. Four cell Embryo and Eight Cell Embryos. The embryo continues to divide. Embryo biopsy for PGD occurs around the eight cell stage. Note the ring of the zona pellucida around the individual cells. Blastocyst. The embryo starts to differentiate into the trophectoderm (a layer of cells around the inside of the zona pellucida) and the inner cell mass (visible as the clump of cells at the bottom right of the embryo). (Image sourced from Guy’s and St Thomas’ NHS Trust website106).

In countries such as Germany, where embryo biopsy is prohibited, polar body analysis is an alternative method of diagnosis. Couples with concerns about damaging the embryo during biopsy can also use it in some circumstances. The polar bodies, relics of meiosis or the generation of the egg107, are extracted using a similar process to the cleavage embryo biopsy. The first polar body is aspirated from the egg soon after collection (or sometimes simultaneously with the second polar body), using a flattened pipette to pierce the zona pellucida. The second polar body is extracted in the same manner when it appears after fertilisation. The polar bodies can give a picture of the genetic composition of the egg by inference. This is not a direct testing method, as this would destroy the egg.

Polar body analysis can be used to screen for single gene, recessive disorders. Complete characterisation of an embryo is not required to ensure that it will be unaffected by a recessive disorder. As long as the embryo has one or no damaged alleles, it will not exhibit symptoms of the disorder (although it may be a carrier). Ensuring that the egg has a healthy allele fits this criterion, regardless of the genotype of the sperm that fertilises it108. Excluding eggs with the damaged allele from transfer will reduce the number of embryos available for transfer since these eggs could be fertilised by sperm with a functional allele, resulting in carrier embryos.

A disadvantage of polar body analysis is that it is an inferred picture of the egg only, not the sperm or the future embryo. It is not a definitive method for aneuploidy screening although it will give a lot of information, as much aneuploidy in the egg occurs during the first phase of meiosis and the formation of the first polar body109. Both polar bodies should be analysed to maximise accuracy of the genetic analysis.

It has been stated that polar body biopsy may be less invasive for the egg/embryo as the polar bodies are naturally extruded under normal circumstances110. The zona pellucida is artificially breached, however, and there is no published evidence to support or disprove the claim that polar body biopsy has no effect on embryo viability.

A major advantage of polar body biopsy is the extra time in which to perform testing, compared with a day three embryo biopsy. Where many tests are to be performed, such as simultaneous testing for aneuploidy, a single gene disorder and HLA tissue typing, both polar body analysis and blastomere biopsy can be used111.

Polar body analysis is not informative where the genetic condition is inherited from the male partner. There are no techniques in use for testing a sperm without destroying it. There have been some work on a technique for duplicating a sperm, testing one nucleus and using ICSI to fertilise an egg with the other. This, however, is highly experimental112 and embryo biopsy or prenatal testing are the only clinically available methods for use with genetic disorders from the male parent.

The small polar bodies are biopsied from a very early embryo that still has two pronuclei. (Image sourced from Braude et al., 2005113).

Accuracy of the genetic testing is crucial for PGD. Whilst more than one thousand healthy children have been born through PGD (from approximately 7000 cases)115, there have also been a small number of reported misdiagnoses116,117. A recent review of three major laboratories reported five misdiagnoses from a total of 754 live births118. Encouragingly, the latest ESHRE PGD data, covering cycles and pregnancies in 2002, reported no misdiagnoses from 382 babies119. Cytogenetic analysis by FISH appears to be slightly more reliable than molecular analysis120. Couples must be informed of the risk of misdiagnosis during pre-PGD counselling and encouraged to consider prenatal testing to confirm the original embryo diagnosis121. Anecdotally, however, uptake of prenatal testing is low.

Mosaicism, or genetic variation between cells, is common in human embryos. For PGS in particular, this is a major problem. Whilst a blastomere may demonstrate aneuploidy, further analysis occasionally shows that this was not universal in the embryo. A proportion of embryos that are diagnosed as aneuploid can later “self correct”, with subsequent testing revealing a “normal” embryo122. This could lead to viable embryos not being transferred in a situation where every healthy embryo is crucial. At worst, a largely aneuploid embryo (that had earlier been diagnosed as healthy) could be transferred, resulting in miscarriage or an aneuploid pregnancy. Genetic testing of two blastomeres reduces the risk of misdiagnosis due to mosaicism.

The techniques used to analyse cells from PGD and polar bodies are essentially the same as those used in other forms of genetic testing, including prenatal testing (Section 6.5). The differences are in the sensitivity of the test and planning and preparation for testing. In addition , the need for rapid testing currently excludes more time consuming procedures from use.

Molecular genetic techniques in PGD are used principally for the identification of small mutations that cause serious single-gene disorders.

In standard molecular or PCR-based tests, the test sample of DNA (the template for the reaction), typically contains thousands or tens of thousands of copies of the genome. PGD involves the sampling of one or two cells, tested individually. With one copy of the genome in each cell, technically, this is a much more difficult process.

In established genetic testing laboratories, testing protocols will be running successfully for many common disorders. Other tests will need to be developed specifically for a family. To maximise the chances of successful testing, each test must be carefully validated and carefully controlled. DNA samples from both parents are analysed, prior to any IVF treatment, to ensure that the existing or new tests will work on that couple’s genetic background and the specific mutations they carry. Individual lymphocytes from a parental blood sample are used in the final stages of testing.

To increase sensitivity of the reaction and detection of PCR products, a number of variations on the basic PCR protocol are used. Fluorescent molecules are used to label and quantify the PCR products, increasing the sensitivity of the test. It is also straightforward to monitor a fluorescent PCR reaction in “real time” (as it occurs), revealing how efficient the PCR reaction was.

To increase the specificity of testing, a method known as nested PCR is used to selectively “pre-amplify” specific regions of interest. Large pieces of DNA are pre-amplified in an initial round of PCR, before the actual molecular test in a second round of PCR. The pre-amplified larger DNA fragments contain the primer binding sites for the molecular tests and some more sequence either side. The mutation test primers bind to internal areas of sequence in the pre-amplified DNA fragments. Nesting means that the occasional random piece of DNA amplified unintentionally (as often happens in PCR) is less likely to be a template for the specific mutation test. The random fragments do not have the known areas of sequence (for the test primer to bind to) nested inside the intentionally pre-amplified DNA fragments.

To increase the utility of testing (and reduce misdiagnosis), many tests are combined into the same PCR reaction. This multiplexing enables more information to be produced for analysis from just the one cell. As well as the actual mutation(s), a number of other molecular markers near the mutation are analysed.

A phenomenon called allele drop out is the most common type of PCR failure in PGD. This is where one of the embryo alleles is preferentially amplified (or copied) over the other. If a damaged allele only is amplified then the embryo would be diagnosed as affected when it may or may not be. If the healthy allele only is amplified then the embryo is diagnosed as healthy. The most reliable PCR result is when one healthy and one damaged allele are amplified. Allele drop out can be usually be picked up by analysis of one or more highly variable markers close to the mutation site in the DNA. Maternal and paternal cells are analysed concurrently with the embryo cells. With the extra information from the other markers and by comparing it to the parental results, not only can it be seen whether the PCR worked properly but also how the

alleles are being inherited by the embryo (from the mother and father). The embryo results should be half like the paternal results and half like the maternal results.

There are many other opportunities for the PCR test to fail. With just one or two cells to analyse, care must be taken at biopsy onwards not to lose any of the exceedingly small blastomeres. The extreme sensitivity of single cell PCR increases the likelihood of contamination from other DNA, even from an extra sperm or a single particle of dust. ICSI fertilisation is used so that no extra sperm are present, any cells surrounding the fertilised egg or embryo are stripped off, and special “clean” laboratory practices are used to minimise the opportunities for contamination by skin cells or dust.

Controls are built into the testing procedure. Samples of water (used to wash the biopsied blastomeres) are analysed to make sure that they do NOT produce a result (from contamination). Often, samples with different (known) combinations of alleles are tested, to make sure that they give the expected results. Analysis of two blastomeres from the one embryo (if available), should give identical results. By comparing the maternal, paternal and embryo results with the controls, geneticists can see if there is a problem. Embryos are not transferred if they yield uncertain or ambiguous results.

Whole genome amplification (WGA) is a new method for copying the DNA in the nucleus many times over (up to 1000 times)123. It is an extreme combination of multiplex and nested PCR to amplify the whole genome of a cell. This has the potential to increase the accuracy of the test by increasing the copies of the DNA area of interest, as well as allowing multiple tests, either as controls and/or because more than one test is needed, for example in HLA tissue typing testing. It is used in newer diagnostic methods that can screen the whole genome, such as comparative genome hybridisation (CGH) and microarray CGH. Some areas of the genome are technically difficult to copy and regions with multiple repeat sequences and the middle (centromere) and ends of chromosome (telomeres) are not usually amplified. Careful controls must be used to ensure that areas needed for testing are actually amplified. Clinical use has been limited due to time constraints between biopsy and embryo transfer124.

Pcr is a technique used to exponentially copy a defined area of Dna. Many copies of a piece of Dna are easier to manipulate and analyse.

the specific area to be copied is known as the template. short Dna “primers” are designed to bind to the Dna template of interest in such a way that they define and limit the area (start and finish) of Dna to be amplified. these primers, synthesised in the laboratory, are essential to start or “prime” the reaction.

nucleotides are the building blocks of Dna. the enzyme, Dna polymerase, chemically joins individual nucleotides to create a long chain of Dna (i.e., a polymer of nucleotides). the Dna polymerase cannot start without at least a short piece of double stranded Dna to add nucleotides to, in this case the primers bound to a single strand of Dna

template. the (originally) double stranded Dna template is made single stranded by heating to 95˚c, then rapidly cooling. the polymerase enzyme adds nucleotides on to the ends of the bound primers, using the original Dna strand as a guide or template.

one double strand of Dna becomes two identical double strands as each of the original strands is “complemented” in a “cycle” of Pcr. as this cycle is repeated, the template (now two pieces of identical Dna) is again made single stranded, more primers bind, the polymerase extends off them and two double strands become four, four become eight with the next cycle etc., etc. approximately 30 of these cycles are repeated. From one defined double-stranded piece of Dna, theoretically 1,073,741,824 copies of the template Dna can be made in 30 cycles; in practice it is less.

there is a limit to the size of the Dna that is amplified. Between 100 nucleotide pairs and 2000 nucleotide pairs is routine. any longer than this requires special reaction conditions.

Fluorescent in situ hybridisation (FISH) is used for identifying chromosomal translocations, embryo sex for X-linked disorders and aneuploidy. The principal use is to minimise the risk of recurrent miscarriage and IVF failure. The technique employs chromosome-specific DNA probes with fluorescent labelling to detect chromosome anomalies.

Because of time constraints, cytogenetic testing in PGD is restricted to FISH analysis of interphase (non-dividing) cells. There have been attempts to induce the biopsied blastomeres to condense, as for FISH on metaphase (early cell division) cells. This nuclear transfer or conversion technique involves fusing the blastomere with human or mouse eggs, followed by chemical treatments125. It does not appear to have been incorporated into the testing repertoire, however, at least in the published literature.

European Society for Human Reproduction and Embryology (ESHRE) best practice guidelines recommend that at least five chromosome pairs from 13, 14, 15, 16, 18, 21, 22, X and Y be used for aneuploidy screening126. Each chromosome-specific probe is labelled with a different fluorescent colour molecule. If too many probes are used at once, interpretation becomes a source of error from overlapping and hidden fluorescent signals. Some laboratories are now using one set of FISH probes on individual cells, washing the probes off and using a second set of probes. In this way, more chromosomes can be screened, yet this is still short of a full chromosome screen and the embryo may still be aneuploid.

Contamination during cytogenetic testing is not such a problem as in molecular testing but it is recommended that maternal cells surrounding the embryo (cumulus cells) and extra sperm be removed. These maternal cells could be confused with the embryonic blastomere and both sperm and maternal cells could overlay the blastomere and prevent analysis of the embryonic cell.

Whilst FISH is fast and has a higher accuracy than molecular testing, it also has its limitations. Failure is variously estimated to be between 5% and 12%127. Whilst this could lead to affected embryos being transferred, the biggest dilemma is that otherwise healthy embryos are not transferred due to an ambiguous result.

Many commercial kits are available for aneuploidy screening. For translocations, however, most couples have a unique breakpoint. This can entail development and extensive testing of a new set of probes for each translocation. Translocations can be hard to diagnose using interphase FISH. In some situations, it is impossible to differentiate between “normal” embryos and balanced translocation carriers. Whilst carriers are typically healthy, they are likely to have fertility problems of their own later in life. The translocation causes carriers to form a proportion of unbalanced gametes and as a result, aneuploid embryos.

FISH performed on an interphase stage cell shows three spots from the green probe: a chromosome 21 trisomy or Down syndrome. (Image sourced from Fertility Associates website128).

After genetic testing is complete, embryos for transfer are separated from those with specific genetic problems.

A number of ‘healthy looking’ embryos are transferred to the uterus, if available. How many depends on the number available and the likelihood of implantation, as with IVF. One might be transferred if the mother is young and has no fertility problems; more embryos are transferred when there is a history of implantation failure or the mother is older. To reduce the rate of multiple births, the number of embryos transferred is kept to a minimum.

There is an additional tension where PGD is funded privately. The cost of treatment results in pressure for a pregnancy at each attempt. This is increased by the fact that PGD embryos do not freeze well and storage for later embryo transfer has a low rate of success (discussed later in this section). It is difficult to adhere to a single embryo transfer policy when this might be a couple’s only attempt at PGD, yet multiple fetuses also put the pregnancy at risk. This is a situation where it is important for the risks and benefits to be discussed by clinicians and couples. The improving embryo freezing techniques under development and increasing pregnancy success rates will eventually mitigate this problem to some extent.

Currently, embryos are judged as fit for transfer to the uterus using morphology - they are selected if they “look good” according to the embryologist’s judgement. Criteria include early cleavage, one defined nucleus per cell, no fragmentation and evenly matched cell sizes, although there are many conflicting reports on these aspects129. There is a great deal of research activity to identify markers for embryo viability and likelihood of implantation. Some of this work shows that many eight cell embryos that “look good” are in fact aneuploid and, vice versa, occasionally a few embryos that would not normally be selected are in fact euploid and can develop into healthy children130,131,132.

It is desirable to be able to preserve spare embryos from a PGD cycle. Some couples with single gene disorders and strong views about the sanctity of the embryo may opt to freeze affected embryos in the hope of a cure for the disorder in the future.

Freezing (cryopreservation) of surplus embryos for a later cycle in IVF is a standard technique. Biopsied embryos, however, are extremely sensitive to the process of freezing and thawing, presumably because of the breach of the zona pellucida. The blastomere survival rates following thawing typically have been so low in the past that it was considered not worth trying to preserve embryos that were not transferred fresh.

Embryo survival is defined as those embryos that have 50% or greater blastomeres intact after thawing. Blastomere survival following thawing is considered an indicator of later successful implantation and pregnancy: the more blastomeres that survive, the greater the chances of a _pregnancy133,134,135_.

Embryo freezing would enable more extensive testing of the biopsied blastomere(s) by allowing more time for testing. Typically, there is up to two days between biopsy and replacement of the embryo in which to complete all required tests. This could be extended indefinitely if cryopreservation could be used on biopsied embryos136.

Freezing technology is constantly improving and better freezing protocols and solutions will be developed137,138. These improvements will also enable the use of different and more time intensive testing technologies. Additionally, it seems that blastocysts may be more resistant to the freeze/thaw and so would be better candidates for cryopreservation139.

Trophectoderm biopsy is the sampling of the differentiated trophectoderm tissue from the blastocyst stage embryo (approximately five to six days). The trophectoderm goes on to form part of the placenta once implantation occurs. The zona pellucida surrounding the embryo is breached or “hatched” on day three or four by laser. As the embryo starts to differentiate, the trophectoderm extrudes and is biopsied.

Technically, this is not a new methodology140 but the limited ability to culture embryos long- term prevented its widespread application until recently. With the development of sequential culture media (media that is specifically for different stages of development), interest in the technique has revived.

There are a number of advantages of trophectoderm biopsy. Approximately five to twenty cells can be taken for analysis, which improves the accuracy of the testing. The mosaicism seen in eight cell cleavage embryos is possibly resolved by the time the blastocyst stage is reached, decreasing the chance of misdiagnosis. The inner cell mass, which goes on to form the fetus, is not biopsied, theoretically improving the safety for the fetus. Screening embryos later is though to be efficient. A number of embryos that would be genetically analysed with cleavage stage biopsy never actually develop to blastocyst stage, therefore fewer blastocyst embryos need to be analysed. With the higher embryo quality, less embryos can be transferred, reducing the risk of multiple pregnancies. Finally, blastocyst embryos appear to be more (although not completely) resistant to freeze/thaw stresses. Fewer embryos can be transferred in the knowledge that spare frozen embryos can be thawed at a later stage, if the first embryo transfer fails.

The great disadvantage of trophectoderm biopsy is the reduced time in which to complete genetic testing. Most tests can be completed in 12 to 24 hours, although this does increase the pressure to complete them. The improved freeze/thaw tolerance provides another option if time is short or if more extensive testing is required. The other drawback is that the trophectoderm may not be representative of the inner cell mass that goes on to form the fetus,

i.e. the embryo is a mosaic. Consequently, an embryo that could result in a healthy child will not be considered for transfer, or alternatively, an embryo that could result in an aneuploid pregnancy could be transferred.

There have been a number of papers published by major laboratories in Australia recently141,142,143. The indications are that most if not all, Australian laboratories are seriously investigating the technique and possibly intend to move to trophectoderm biopsy for PGD.

Comparative genomic hybridisation (CGH) and microarray CGH technologies have been discussed in section 6.6: Up and Coming Technologies. Many issues relating to their use in prenatal testing are the same in PGD. Some aspects are, however, unique to PGD and the technology is still in the early stages of development for PGD.

In PGD, it takes typically one to two days to complete genetic testing before embryos must be stored or transferred. CGH and microarray analyses currently take around three days to complete, although there are some developments in “fast” protocols146. The use of cryopreservation with these new methods will substantially reduce the pool of embryos for transfer as biopsied embryos are particularly sensitive to the freeze-thaw process. There will not be widespread use of CGH technology until efficient freezing technologies and/or reliable fast protocols are developed.

The need to use whole genome amplification (WGA) is a vulnerability in the use of CGH and microarray CGH147. WGA is unable to amplify certain regions of the genome, particularly those rich with repeat sequences. This may preclude its use for diagnosis of disorders caused by repeat sequences, such as Fragile X. It also raises the spectre of increased misdiagnosis through uneven copying (amplification) of genome. This technique is not necessary in prenatal testing as the quantity of tissue biopsied is much greater.

If the reliability issues of WGA can be solved or bypassed, then CGH and microarrays have increased capability to detect aneuploidies over interphase FISH protocols. The improved detection has the potential to increase the success rate, of not just PGS but also PGD, through increasing implantation and reducing miscarriage. All 46 chromosomes can be screened for aneuploidy and segmental aneuploidy can be detected, not just whole chromosome changes. Translocation screening becomes much more straightforward and not so dependent on test design. Reciprocal translocations, where there are no changes in the number of chromosomes (just the position), are, however, undetectable. With microarrays, multiple traits can be screened for, so the single gene disorder and aneuploidy screening can be performed simultaneously on one DNA sample. The inability to detect whole ploidy (all the chromosomes) changes is more of a problem for PGD screening of embryos, as these could be transferred as “normal” embryos.

The same reservations around what is disease-causing and what is natural polymorphism exist for PGD and prenatal screening. This will be explored further in Year Two.

There are a number of uses of PGD, other than for serious disease and aneuploidy screening. This section will merely review the technology, not the ethical implications and other concerns raised.

Sex selection for the diagnosis of X-linked disorders was one of the first uses of PGD. Sex selection for social reasons is banned in some countries (such as New Zealand) and not in others (such as the USA). The technology is probably the most straightforward of all the PGD applications to date.

Most carriers of damaged alleles will never suffer symptoms of the relevant disorder. Some families, nonetheless, are using PGD to select against carrier embryos. This substantially reduces the chance of the disorder occurring in the family in future generations. Carrier screening implies, however, that embryos that have the potential to become healthy children are not implanted. Again, the technology is the same as that used when screening for embryos affected by serious disease.

Families are starting to use PGD for disorders that have a later onset (such as Alzheimer disease) that are not fully penetrant and that are susceptibilities or predispositions (for example, to cancer).

PGD is already in use for Huntington disease - a dominant, serious, fully penetrant, but late onset disorder. Other recent uses include familial early-onset Alzheimer disease148 and a number of familial cancer predispositions, such as early onset colon cancer (familial adenomatous polyposis, FAP) and BRCA 1 and 2 mutations for breast and ovarian cancer. FAP often occurs in the early teens and is fully penetrant. Breast cancer resulting from BRCA mutations has later onset and is approximately 80% penetrant (by age 70) and 6% for males149.

There are no particular technical difficulties associated with this type of testing, if a single gene can be identified for testing.

Some disorders, including haemoglobin disorders such as sickle cell anaemia and the thalassaemias are able to be cured using a bone marrow or a stem cell transplant150. Tissue typing is performed so that the transplant is not rejected by the recipient’s immune system. The immune system recognises proteins on cells as “self” or “foreign”. If certain proteins are identical in the transplant material and the recipient, the transplant will be (mistakenly) recognised as self.

HLA proteins are the major proteins identified as foreign and self. HLA proteins are strong stimulators of the immune system (antigens) and highly variable, with many alleles in the population. If the donor and recipient tissues are matched then the recipient immune system is unlikely to reject the transplant. Where there is an affected child who could be cured with a stem cell transplant and a compatible donor is not available, a family can choose to use PGD to ensure that their next child will have identical HLA proteins. With many single gene disorders, PGD can ensure that the next child is unaffected, as well as being a tissue match for the sibling. If the next child is a tissue match then stem cells, taken from the umbilical cord blood at birth, are transplanted into the affected sibling.

Preimplantation tissue typing can also be used for the sole purpose of ensuring the embryo is a suitable stem cell donor for a future transplantation to an affected sibling. This situation would apply if the affected sibling had a leukaemia.

Technically, the testing is more involved than for simple single gene disorders. Approximately six to ten different tests are performed to ensure a tissue match alone151,152,153. These genes are inherited as a gene block on chromosome six and are not scattered over the genome. There is a one in four chance of an embryo being a match for its sibling (similar to a single gene disorder). Chromosome copy number is often tested simultaneously, firstly to ensure that aneuploidy is not interfering with the test result and often because of maternal age, to increase the likelihood of a pregnancy.

Embryonic stem cells hold promise for treatment of particularly degenerative disease. To generate these stem cells the inner cell mass is removed from an embryo, destroying the embryo for reproductive purposes154. A recent innovation in the field of stem cell biology is the creation of stem cell lines from blastomeres, extracted from an embryo using PGD. It has been shown that blastomeres can be taken from mouse embryos and used to start embryonic (and trophoblast) stem cell lines155. The embryo remains viable. It is not yet know whether this technique will work in human embryos.

Advantages (and disadvantages) of PGD and PGS have been woven through the description and discussion of these techniques. It is worth restating, however, that the principal advantages of the procedures are that diagnosis and negative selection are performed before there is a pregnancy to terminate, and that the technology may increase the chance of a pregnancy and reduce the rate of miscarriage in “at risk” women.

There are, however, a number of negative aspects to the technologies. Prospective parents should be advised of these risks before treatment begins so that they can make informed decisions about their treatment options. Most, if not all, clinics offering PGD have genetic counsellors on their staff and counselling is incorporated into the European Society for Human Reproduction and Embryology “Best practice guidelines for PGD”157.

PGD does not guarantee pregnancy. Cumulative loss or complete failure will occur at any stage of the process, through ovarian stimulation, egg recovery, fertilisation, embryo division, genetic testing (from ambiguous or disorder-positive results), implantation and full term pregnancy. The embryo biopsy actually has a very low published failure rate of approximately 1%158. Aside from the biopsy, only the genetic testing is unique to PGD compared with IVF for infertility. In the most recent ESHRE review, 91% of embryos were successfully characterised genetically159. All other risks of and embryo loss in PGD are shared by the IVF process and to some extent, natural fertilisation. The implantation rate for PGD is often slightly higher than in IVF control groups because there are not the confounding subfertility factors, although approximately 20-30% of couples using PGD will have fertility problems as well160.

Despite the number of fertile couples using the technology, the successful birth rate using PGD is disappointingly low161. This is to be expected in older women and women with recurrent implantation failure, yet a number of young, fertile individuals are also using PGD (for single gene disorders in particular). The average age of women using PGD is 32 and 38 for PGS162. The clinical pregnancy rate per egg retrieval in the latest ESHRE review was 18%, 18% and 24% for PGD (including chromosomal translocations), PGS, and social sex selection respectively. A higher rate is reported (as expected) when pregnancy per embryo transfer is reported (23, 25 and 34% respectively). Total live births per egg retrieval was 15%, including a small number of twins163.

PGD is not a guarantee that any resulting pregnancy and child will be perfect, or even healthy. The genetic testing can only find what is looked for so, for example, whilst a fetus may be free of the Tay-Sachs disease it was screened for, it may be born with cystic fibrosis. Aneuploidy is a risk, both when single gene disorders are analysed (without aneuploidy screening) and because of the restricted number of chromosomes screened using interphase FISH.

Aside from chance or undiagnosed abnormalities, misdiagnosis is the other key challenge of PGD. This is discussed in more detail in Section 7.2.5: Preimplantation Genetic Testing. Given the sensitivity of the testing, the reported misdiagnosis rates are surprisingly low. The three principal reasons for misdiagnosis are:

There has been one report of a misdiagnosis that was possibly through a natural pregnancy from unprotected sexual intercourse around the time of egg recovery, during IVF164.

It is important that misdiagnosis is reported. Useful and sometimes surprising information can be derived from such an analysis. By encouraging awareness of a particular problem, it can be avoided in the future and/or be solved165.

A serious technological limit on PGD is the low success rate of cryopreserving or freezing embryos. The time between biopsy and embryo transfer limits the testing procedures that can be used. Successful storage of spare embryos would reduce the number of IVF cycles and therefore the cost involved with using PGD.

PGD is a relatively new (1992) technique. It is considered invasive to the embryo as the zona pellucida is prematurely breached and blastomeres are removed. The embryo, however, is a very plastic entity. The (natural) early division to create identical twin embryos, the percentage of cells surviving freeze/thaw in IVF and the successful use of embryo biopsy illustrate just

how tolerant the early entity is to physical insult. The long term consequences for children born from the technology are, however, unknown.

The European Society for Human Reproduction and Embryology (ESHRE) collects PGD data from many European and a number of other institutions (currently 66 internationally167). There have been close monitoring up to birth to ensure there are no particular risks resulting from use of the PGD technology, especially from the embryo biopsy (other potential risks are shared by the IVF and ICSI techniques). There are, however, no published data on the later health of PGD children as they grow and mature.

It is a generally reported trend that children born through the use of IVF have a slightly higher rate of serious congenital malformations than do their naturally conceived counterparts (especially diseases resulting from imprinting errors, such as Beckwith-Wiedemann syndrome168). This is true even when studies are limited to singletons, who have a lower malformation rate than twins and triplets169. It has also been reported that children conceived using the ICSI technique have an additional risk of congenital malformations in some studies170 but not others171,172,173. There is a great deal of controversy over the size of the risk to children conceived through IVF with or without ICSI.

There are many confounding factors in the interpretation of these types of studies. There are few data on whether the original subfertility or infertility is, in itself, a risk factor. There are reports of increased obstetric complications in subfertile women who conceive naturally, including increased risk of death of the fetus or child174175176. In a recent study that looked at subfertile women with singleton pregnancies, IVF and ICSI were compared to natural and intrauterine insemination methods of ovulation induction. These data suggest that reduced duration of pregnancy and low birth weight are direct results of the IVF and/or ICSI techniques177. It is, however, for the most part difficult to extrapolate these findings to congenital malformations, although De Geyter et al.178 suggest that abnormal imprinting may provide an explanation for some of the observed effect.

There are also design faults in many of these studies. As ICSI is a relatively new technique, sample sizes in studies are often small. There is no single method for classification of major and minor malformations and so different studies use different classifications. It is also difficult to isolate which aspect(s) of reproductive technologies may be contributing to this result (ovarian stimulation regime, culture media, freeze/thawing, drugs to support the initial pregnancy, etc.) as there are many protocols for each179. In register-based studies, these factors are not generally taken into account, although they should be similar in single organisation studies.

Follow upstudies indicate noappreciable differences in health, motorandcognitive development between ICSI and naturally conceived children at five180,181,182,183 and eight years184. There was, however, an increase in the number of urogenital malformations in ICSI males, perhaps a result of paternal infertility factors being genetically inherited185. Ongoing monitoring will look for later onset disorders and susceptibilities that may result from, for example, imprinting disturbances. It has also been reported that IVF children were taller (particularly girls) than naturally conceived children and had “more favourable” lipid profiles186.

It is important to remember that these studies are reporting the increased risk of malformation and that the actual numbers of malformations, with or without fertility treatments, are not dissimilar. Olivennes notes:

“The malformation rate in the general population is in the area of 1%-3%. A 30% increase puts this rate at 1.3%-3.9%. This means that more than 95% of children are not carrying a malformation.”187

In fact, the greatest risk factors for IVF (and other) children are multiple births and maternal age188. These factors are accounted for in selecting control cohorts for these studies. Nonetheless, twin pregnancies (more common in IVF pregnancies) and older maternal age are both associated with premature birth, lower birth weight and higher risk of neonatal mortality.

As yet, there are very few data on the safety of PGD. The technique is new and the numbers of children produced are in the low thousands and found all over the world. The latest ESHRE PGD consortium data189 concluded:

“It is now clear from these different reports that the pregnancies obtained after PGD are quite comparable to those obtained after ICSI (Bonduelle et al., 2005), giving a first indication that embryo biopsy is not detrimental to the course and outcome of pregnancy. As in ICSI, no particular complication stands out, and the most important problem remains the multiplicity, causing most of the morbidity and mortality.”190

There is, however, an immediate need for more follow-up data to systematically monitor children past the neonatal stage, for more subtle problems that may or may not arise from _PGD191,192_.

PGD is technically very demanding and its current, apparent reliability is a significant achievement. It is a positive technique for a number of families where there is a characterised, serious heritable genetic disorder.

The concept of “designer babies” or the use of selection for enhancement of nonmedical traits has been the subject of media and popular discussions. Nonmedical genetic testing can be applied to the prenatal testing context although there seems to be less discussion of this in relation to “designer” children. The controversy appears to be around the (currently) theoretical possibility of using PGD to select for or against more complex or behavioural traits. There are, however, technical limits to the use of the technology for these purposes.

PGD is purely a diagnostic technique and it does not involve technologies (principally genetic modification) to “improve” embryos. Such modification is not technically possible currently. Whilst genetic modification of embryos is routinely carried out in some species, the limitations and long-term effects in human embryos are uncertain and in countries where there is regulation, germline therapy or genetic modification of embryos is, for the most part, outlawed.

The current usage of PGD is negative selection, where the seriously affected embryos are removed from the pool of embryos available for transfer. It is not selection of the genetically elite embryos.

It is conceivable that there are “desirable” traits that are relatively simple genetically. One clear example of this is sex and the desire to choose a child of a particular sex for social (nonmedical) reasons. There may be others where there is a major gene effect: absolute or perfect pitch is the ability to identify and/or vocalise a specific note without an external reference. Whilst the genetic basis is not understood, it is likely to be heritable, possibly as a predisposition with a major gene and environmental effects193,194. The vast majority of examples used to illustrate the concept of “designer” babies are, however, complex and often (as with absolute pitch) multifactorial, with environmental effects on the phenotype expression.

Only a small number of markers can be used for testing a batch of embryos before all the embryos will test positive or negative for something. This issue conflicts with the vision of the future presented by some media and commentators, where embryos are characterised and embryos that have predispositions for any perceived negative trait are discarded. Take, for example, a complex trait determined by just three genes. If both parents are heterozygous (carriers) for each gene, the chance of an entirely negative or positive embryo is practically nil. Even examination of two genes will reduce the chances of a completely negative or positive embryo to one in sixteen. If more than one complex trait is tested for then most couples will have no absolutely negative or positive testing embryos. This does not take into account the significant environmental effects usually seen in multigenic traits.

The opportunity to select for or against a complex social trait such as intelligence or “criminality”, whilst theoretical, is also limited. Currently, the genetic basis of social traits is understood poorly. These traits also tend to have a high environmental component. For example, a common 5-HTT gene variant or allele (a serotonin transporter) that plays a role in depression is only an influence, not a determinant, if the carrier has had many stressful life events or has been abused. Two copies of the predisposing allele were shown to have a stronger effect than one. If the carrier had a happy childhood, then it has no significant role in the development of depression195. There is a similar antisocial behaviour effect linked to a MAOA gene allele and childhood maltreatment196. In other words, these genes help determine how people deal with their environment. It would be more effective and practical, perhaps, to intervene where children are in high-risk family situations.

Another limitation of the “designer” babies concept is that selecting for particular “desirable” genetics is only possible if those desirable genes are carried by the biological parents. If (to use a frivolous example) a blue-eyed couple (recessive eye colour) desire a brown-eyed child (dominant eye colour), they will be disappointed as neither of them carry a gene variant or allele for brown eyes. It is simply not possible for this couple to have a naturally brown- eyed baby. Whilst you could (theoretically) select for the best possible combination of genes available to produce a mostly intelligent child, you are limited by the numerical limitations of complex traits already discussed, as well as the environment provided by the parents. It will not be possible to produce a family of so-called geniuses using PGD technology alone, if there is no genetic background (and appropriate environment) to facilitate this.

These nonmedical complex traits might become genetically well characterised in the future and the information may show how the genes and environment interact but it is unlikely to make the selection of “intelligent embryos” any easier. Mate selection and manipulation of environment are easier and cheaper ways of having a more significant effect on “desirable” characteristics than technology and positive selection of “the right genetics” ever will have on children. It is likely, however, that debate will continue on what constitutes a serious genetic disorder.

New Zealanders have had to travel to access PGD until recently, a situation known as reproductive tourism. The majority have used clinics in Australia and, anecdotally, most procedures have been for serious monogenic disorders rather than PGS. There is no record of how many New Zealanders have taken this path. Now that PGD is legal in New Zealand, a number of organisations have shown an interest in developing the skills base to offer the testing to couples.

Fertility Associates, an Auckland-based fertility treatment centre, is the first to offer New Zealand-based PGD. They are using a permutation termed “transport PGD” (also known as satellite PGD) in which the genetic testing is performed in a specialised, centralised laboratory. This technique is also used in Australia and other countries so that people outside main population centres can access PGD.

The embryo biopsy is performed in New Zealand in the Auckland laboratory using a laser to pierce the zona pellucida. The biopsied cells are placed in a buffer solution in a tube for PCR analysis or on a microscope slide for FISH analysis. The cells are then couriered to Monash IVF in Melbourne (Australia) for genetic analysis. This takes approximately six hours or overnight from clinic to clinic. The testing at Monash IVF takes between 24 and 36 hours. Once the results are communicated back to Auckland, suitable blastocyst-stage embryos are transferred to the uterus.

Monash IVF is contracted to provide testing for five major conditions: Huntington disease, cystic fibrosis, spinal muscular atrophy, beta-thalassaemia and Fragile X syndrome. They will also provide aneuploidy screening using probes for chromosomes 13, 15, 16, 18, 21, 22, X and Y, sex-linked analysis (for X-linked disorders) using X, Y, 13, 18 and 21 probes and reciprocal and Robertsonian translocation analysis. Any testing for conditions outside this contract can be performed on a case-by-case basis. Feasibility and test validation is undertaken for each single gene test outside the five mentioned above and all translocation tests. The charge is currently approximately AU$900 and can take up to six months to complete197.

According to the agreement, consent, counselling and ethics approval services are to be provided by Fertility Associates and the procedures must comply with both New Zealand and Australian law. Fertility Associates must recommend prenatal screening to ensure that no errors have occurred in the genetic testing. There is also a staff training agreement to train and maintain skills for the biopsy and cell fixing198.

Transport PGD to Australia may not be feasible in the long term, however. The three principal clinics offering PGD in Australia (Monash IVF, Melbourne IVF and Sydney IVF) appear to be showing a preference for trophectoderm biopsy, to counter the mosaicism problem in eight cell embryos199. Whilst transport PGD is still possible in Australia, the time constraints of trophectoderm biopsy, travel and formalities such as passing through customs make this problematic for New Zealand clinics. There are a number of options including New Zealand only having access to the (presumably inferior) cleavage stage biopsy through transport PGD, starting a New Zealand testing facility or utilising future improvements in freezing biopsied embryos.

The New Zealand government has recently announced public funding for PGD. Funding for 40 cycles of PGD per annum nationally was announced late in 2005, but only for couples who have a high risk of passing on a serious, single gene genetic condition. Up to two cycles per couple are to be fully funded200. Public funding is to be directed through the fertility clinics’ existing contracts with District Health Boards. It could be argued that the two clinical genetic services (Central Regional Genetic Service and Northern Clinical Genetic Service) would be better placed to manage this funding, as they do other clinical genetic testing services in New Zealand.

Whether or not New Zealand develops a full capability for this technology is heavily dependent on the projected and actual uptake by the population. PGD is a highly specialised technique and requires skilled personnel. Staff retention, competence and skill maintenance are crucial issues for this technology. If a minimum number of testing procedures are not reached or if the testing is divided between too many facilities, all three aspects will suffer. This is to the detriment of accuracy, safety, efficiency and ultimately the couples using the service.

New Zealand’s first NZ-biopsied PGD pregnancy is currently in progress. The mother is a genetic mosaic, with a five-year history of miscarriage201. The pregnancy is 16 weeks on as of 11 February, 2006202. This treatment, which was privately funded, was reported shortly before public funding was announced. As it did not involve inheritance of a serious genetic disorder, it would not have been eligible for public funding if available at the time.

The minister’s press release indicated the Ministry of Health expects approximately 150 cycles of IVF/PGD to be performed in New Zealand annually, of which 40 will be to detect serious inheritable genetic diseases203. It may be expected that there will be an initial surge in demand as couples who have been anticipating the technology take advantage of it, as well as the expected new users who are identified each year.

It is unclear as yet, how the funding is to be allocated. Presumably, criteria are being drafted for rationing this funding, although there is no indication of what these might be yet. The criteria will be most crucial during the initial rush to access the technology, especially if demand may be significantly higher than the funded cycles available.

In conclusion, PGD is not perfect. It is used successfully, nonetheless, enabling many people who would not otherwise be able to, to have genetically related, healthy children.

A number of issues, however, become obvious during the research for this document and are in need of follow up and/or further scientific research.

Whilst PGD is in its infancy in New Zealand, it would be useful (for research purposes) to have national and/or Australasian statistics on the usage and outcomes of the procedure. This monitoring could entail extracting those statistics from the ESHRE database. Alternatively, the ANZARD database205 (from reporting of IVF) could be expanded.

Genevieve would like to thank the researchers on this project for their support and many stimulating discussions, and in particular Drs Tony Merriman and Ian Morison, and Prof Stephen Robertson for valuable comments and feedback. Genevieve would particularly like to thank Drs John Peek and Richard Fisher and Fertility Associates for their helpful and entertaining discussions about PGD in NZ, and also for allowing access to the Fertility Associates clinic laboratory for a glimpse at how it all works.

Allele one of two or more DNA sequence variants in a population; one of two copies of a gene in a human cell.

Aneuploidy not euploid; where there are additional or missing chromosome(s) or segments of chromosomes.

ART artificial reproductive technology. Autosomal of the autosomes or non-sex chromosomes. Blastocyst a day 5 or 6, differentiating embryo.

Blastomere a cell from an undifferentiated embryo (pre day 5). Chromosome a structure that contains genomic DNA.

DHB District Health Board; a local administrative and funding health structure in New Zealand.

DNA Deoxyribonucleic acid; the chemical polymer that encodes genetic information (including genes) and makes up chromosomes.

ESHRE The European Society for Human Reproduction and Embryology. Euploid having the true or “normal” number of chromosomes.

Gene a segment of DNA that contains the instructions for producing a specific protein in the right place, at the right time.

Haploid having one copy of each chromosome; half the normal number of chromosomes in humans.

ICSI Intracytoplasmic sperm injection; an artificial method of fertilisation by injecting a sperm into an egg.

ICM inner cell mass; the part of the differentiated blastocyst embryo that goes on to form the fetus.

in vitro literally, in glass. Used in relation to processes that have been taken out of the body; artificial.

IVF In vitro fertilisation; where fertilisation occurs outside a woman’s reproductive tract.

Meiotic/meiosis the specialised cell division that produces sex cells, i.e. sperm and eggs. Oocyte/ovum egg; the female gamete.

PGD preimplantation genetic diagnosis; a technique for genetically analysing a single cell from an embryo.

PGS preimplantation genetic screening; PGD for to search for random aneuploidies.

Pregnancy is measured in weeks starting from the first day of the most recent menstrual period.

Recessive whose effect is masked by the effect of other alleles; the recessive phenotype is expressed only when both copies of a gene are recessive.

Sex chromosome The X or the Y chromosome. The presence (male) or absence (female) of the Y chromosome determines the sex of an individual.

Trophectoderm The part of the differentiating early embryo that goes on to form the embryonic part of the placenta.

WGA whole genome amplification; a technique that uses PCR to make many copies of a whole genome to aid analysis.

Zona pellucida The outer shell of the egg and early embryo that must be pierced to access the embryonic cells during biopsy for PGD

N. Scriven, J. Traeger-Synodinos, K. Vesela, L. Wilton and K. D. Sermon, “ESHRE PGD Consortium data collection V: Cycles from January to December 2002 with pregnancy follow-up to October 2003” (2006) 21 Hum Reprod 3-21.

H. Lubs, R. J. Mahony and et al., “Chorionic mosaicism: association with fetal loss but not with adverse perinatal outcome” (1992) 12 Prenat Diagn 347-55.

P. Devroey, “Incidence and prediction of ovarian hyperstimulation syndrome in women undergoing gonadotropin- releasing hormone antagonist in vitro fertilization cycles” (2006) 85 Fertil Steril 112-20.

K. Pantos, “Birth of a healthy infant following trophectoderm biopsy from blastocysts for PGD of beta-thalassaemia major” (2005) 20 Hum Reprod 1855-9.

B. S. Hagberg, A. Berner and A. G. Sutcliffe, “International collaborative study of intracytoplasmic sperm injection- conceived, in vitro fertilization-conceived, and naturally conceived 5-year-old child outcomes: cognitive and motor assessments” (2005) 115 Pediatrics e283-9.

To gain a full appreciation of a likely Mäori response to pre-birth genetic testing it is necessary to contextualise the discussion within broader debates regarding emerging health biotechnologies.

For example, we were quickly reminded by research participants that power and control and the potential for social disparities to be accentuated were as much of an issue for pre-birth genetic testing as it is for other biotechnological innovations. Mäori responses to genetic engineering biotechnology, the domination of genetic science by corporate agendas, and suspicion of health professionals and innovations resulting from successive negative colonial experiences, are factors likely to influence how Mäori might respond to pre-birth genetic testing. This is articulated by Jessica Hutchings1:

But because this area is, not so much about helping people, it’s more about making money and doing high profit driven sciences, that’s driven by a multi-national and a free trade agenda and globalisation ... I know why it is, from my perspective it’s about money, it’s about profit and it’s about power.

This chapter situates the discourse on Mäori perspectives of pre-birth genetic testing within broader issues confronting Mäori as a result of the biotechnology explosion in the last ten years and the completion of the human genome project. It details Mäori values, concepts, cosmology and traditions to provide a platform to analyse the implications of genetic testing on Mäori people and Mäori culture.

Broader issues around equality of access to health services, discrimination, and the potential erosion of cultural and spiritual values will need to be addressed if biotechnological innovations emerging from the mapping of the human genome are to be met with anything but suspicion and scepticism by Mäori.

Similarly, in order to understand how pre-birth genetic testing may influence Mäori, it is necessary to have some understanding of Mäori cultural values, beliefs and perspectives. Literature on Mäori responses to genetic engineering is useful to assist with this understanding particularly as there is limited literature and information on Mäori views about pre-birth genetic testing.

The study conducted for this project is reported in Part B of this chapter where we reproduce and discuss the findings gathered from a selected group of Mäori interviewees with relevant experience and knowledge (see the appendix to this chapter for an outline of the research process undertaken). The interviews both supplement and fill gaps in information gained from research literature and other sources, and provide depth and breadth for Mäori perspectives of pre-birth genetic testing. Participants were chosen because of their broad range of expertise in matauranga Mäori (Mäori knowledge), Mäori health, and socio-political issues regarding genetic engineering. Whilst participants were, for the first time, asked to consider the impact of pre-birth genetic testing on Mäori they were able to draw heavily on their own knowledge base and considerable expertise.

With responses being considerably diverse, we have found that there is no clear single Mäori world view on the possible impacts of pre-birth genetic testing on Mäori. They range from a deep seated suspicion of the technology as merely another tool for powerful corporations and health professionals to increase societal inequities, to an acceptance based on the potential health benefits for whanau and tikanga Mäori.

Pre-European Mäori used social controls to protect and maintain the collective wellbeing of whanau and hapu. Arranged marriages, surrogacy, abortions and infanticide were practised and the importance of whakapapa paramount. Whilst these practices sometimes seem consistent with Mäori cultural norms and values, there are diverse opinions about how and why they are carried out today. For example, one participant stated that abortion is not acceptable unless absolutely necessary and another felt it is important to distinguish between those Mäori who want to participate in this discussion from a general perspective or from a Mäori perspective. This is a classic example of the diversity in Mäori views. We do not seek to homogenise Mäori and present a singular Mäori world view on pre-birth genetic testing. Rather, as a participant states below, we seek to explore the diverse perspectives from a particularly Mäori point of enquiry.

So there’s not a clear picture one way or the other about where Mäori today might be. There’s such a mix but I think the task that is becoming clearer is that where we as Mäori are actually engaging with like abortion or birth, as Catholics or Christians as Scientists or as just someone out in the suburbs ... It’s that “Kia Ora”, well really you just happen to be a Mäori Catholic, you’re a Catholic actually and your views are Catholic ... and so that’s where it’s coming from. So what is this Mäori view...there is a challenge to distil out what is distinctively Mäori and that will only be a part of the answer because it doesn’t mean to say that we all should or even can embrace [it].2

Mäori acquiescence of genetic testing is by no means universal or absolute. Caution has been expressed regarding the need to maintain the integrity of the process as unborn foetuses have a mauri and wairua that must be respected. The spiritual and emotional concerns of parents and whanau need to be accounted for as well as issues of equity and access to effective pre- birth genetic testing services.

Identifying how to respond to Mäori cultural values and practices in a regulatory regime is challenging. Regulation in any area must command popular support and be guided by principles of proportionality, certainty, clarity, accountability, efficiency and accessibility. As a Mäori values system is distinct from that of the majority population, protecting its integrity, holism, nuances and institutions within a regulatory framework is difficult.

The Treatyof Waitangi(‘the Treaty’) affirmstheethicalandlegalbasisforstrivingtoappropriately recognise Mäori values, and is supported by four other legal doctrines: international human rights standards, aboriginal title, the fiduciary duty imposed on the Crown, and the status of tikanga Mäori as a system of customary law. The Treaty and supporting legal doctrines also establish the founding principles which must guide any regulatory response. The essential factor is ensuring that Mäori retain the right and ability to define and redefine the application of Mäori customary values to pre-birth genetic testing. This means that Mäori who wish to engage with pre-birth genetic testing should be able to do so with confidence that their cultural preferences and customary values and practices will be respected and maintained.

Part a: setting tHe scene
1 MÄori culture, sPiritual etHics anD genetic science

A discussion about Mäori culture, practices and perspectives can be understood through exploring stories of cosmology and creation. Mäori cosmology provides not only an understanding of how tupuna (ancestors) viewed the world and their place within it, but also informs contemporary understandings, attitudes and concerns towards birth processes and the use of technology.3

[M]yth and legend in the Mäori cultural context are neither fables embodying primitive faith in the supernatural nor marvellous fireside stories of ancient times. They were deliberate constructs employed by the ancient seers and sages to encapsulate and condense into easily assimilated forms their view of the world, of ultimate reality, and the relationship between Creator, the Universe and man ... These conceptualisations form what is termed the ‘world view’ of culture ... a systematisation of conceptions of reality to which members of its culture assent and from which stems their value system. This ‘world view’ lies at the very heart of the culture, something interacting with and strongly influencing every aspect of the culture.4

Mäori customs, values and attitudes are derived from an indigenous5 body of knowledge which seeks to understand the universe and its origins. Mäori cosmology looks deeply into the infinite darkness of eternity that existed before life began. The two fundamental principles in this cosmology are whakapapa (genealogy) and the personification of natural phenomena. Mäori developed complex genealogical constructs through metaphorical language and poetic imagery to explain the universe and its origins, and the creation of life itself.6

Most accounts of the universe and creation itself are arranged in genealogical order. Some start with a description of Te Kore (the realm of ‘chaos’, ‘nothingness’ or ‘potential being’). In this realm lived Io, a supreme being whose ihi (essence) bore Te Po (the night realm) and Te Ao Marama (the full light of day). Io then created a single ancestor from whom came Rangi and Papa, who after separation came to be known as Ranginui the ‘sky father’ and Papatuanuku the ‘earth mother’.7

The three cosmological realms of Te Kore (the realm of potential being), Te Po (the realm of becoming) and Te Ao Marama (the realm of being) are all linked together to form the continual progression of life from conception, birth, life and death. Along this pass, in the opposite direction, the departing spirits descending to Hawaiki, and ‘that which is in the process of becoming, ascending to the world of being.’ Thus, the universe is holistic and dynamic; there is within it an ongoing process of continuous creation and re-creation.8

Furthermore, a traditional Mäori view considers everything in the universe to be linked in some way to Ranginui and Papatuanuku through whakapapa. There is no separation between the cosmology or whakapapa of the natural world and the supernatural. Both are part of a single system, creating a fixed and unalterable bond between humans and the physical world. All Mäori therefore are descendants from gods, goddesses, guardians and super-humans.9

One must first have an understanding of Mäori cosmology and te ao Mäori, in order to understand traditional Mäori relationships with the land and the subsequent spiritual and cultural concepts, values and beliefs that stem from this relationship.

In this report, pre-birth genetic testing is analysed based on te ao Mäori and matauranga Mäori. This report situates perspectives provided by the ‘research participants within a Mäori worldview to avoid any watering down or misunderstanding of these concepts’10. Within this context, the participants raised concerns with genetic modification stemming from the paradigmatic differences in te ao Mäori and the Western science tradition from which genetic science developed. Reconciliation of Mäori spiritual, cultural and ethical concerns is often at odds with the reductionism on which genetic modification is based.

There is now an established body of literature and research documenting Mäori responses to genetic modification. Whilst this research literature remains relatively new and the discourse evolving, it is useful to examine what Mäori have said about genetic modification to gain deeper understanding of views about the potential implications of pre-birth genetic testing.

Articulation of Mäori cultural perspectives and concerns about genetic modification came to prominence as a result of a high profile application to the Environmental Risk Management Authority (ERMA) in 1998 seeking to genetically modify cattle using human genes. Significant submissions were also provided to the government’s Royal Commission on Genetic Modification in 1999.11 Further information from the Royal Commission revealed two areas of concern. The first is primarily political and based on the Treaty of Waitangi. The second relates to cultural realities and values, most of which are regarded as being antithetical to genetic modification and particularly transgenics.12 It is therefore very important when investigating potential Mäori responses to pre-birth genetic testing to look and gain some insight into the bases for Mäori cultural, spiritual and ethical perspectives and concerns.

The following discusses Mäori responses to genetic modification with the aim of gaining understanding and insight into the potential impact of pre-birth genetic testing on key Mäori concepts such as whakapapa, mauri, wairua, mana, tapu, noa, rangatiratanga and kaitiakitanga. These key concepts are outlined below not necessarily as a definitive classification but rather to provide a lens through which to analyse the implications of pre-birth genetic testing on Mäori.13

The Mäori world view has its roots deeply entrenched in whakapapa with a focus on the importance of relationships between tangata whenua (people of the land) and the natural world that reflect the links between Mäori, the universe and the environment.14

Whakapapa is the genealogical descent of all living things from the gods to the present time.15 ‘Papa’ is anything broad, flat and hard such as a flat rock, a slab or a board. ‘Whakapapa’ means to lay upon one another and is used to describe both the recitation of genealogies, and

also to name the genealogies. When a child is born, the child is born into a kinship system which has been in place for many generations. Whakapapa provides identity within a tribal structure and can be traced right back through to the beginning of time.16 Mäori cosmological narrative, previously outlined, in which the origins of the world and all living and non-living things are inter-connected, is essential in understanding discussions surrounding whakapapa. Whakapapa enables Mäori to be located within the context of all that exists in the world and articulates a specifically Mäori identity.17

Whakapapa is one of the fundamental ways in which Mäori come to see and think about the world. Whakapapa is also a way of learning, a way of storing knowledge, and a way of debating knowledge. It is inscribed in virtually every aspect of te ao Mäori (the Mäori world).18

The continuity, values and practices of Mäori societies began with whakapapa19. Whakapapa is the ‘determinant of mana rights to land, to marae, to membership of a whanau, hapu, and collectively the iwi, the whakapapa determines kinship roles and responsibilities to other kin, as well as one’s place and status within society’.20 All in the Mäori world can be seen to connect back to a founding ancestor through whakapapa.

Whakapapa accordingly plays an important role within whanau. Access to genealogical knowledge is integral to the functioning of a whanau in a number of ways. Birth order and generational level affect patterns of behaviour between whanau members and provide the basis for deciding issues of precedence and leadership. Whakapapa enables whanau members to establish links with one another, with wider hapu and iwi, and with a wide range of whanaunga.

Understanding whakapapa is essential to gaining insight into Mäori concerns about genetic modification. As Roberts21 states, it is through whakapapa that everything from a rock, a tree, the ocean and humans are all balanced intricately. Mäori therefore have voiced concerns with the potential that genetic science has in threatening this delicate balance.22 This is reiterated by Gibbs:

It is clear therefore, that genetic manipulation of the human genome may be seen by Mäori as interference with the basic structure of relationships between generations and between species, which is central to both the practical and spiritual aspects of Mäori life.23

Recent research relating to genetic testing has highlighted Mäori concerns about protecting Mäori ways of defining and explaining the world and the cultural traditions and interpretations that are bound up in whakapapa.24 Issues also remain not only for the potential disruption of whakapapa, but the subsequent breach of tapu that such disruption may engender. Some of the Mäori concerns around genetic modification focus heavily on whakapapa and mauri and the impact on Mäori spiritual values (wairua). In contrast, lesser emphasis is placed on genetic testing that does not involve the mixing of whakapapa through transgenics and therefore does not involve mixing of genes between species or, as some Mäori have put it, ‘mixing whakapapa’.

Understanding mauri is important when exploring the potential impact of pre-birth genetic testing on the Mäori world.25

Mauri is a special power possessed by Io that makes it possible for everything to move and live in accordance with the conditions and limits of its existence. Everything has mauri including people, fish, animals, birds, forests, lands and rivers; mauri is the power which permits these things to exist within their own realm and sphere.26

Mauri can be thought of as the life force of humans. Mauri is the spark of life, the active constituent that indicates a person is alive. ‘Tihei mauri ora’ is the sneeze of life which signals the independence of the child from the womb, and is a manifestation of mauri existing as an essential and inseparable part of that particular person. Life is extinguished with the last breath, the body stops and becomes cold -this is when mauri leaves the body and the person dies.27

Humans are regarded as possessing a ‘higher order’ mauri, compared with other forms of life. Along with the obligations inherent in kinship relationships, this notion confers on people a responsibility to protect whanau, hapu, iwi and the environment.28

The importance of mauri in debates about genetic modification concern the transfer of genetic material from one organism to another and subsequent impact upon mauri:

In the Mäori conception all life forms – animate and inanimate – have diverse origins as all have a genealogy back to the gods; the source of their life and being. Each life form, including each person, is therefore imbedded with its own mauri and each makes a substantial contribution to the cosmos and all things that live within. This mauri and the life forms are linked together, including humanity, by whakapapa, through mutual descent. As the mauri of all living things is connected by these kinship ties, acts that change or degrade the essence of one life form have an impact on the integrity of all other life forms.29

Mäori concerns relate to the impact of biotechnologies on whakapapa, mauri and the natural order of the universe. These concerns are also linked to the potential for changes in the essence of human beings and other living things, whose genes have been manipulated.

Manipulation of mauri is also seen to have implications for the nature of relationships between people and other living organisms. Genetic modification is considered by some to be tampering with the very spiritual essence of being Mäori, which is deemed unnatural and to be taking away the ‘mystery’ of life.30

Such concerns extend to mattters relating to the disposal of affected embryos and foetuses, and involve broader ethical and moral debates over when life begins and the subsequent question about whether or not an embryo or foetus has mauri. There could therefore be perceptions of negative implications of the disposal of an embryo or foetus, with subsequent impact on mauri, for prospective parents and their whanau.

Barlow31 conceives of wairua as the spirit within all things – all things have a physical body (tinana) and a spirit (wairua). These physical and spiritual properties are joined together by mauri but “when a person dies, their physical remains are interred in the earth; their spirit lives on and travels the pathway of Tane to the gods that created them”.32

Tapu has two aspects, the first of which is known as intrinsic tapu and is concerned with the recognition of the inherent worth of each individual and the sacredness of life. This is important as Mikaere states that ‘[n]o individual stands alone: through the tapu of whakapapa, she or he is linked to other members of the whanau, hapu and iwi, and to other Mäori as well. Every person is linked to the generations to come and to those that have been before. Every person has a sacred connection to Rangi and Papa and to the natural world around them.33 This form of tapu extends to the body, with the head generally considered the most tapu part of a person.34

The second aspect of tapu is the spiritual prohibition or protection which can be invoked in a number of different circumstances. The function of tapu in this instance is the maintenance of social control and discipline, and the protection of people and property.35

Opinions can vary regionally on which things possess significant tapu over others. For instance a coastal iwi may regard a whale as tapu, while an inland iwi may not. Tapu can also apply to individual things as well as groups of things. For example a particular tree might be seen as tapu, while the class of trees it belongs to may not. When a person or thing is deemed tapu, certain restrictions or sanctions come into effect while its spiritual efficacy is enhanced. Tapu is managed carefully as it is seen as dangerous and matters involving tapu are often reserved for specially gifted and competent tohunga to deal with.36

Tapu is frequently invoked in discussions surrounding Mäori and genetic testing and genetic modification. According to Satterfield et. al,37 ‘[t]he general consensus or consistency with which human body parts are said to be subject to tapu has potentially significant implications for genetic modification when human genetic material is used, in that most conceptualise a gene as a body part’. There is limited understanding of the precise way in which to deal with tapu in the context of genetic modification. While some argue that humans are simply too tapu to be subjected to this kind of technology at all, others maintain that the tapu of humans does not constitute a barrier to genetic modification.38

Noa is often paired with tapu in that noa refers to restoring a balance. A high level of tapu is seen to be dangerous, and in these instances it is the role of tikanga and tohunga to reduce the level of dangerous tapu until it is noa or safe.39

The principle of noa has been used, not necessarily in specific relation to genetic modification, but for example, in categorising organisms. It has been suggested that it might be considered more appropriate for a noa organism to be modified than a tapu organism, and consequently that it may be unacceptable for a noa organism to be transferred into a tapu organism.40

Such notions are important in this debate as they may form the basis of anxieties and stress that a Mäori patient might feel when being treated or subjected to medical procedures or diagnosis:

If I was to go to the doctor, I whakanoa myself - I leave all those things tapu that I practise. I leave them here - why? Because I am going to the doctor who I know is going to help me and I trust that will help me. So he doesn’t want all my hang ups to get what he needs to do for me. He wants to just do what he can for me and when I get out then I come back and [can] be tapu again ... So, to whakanoa means to leave all those personals behind and go according to the kaupapa of your need.’41

The protection of some areas of the body thought to be extremely tapu can be temporarily suspended through the practice of whakanoa. This has a number of implications for genetic testing as a Mäori patient seeking use of the technology might require counselling or karakia whakanoa (tapu lifting incantations) to alleviate concerns or anxieties about the genetic testing process, or the use or disposal of his/her genetic material.

While this may be the case, some Mäori have warned against the simplistic notion that Mäori resistance to genetic modification be regarded as a problem easily addressed by the use of karakia whakanoa by tohunga on demand.42

Mana incorporates notions of power, authority, prestige, uniqueness and the recognition of these qualities.43 Mana refers to the intrinsic power of the gods or atua and their spiritual authority (mana atua), the power embodied in the individual person drawn from the land (mana whenua) as manifest in the skill and acumen in a particular area (mana tangata), or as reference to the power rooted in links to the land and its potential to provide human sustenance (mana whenua).

Mana is an integral spiritual concept in discussions surrounding pre-birth genetic testing as it defines the relationship between others and influences Mäori ability to exercise kaitiakitanga and the right of tino rangatiratanga.

Whilst mana has a range of meanings, the most relevant in this debate is that which defines it as the integrity of a person or group that manifests itself in action.44 Central to the issue of pre-birth genetic testing is the maintenance of both collective and individual integrity.45 Relationships therefore, both personal and group, are always mediated and guided by the value placed upon mana. The promotion of the collective good and authentic Mäori responses to new technologies requires appropriate structures, institutions and frameworks for the ongoing enhancement of mana. Generative power is linked to mana also. For example, the integrity of women, or mana wahine, is connected to Papatuanuku and her generative and nurturing powers, while the integrity of men, or mana Tane, is connected to Te Waiora a Tane, the source of life. Besides life-giving powers, mana is also about order (thus enabling life to avoid chaos, destruction, imbalance) and contributes to mana Mäori and the integrity of all Mäori people. Mana therefore is concerned with form and order and the concern for ritual and convention.46

The source of all mana is through ancestry and descent derived from the atua or gods. In traditional Mäori society, this mana atua or mana wairua (spiritual mana) was essential for survival. Together, mana wairua (spiritual authority), mana tupuna (ancestral authority) and mana whenua (authority based on ahi ka) constitute the taonga tuku iho (natural heritage, or legacy) of Mäori. Expression of this total mana was through rangatiratanga or the exercise of chiefly authority in respect of land and all other taonga (valued possession).47

Mana is both inherited and bestowed, but is not something that people or groups can claim for themselves (even if it is bestowed on an individual, it is within the context of enhancing the mana of the group). Mana therefore, has little relevance outside of a collective context as it is through the ‘words, thoughts and hearts of people that mana is established and maintained’.48

In the context of whanau, mana plays an important role also. The whanau as a whole has its own mana that comprises a core of mana tupuna, but is also affected by the behaviour of individual members and the way in which the whanau fulfils its function as a collective. Whanau members have a shared responsibility to work to build up the mana of the group and also to restore it when damaged.49

At one level there is concern over whether the technology will adversely impact on the mana of the patient or any others associated with the process. It could be argued, echoing some arguments in the related context of genetic modification of organisms, that meddling in human genetic testing and reproductive activities is contrary to Mäori culture and values as humans do not have the mana to take on such technology safely - interventions in the human reproductive cycle through the use of pre-birth genetic testing involves interfering with the integrity of the human body (mana tangata) and the will of atua (mana atua).50 An innovation such as pre-birth genetic testing could adversely impact on the mana of not only those who use it but also those who are involved with the technology in other ways, if negative consequences occur. For example, if potential parents decide to undertake pre-birth genetic testing and subsequently have an abortion, they may be targeted and denigrated by others and their personal mana and that of their whanau is put at risk.

At another level, there are concerns that arise in a collective sense over who has the mana to make decisions in regard to utilising this technology, especially if it is perceived to have negative effects on the wider whanau, hapu, or iwi. This is of significance as mana, kaitiakitanga, and rangatiratanga are all infused in the maintenance and enhancement of whakapapa. Professor Hirini Moko Mead51 argues that ideally an event or technology should maintain, enhance or improve mana, and lift everybody who participates in the event. The issue here is about the implementation and exercise of mana through kaitiakitanga, rangatiratanga and consequently in decision-making with regard to this technology:

In terms of rangatiratanga under the Treaty, Mäori assert that they were guaranteed the right to exercise ownership over their taonga resources and the decision-making rights on use and protection that flow from ownership. Taonga resources, in this sense, include significant species and traditional knowledge that might be used to create new life forms or be the subject of a patent.52

Frequently in discussions relating to genetic modification, Mäori ultimately position themselves as kaitiaki (guardians) over all things that pertain to Mäori.53 The term tiaki means ‘to guard’, but also has other closely related meanings depending on the context. Tiaki can also mean ‘to keep’, ‘to preserve’, ‘to conserve’, ‘to foster’, ‘to protect’, ‘to shelter’ ‘to keep watch over’.54 Kai with a verb denotes the agent of the act. Hence, kaitiaki means a ‘guardian’, ‘keeper’, ‘preserver’, ‘conservator’, ‘foster-parent’, or ‘protector’. The suffix ‘tanga’ added to the noun means ‘guardianship’, ‘preservation’, ‘conservation’, ‘fostering’, ‘protecting’, ‘sheltering’.55

Mäori have practised Kaitiakitanga for millennia and have protected and cared for their environment and heritage. The purpose behind the principle was to ensure the protection of mauri of all things both animate and inanimate. The following quotes taken from Satterfield et. al.56 illustrate the importance of kaitiakitanga in relation to genetic modification:

... kaitiakitanga is about ... the mediation of ... the environmental, [the] spiritual and the human. And it’s about [the] management of humans, as much as environmental stuff ... you’ve got to ... do it with integrity.

Kaitiakitanga ... is a really big responsibility in our lifetime, to make sure that we care for this planet, and GMO [i.e. genetically modified organisms] is defiantly a part of that thinking so that we make wise decisions.57

The responsibilities and obligations of kaitiaki are as much an attitude about life as they are about human behaviour. Kaitiakitanga is about decision-making, discussion and debate, and the management and safe-guarding of the physical, human and spiritual worlds.

Mäori are careful also to preserve the many forms of mana they hold, particularly in relation to ensuring the mana of kaitiaki is preserved:

As minders kaitiaki must ensure that the mauri or life force of their taonga is healthy and strong. A taonga whose life force has been depleted ... presents a major task for the kaitiaki. In order to uphold their mana, the tangata whenua as kaitiaki must do all in their power to restore the mauri of the taonga to its original strength ... should they fail to carry out their kaitiaki duties adequately, not only will mana be removed, but harm will come to members of the whanau and hapu.58

The influence of mana and the ability to exercise kaitiaki are central to discussions surrounding pre-birth genetic testing. If pre-birth genetic testing is undertaken and individual and collective mana is in some way compromised, this will in turn affect Mäori ability to exercise kaitiakitanga.

As genetic modification and genetic testing are relatively new and to some extent poorly understood, opinions vary on how kaitiakitanga should be exercised in relation to genetic modification decision-making. The following quote taken from Satterfield et. al.59 indicates a guardianship posture to all genetic material, and while suspending permission to manipulate genetic material at present, leaves open the possibility of genetic modification after significant consultation:

... [I ask myself] is there any Mäori thought in this area, and there kind of isn’t. So, if you went from first principles, Mäori would say that all genetic material is taonga. I mean, it’s been given to us, it’s ours to look after. But it’s not actually ours. You actually don’t own it, but you’re its guardian ... [it’s] something to be treated with reverence which automatically means that you can’t just go ahead and do ... [anything you please]. There needs to be discussion and consultation and some thought put into it. And I don’t think Mäori would be different from anyone else in that respect.60

In contrast to this view Satterfield et. al.61 states that kaitiakitanga is opposed outright to the kind of options genetic modification involves:

... from the point of view of kaitiakitanga - you know, the preservation of whakapapa within food plants, within natural ecosystems, all of that which I said would say well no. I think that those are silly things to do. And they don’t take us anywhere and they in fact undermine our long-term benefit.62

Both of the above views on kaitiakitanga express an inclination for long-term planning. They also show that kaitiakitanga is as much about protecting humans as it is about non-human species and organisms. In this sense it can be associated with the imperative of caring for humans, or with the principles of aroha, manaakitanga, and whanaungatanga. With this, the potential for balancing competing interests (human interests vs. non-human, and human interests vs. other human interests) is also brought to the fore.63

‘Iwi and hapu require the presence of mana and tino rangatiratanga in order to be kaitiaki. Conversely, without kaitiakitanga there is no mana. Without kaitiakitanga, hapu may be unable to manaaki their guests, be unable to appropriately feed or house their guests, resulting in a loss of mana. Kaitiakitanga is an action arising from mana and tino rangatiratanga’.64

Explicit in the recognition of kaitiakitanga and in the right to exercise kaitiakitanga is its relationship to rangatiratanga. Rangatiratanga is an inherent part of the exercise of kaitiakitanga, so without recognition of the latter, the former becomes impossible to exercise. Rangatiratanga invokes the authority to make decisions and take control and responsibility for one’s destiny and kaitiakitanga imposes an obligation as tangata whenua to protect the wellbeing of future generations.

Tino rangatiratanga is often translated to mean Mäori sovereignty. However, this English translation is contested as some Mäori argue that the meaning does not suit Mäori worldviews and limits what is meant by the word. According to Durie65, the concept of tino rangatiratanga can be used to ‘describe Mäori aspirations for independence and self sufficiency ... iwi [tribal] control over people and assets in a particular region’.

To Barlow66 however, rangatiratanga does not describe Mäori power and status because it was a word coined by Pakeha when the Treaty of Waitangi was signed. Barlow believes that the appropriate word is arikitanga, which describes the concept of supreme mana or power of Mäori. Mana motuhake is therefore the preferred term for self-determination or authority among some iwi (for example Ngati Porou).67

Tino rangatiratanga is however frequently used in Mäori discourse and provides a way for Mäori to unite around issues of power and resistance.68 Smith69 states that ‘the politics of sovereignty and self-determination have been about resisting being thrown in with every other minority group by making claims on the basis of prior rights’. Tino rangatiratanga can therefore be seen as a statement about authority or, as Professor Mead70 argues, as ‘honestly and sensibly as self-government or as home rule’.

Within the genetic modification debate, tino rangatiratanga was a key focus regarding the control over issues pertaining to decision-making at both an individual level and at a collective level. Embedded in the acceptance and recognition of rangatiratanga is mana. Tino rangatiratanga was often raised in discussions surrounding an individual’s right to make decisions surrounding genetic modification. The following quote taken from Satterfield et. al.71 outlines a respondent’s use of tino rangatiratanga when pursuing medical treatment.

... we only need to look at Seventh Day Adventists’ use of blood transfusion. The likes of the Holloway case, of parents having the right [to decide] on cancer therapies, and realise that if we are going to be true to our own tino rangatiratanga if you like, it also needs to support others and the rights for them to make decisions.

From this statement, it could be argued that tino rangatiratanga can be elicited to either accept or reject genetic modification and genetic testing.

There are a number of unique concerns from te ao Mäori in relation to genetic modification. These concerns have been outlined in the previous section and will be used as a point of enquiry into pre-birth genetic testing.

Through an understanding of the cultural, ethical and spiritual concepts outlined previously, we seek to gain a better understanding of the potential that pre-birth genetic testing may have on Mäori. The themes that have emerged in relation to pre-birth genetic testing are somewhat different from existing debates surrounding genetic modification. The following section reviews responses from research participants and discusses the themes that emerge from those discussions.

There is clearly no single Mäori view on the potential risks and benefits of pre-birth genetic testing although strong patterns of opinion and agreement on aspects of those potential risks and benefits emerged during this project.

Key principles and practices from within te ao Mäori and traditional Mäori approaches to reproduction, abortion and infanticide were used as a point of enquiry for pre-birth genetic testing. The traditional Mäori practices and associated values that existed in pre-European society do not provide a definitive response as these examples can only guide discussion and inform opinions on contemporary practices such as pre-birth genetic testing. Alongside these traditional stories were also some more contemporary issues surrounding equity and access to pre-birth genetic testing services. An area of considerable concern to be addressed in the legal section of this report is balancing an individual’s right to access genetic testing and their responsibilities to the collective, particularly hapu and iwi.

The overarching principle of whakapapa and its pervasive influence in all matters of the Mäori world is fundamental in a number of historical (and some may argue contemporary) practices regarding reproduction. Whakapapa traditions are replete with examples of arranged marriages (taumau) and predetermined strategic tribal alliances that had beneficial purposes for collective groups. Strong individual and whanau characteristics were also nurtured and passed down through whakapapa lines. The notion of Mäori encouraging, supporting and pre- determining desirable characteristics in society was discussed by a number of participants:

That was one of the considerations around arranged marriages, the importance ... .

bloodlines. ... There was an awareness of genetics, heriditary traits you mix the right blood and you get come up with a good result.72

While a number of participants outlined notions of ‘strong bloodlines’ and strengthening whakapapa as an important component of reproduction and Mäori society, another participant outlined some of the more spiritual practices surrounding te ao Mäori and pre-birth:

I wonder from a traditional perspective what the perceptions were of pre-birth I

mean I’ve heard bits about the health of the child, the amount of prayers and spiritual involvement as well in terms of. makutu, and the way that makutu had a negative impact

or haehae or any of those kind of things negatively impact upon a pregnancy one could

This ‘negotiation’ or ‘manipulation’ surrounding reproduction and whakapapa was also exercised by the atua and selected marriages:

So there are pregnancies that are attributed to the gods and there are pregnancies that are made by well selected marriages between He Ariki Wahine na He Ariki Taane, tenei tuu Rangatira ka moe, ka puta ko tenei kawai tuakana, kawai mataamua, kawai tapu nei, so all our history is full of it ... The culture is absolutely full of it.74

The maintenance of bloodlines and the arranged marriages were an attempt also at maintaining mana and strong rangatira lines. They were:

...very much part of Mäori thinking, and so much so like some things that have been hidden because of our Victorian time, so brother sister, marriages ... because if sister comes out first, well we’re not letting any prick in here take our tuakana off there, so you have to marry your brother ... It’s certainly there in the Hawaiians. It’s not just us. It’s in the Pacific, it’s in the Polynesian culture, very much. Looking at kawai and thinking about...because it was believed, you see it come from the atua, [it] is where these kawai come from.75

While participants had a number of stories relating to reproduction and bloodlines, either through taumau, spiritual interventions or the atua, they were all bound by a desire to strengthen whakapapa and ensure the continued well-being of collective groups.

Based on traditional Mäori approaches to determining bloodlines, and the reproduction or maintenance of desirable characteristics through a number of functions and processes, a perspective emerged through which such practices could be linked to the contemporary technology of pre-birth genetic testing. Whakapapa was outlined as the fundamental principle bound up in reproduction and child-birth. These notions hold similar importance today, and links were drawn with the potential that pre-birth genetic testing had to foster these traditional ideals.

Interestingly, the degradation of whakapapa values has often been illustrated in debates surrounding genetic modification. While we do not deny the negative potential that pre- birth genetic testing may have for whakapapa, the fact that transgenics and genetic testing are considerably different was an influence. There is a view amongst Mäori that distinction should be drawn between pre-birth genetic testing and genetic modification per se, in terms of the impacts on whakapapa:

Yeah, but the messing with whakapapa to me is different from this because this is when life is being conceived, whakapapa has already been created, so the messing with whakapapa is like when you do things like your genetic modification, you’re introducing like the sperm donation, where you’re ending up with different lines. This is about parents who are having a child ... so the whakapapa mix, the A and B is going to be C, the C is going to be it no matter what because you’re not changing A and B. The messing with whakapapa is changing A and B, the parents.76

Consequently, the potential through which links can be made between whakapapa, bloodlines and the determination of future characteristics are of particular relevance in the context of pre-birth genetic testing. The potential for pre-birth genetic testing as a positive influence

on whakapapa was mentioned when outlining the use of technology to alleviate a number of Mäori health concerns:

I don’t know how I feel about this but we’ve got for instance, huge issues of diabetes, we’ve got huge negative stats of hepatitis ... all these things in our society. What if through this kind of process we could actually eliminate some of those things that kill our people? Now I don’t know what they can do at the moment, but they might find that people of a certain gene are more likely to have or be the carriers of hepatitis or whatever the thing is, would we still be that, if we found that we could wipe out cancer through this, they identified the gene or genes or whatever, this is just hypothetically speaking, and that could wipe out cancer. Would we still be so thing to say ... about “oh will I have a child, what’s the ethical decision about having a child that might be disabled all their life”, but it could be actually about the future of a whole people.77

Similar notions were outlined in relation to the potential for pre-birth genetic testing to benefit Mäori; one participant raised this in relation to Mäori youth with sexually transmitted diseases:

We’ve got huge things that are going to be impacting on us in the next 10-20 years that are going to affect our fertility, and we might not be able to just as black and white ... say that we don’t get into this any more, and one of the points I made ... was just the huge proportions of Mäori that have STD’s, that impede fertility like chlamydia and gonorrhoea and outrageous numbers of our youth are falling to these diseases, and 20 years down the track this might have a profound impact on the Mäori population, so when then do you start looking at the survival of the collective, or the right of the collective over the individual?78

With increased rates of sexually transmitted diseases, come increased issues surrounding infertility and Mäori may increasingly utilise fertility interventions such as in vitro fertilisation, in conjunction with pre-birth genetic diagnosis.

Whakapapa and reproduction are of considerable importance to Mäori and pre-determining desirable characterises within future generations was practised in a number of manners such as taumau and spiritual interventions. A view was expressed that pre-birth genetic testing may be a contemporary extension of such cultural practices.

2 traDitional aPProacHes to inFanticiDe anD aBortion - can Parallels Be Drawn?

Another theme for discussion that emerged in relation to traditional Mäori practices was that of infanticide and abortion. It was from these discussions that comparisons and contrasts were drawn with pre-birth genetic testing and the potential this technology has for undertaking terminations of foetuses and embryos.

The potential for increased rates of abortions and the destruction of embryos resulting from pre-birth genetic testing raises a number of ethical issues for Mäori and non-Mäori alike. The reasons behind the termination of embryos and foetuses based on traditional practice

are not easily ethically or morally discernable and application of this notion may not be easily applicable to pre-birth genetic testing. Views on the appropriateness or otherwise of infanticide and abortion were varied.

One view expressed was based on the protection of the sanctity of life (mana tangata), and as such, would oppose a technology that might increase the number of aborted foetuses. This was a strongly held view and stressed that abortion in the modern day context should only be carried out in extreme cases.

Regarding abortions ... the kuikuia abhor the idea of [abortion], it stops the genetic whakapapa of that family, although ... for instance if a woman was raped then they would take this rongoa to stop the birth of the child.79

Examples of values and traditions stressing the importance of protecting future generations and nurturing the potential of the unborn children are a common feature amongst Mäori society. Many myths, traditional prayers, incantations, songs and rituals within te ao Mäori exemplify the importance of the reproduction process as being sacrosanct.

Juxtaposed with this view are also a number of traditional instances outlined by participants in which infanticide and abortion were practised:

It’s interesting to think about thehe old practices within te ao Mäori because there are instances of inducing abortion or, getting rid of babies that were born haua. I think there was the real practical attitude around the decisions that were made in the interests of members of any particular whanau.80

Well in the olden days ... what they would have done was that any deformed babies were actually put to death because they knew these babies were going to die anyway, so some of them would try to use the rongoa Mäori to help the foetus, otherwise when it was born and something was wrong then it was put to death.81

I’ve also heard anecdotal things of people saying that there were no Down syndrome babies in pre-European society, well there might have been a reason for that, not necessarily just because they didn’t exist.82

Whilst there is evidence within the traditional Mäori world view of infanticide and abortions, decisions were rarely made lightly and were often undertaken to protect the wellbeing of the collective:

If it was going to be detrimental, for instance, to the collective, the collective security, collective economy, the collective ... life, if they were going to be put in danger, then an individual could be sacrificed ... yes the mother might have been upset or what not, but it happened and there were reasons for that. It wasn’t just because it was callous, it was about the security of the collective. The same way that we hear stories of the babies being smothered and killed if an enemy party is approaching because they might endanger, with the crying and that, they might endanger [the collective]. Well, there’s a number of cases that you hear about, and it’s not that there’s no pain there, it’s not that the mothers aren’t absolutely grieving, but it’s for the collective because the whole tribe will die. If you’re hiding and you do actually not want to be found and your baby starts crying then everyone dies.83

The conditions in which abortion and infanticide occurred, the manner in which the decisions took place, and the reasoning behind the actions themselves, are decidedly different to lead one to undertake such actions today. The individual nature which pre-birth genetic testing decisions are made at present means that broader societal and collective issues are rarely taken into account.

In combination with these debates are notions surrounding the status of the embryo and the foetus. In existing Western debates, understanding when life begins allows the reconciliation of ethical issues when determining when one may terminate an embryo or foetus. Approaches to life are considerably different in te ao Mäori from existing debates in Western discourse:

Well I guess the Mäori creation story [of] cosmology has life beginning at the very beginning, which is the mixing of the elements ... So from a Mäori world view that life was created at the absolute mixing of the chemical elements. I think they knew that, but that’s different from making a value judgement on how life should be treated at those times. ...

Mäori believed right from the beginning it’s life, if you look at those whakapapa, and in fact any world view that is based on genealogy to the point that it explains the creation story, I think you have to say that whakapapa at all levels is recognised. So I believe it’s right at the beginning, right there, the mixing of the elements, the mixing of the fluids to create the body, that’s from that whakapapa.84

According to this narrative, life in te ao Mäori occurs at the absolute ‘mixing of the elements’. The status of the embryo and foetus within te ao Mäori is significantly different from existing debates that shape current regulation. Based on highly contested Western understandings of when a foetus can feel pain, or when it is legally ‘alive’, determines the point at which termination can occur.

In saying this, a number of Mäori today still readily utilise abortion and in vitro fertilisation and other medical techniques such as organ transplants. It appears these technologies have escaped the close ethical scrutiny that genetic science has been subjected to and could arguably be said to have been accepted and readily utilised:

We already accept a woman’s right to terminate life through abortion. . Is a woman’s choice to terminate an embryo, or a foetus, through PGD or PND any different than this? If we aren’t prepared to judge a woman’s right to abort then I think that we run the risk of being a bit precious about the technology rather than the issue.85

While abortion and infanticide took place in traditional Mäori society, a simple transferral into contemporary society and application to pre-birth genetic testing may be untenable and inappropriate. The conditions under which such actions took place were usually based on collective notions of well-being. This is not to deny outright the termination of the embryo and foetus through pre-birth genetic testing today.

There was no dominant viewpoint on the appropriateness or otherwise of the termination of embryos and foetuses through pre-birth genetic testing and in relation to traditional practices from research participants. Views were expressed in the context of traditional practice, and parallels were drawn, but significant doubt remained on the contextualised nature under which the act was undertaken.

However, while many do not deny the ethically and morally compromising status of pre-birth genetic testing, especially in relation to many aspects of te ao Mäori, they could not deny the influence that practices such as abortion, in vitro fertilisation and surrogacy had on informing their opinions in relation to pre-birth genetic testing.

The discussion here moves to some of the more contemporary themes surrounding pre-birth genetic testing and the potential the technology has, not just for benefiting Mäori, but also for exacerbating existing social inequalities.

Notions of protecting the health and well-being of future generations implicit in whakapapa can be seen in the innate human qualities of alleviating suffering. The values of aroha, manaakitanga, and whanaungatanga, while not explicitly mentioned, can be gleaned from a number of discussions from participants. One participant states quite simply:

I think this is a good idea this genome research project because when you look at all the mothers that have their babies they don’t really know whether there is something wrong with their babies, their foetus , I think the pre-birth genetic testing is a good idea for Mäori women.86

As with many existing discussions surrounding genetic modification, our participants outlined the manner in which they felt compassion for those affected by genetic disorders:

I’ve got a perception which is based on my own, you know, if I had a disabled child I would love that, I would care for it, I would do whatever... My current partner, we were having this discussion and the father of my kids said, his approach was those you look after, those most in need, like the disabled kids are the best people in the world.87

Confronted with the ability to alleviate genetic disorder and the suffering of one’s own child, this participant questions the notion of allowing such distress to take place:

If there is the power to change it, would you? If you knew that your child was going to have a terminal disease that would kill them by the age of two or three and be in absolute pain and agony for that two or three years. If I had had that choice, I wouldn’t want to see anybody go through that pain, child or not ... This is an uninformed perspective, you have to appreciate that, in terms of the actual conditions that will affect us and how this might actually help eliminate disease, eliminate dysfunction, eliminate disability.88

Based on alleviating both the suffering of whanau and the potential pain that genetic disorder may inflict upon an individual, the principles of aroha, manaakitanga, and whanaungatanga could be invoked as reason to support pre-birth genetic testing.

Based on Mäori levels of deprivation and socio-economic standing, it can be assumed that Mäori utilisation of pre-birth genetic testing will be significantly less than that of non-Mäori. This would likely be exacerbated if pre-birth genetic testing is not publicly available.

Resource allocation is inevitably about money and the tensions that abound between those who can pay and those who cannot. Such views and the implications were outlined by one participant:

Absolutely, this technology is a part of that, fixing a lifestyle problem. That’s the thing about a lot of technology based research now, it is directed towards addressing lifestyle health issues rather than fundamental health issues. And that’s what I see as the dilemma around making technology available and resource allocation. PGD is not high on the Mäori health priority list and you would question whether or not it should get resources over issues like diabetes and cardiovascular disease. However, there will be Mäori that might want to use the service and would likely be disadvantaged if it is only available privately.

Concerns remain that because Mäori do not presently access this technology as readily as non- Mäori (and it could be argued that Mäori will, based on current health forecasts, continue to exercise the same levels of utilisation in the future), there may be potential for ‘eugenic like’89 discrimination to take place in the future. Current levels of utilisation for technologies such as pre-birth genetic diagnosis are levelled in New Zealand at predominantly Pakeha, and on a global scale at developed nations. The participant below outlines similar fears:

Well there’s good evidence that even when Mäori are at the same level of sickness as everyone else, they’ve got worse outcomes and what that suggests is that health resources are not evenly distributed and so if there’s an inequality in any distribution of these health resources then what does that mean for advanced reproductive technology, which is this area. Because there’s a kind of view in the world that the first world people are slower at breeding than third world peoples and I think one of the reasons for reproductive technology is to try and reverse that, and so ... there’s a little bit of a feeling that there might be some eugenic stuff there going on ... so we want some nice good white babies, not some brown babies.90

While it may be unfair to subscribe to generalisations of eugenics based on utilisation rates by non-Mäori at this early stage, we argue that there is potential in the future for discriminatory behaviour against Mäori. Care must be taken, however, for as another participant argues:

If you’re not in on it will you lose the opportunity to build a super race. You know all the other kids will come out ... any imperfections would have been long since deleted, you’d finish up with a group of people who didn’t want any part of it, who have higher levels of deformity and abnormalities.91

A view exists that, potentially, those not utilising the technology may be left with high levels of ‘deformity and abnormalities’, while other population groups may be building a ‘super race’ devoid of ‘imperfections’. Such notions were outlined as being morally and ethically compromising:

If you want to build a stronger Mäori race, it would be quite good to eliminate as much of the blemishes in there. I think Hitler was trying to do that. It’s probably very unethical and immoral to do it.92

While this participant uses the eugenics argument with Mäori as an example, the point is still clear that the elimination of ‘blemishes’ within ethnic groups is of concern.

Assumptions of eugenic discrimination against Mäori are based on the uneven use of pre- birth genetic testing between Mäori and non-Mäori. At the heart of matters regarding access to this technology are broader arguments surrounding equity and resource allocation:

We’re not exactly short of people and we have very big problems with the way resources are distributed, both between the first world and the third world - the whole 80% of the world’s resources are consumed by less than 20% of the world’s population. Now we’re part of the developed world except we’re an indigenous population, as Mäori who appear to be more like third world in a lot of our health status, certainly we are in common ... [in] health status with all other indigenous peoples, within the first world. For instance, we have similar health status to Native Americans, Aboriginal people in Australia, so because of that we have an obligation when looking at these kind of issues to consider the wider context of equity and if these sorts of things end up being accessible only to those who are wealthy, only to those who have resources, only to those who have a large extent personal and political autonomy for themselves and their whanau. Then Mäori won’t be included, koia teera, there would only be a handful.93

The issue for this participant is the manner in which resources are allocated not just within New Zealand between Mäori and non-Mäori, but also at a global scale between developed and developing nations. While Mäori are part of the developed world they still experience levels of health and well-being similar to that of the third world or other indigenous peoples from developed nations. The point here is that pre-birth genetic testing has the potential to be another example of resource misappropriation based on broader issues related to equity and access. As such, concerns remain about further discrimination stemming from this.

When analysing the potential for Mäori uptake in pre-birth genetic testing, it is useful to reflect on broader issues regarding the utilisation of health services in general. The nature and extent of Mäori engagement with emerging biotechnologies regarding the human genome can be gleaned from statistics for existing health care service utilisation and Mäori birth rate trends. Perceptions of a health system that has failed to address Mäori health disparities and continued over-representation in negative health statistics will influence Mäori responses to pre-birth genetic testing.

Mäori health disparities are linked to a range of factors including lower socio-economic positioning, such as living in deprived areas of New Zealand (56% of Mäori live in the most deprived areas of New Zealand).94 Key Mäori health priorities include probable asthma,

diabetes, high blood pressure, obesity, iron deficiency, and injuries, and in negative health behaviours such as smoking, and low levels of physical activity. Suffice to say, key health issues facing Mäori do not include the need for reproductive technologies such as pre-birth genetic testing.

However, whilst pre-birth genetic testing may not provide immediate improved health outcomes for Mäori the preventative nature of the technology and the potential for genetic ‘improvements’ for some Mäori whanau might prove persuasive in the future.

A theme of interest that emerged from discussions was the preventative potential of pre-birth genetic testing:

I think the health thing is a social prevention. If you can prevent a health problem from arising, we’ve won - prior intervention is the most useful type of prevention if you’ve got a mechanism to do it, very few mechanisms can do it, this would be one.95

The preventative potential of technologies such as pre-birth genetic testing can lead not only to prevention of genetic disorders but also the prevention of distress by those involved:

Well I think, in general terms, prevention is ... the cure, so that ... if you’ve got any technology that’s likely to prevent a disorder and it’s gonna work, and I think that’s a good approach. So this raises the added complication to prevent the disorder by getting rid of the lot, which is a strange sort of prevention, and so the question is whether it’s linked more to the prevention of [the] disease sufferer or the prevention of distress by parents and probably by the child. So that’s one area that’s prudent I guess is the preventative medicines. It is primary prevention.96

However this preventative potential has to be offset with continued under-utilisation of health care services for Mäori. Current trends indicate under-utilisation of and expenditure on primary medical care and related services to Mäori.97 While there are a variety of health services available in New Zealand, from general practitioners to public and private hospitals, the level at which they are utilised varies widely between different population groups.98 Mäori are under-represented in all health service utilisation involving, for example, general practitioners, pharmacists, dentists, accident and emergency and after-hours care, and private hospitals.99

The potential for Mäori to utilise pre-birth genetic is important as it will influence the potential Mäori will benefit from this technology. Based on current trends with private service utilisation and existing data on personal income, it is likely that utilisation of pre-birth genetic testing by Mäori will be less than that of non-Mäori. This is significant considering the potential for Mäori to utilise pre-birth genetic testing due to increased Mäori fertility rates, birthing rates and population growth.100

Increased population growth and high fertility rates, compared with those for non-Mäori increases the potential pool of Mäori who might utilise pre-birth genetic testing. However, this uptake is likely to be offset by a number of barriers such as bad past experiences with health services, other health priorities, mistrust of professionals, lack of funds and the lack of confidence amongst Mäori that their spiritual and cultural values will be appreciated and accounted for.

Mäori values, concepts and perspectives of health and well being, and the importance of reproduction, childbirth and whakapapa within Mäori society, are of vital importance when accessing health care services. The spiritual and emotional concerns of parents and whanau also need to be better provided for if Mäori are to utilise, and fully benefit from pre-birth genetic testing.

The tensions between the right of the collective and that of the individual are at the centre of the debate for Mäori and pre-birth genetic testing. These tensions are derived from an individual’s right to make a decision to engage with pre-birth genetic testing, and the broader implications this may have over Mäori communities at the level of whanau, hapu and iwi. This tension is fuelled by the collective manner in which many whanau, hapu and iwi groups either make decisions or perceive issues.

Traditional Mäori decision-making was made with the collective wellbeing of the tribe the paramount concern. Individual choice and decision-making was not exercised in the interest of one person’s well being, but rather, in relation to the outcome most suited to the collective. With the advent of colonisation and the introduction of Western notions of individualism, ideas of collective decision-making and choice have been diluted. However, decision-making at collective levels is still practised by Mäori today.

When discussing pre-birth genetic testing, a recurring theme in regard to individual rights, choice, and collective responsibility, was the pervasive importance of the collective over the individual in traditional Mäori society. This was outlined on a number of occasions, for example:

Traditionally there was a huge community involvement, again depending on your whakapapa and everything, with families, about who you would be with, and what were you to do and all the rest of it. It was something that was more communally, it wasn’t individual right and that’s again with arranged marriages, all that kind of stuff. The naming of the baby, who the baby was to be ... all that kind of stuff was decided pretty much by those of status within the group.101

Decisions surrounding reproduction, marriage and the naming of babies were often made collectively. This was done not with individual interests in mind, but for the security and well- being of the group as whole:

Where the good of the majority is at risk ... there are records of kids who were killed by their parents rather than being taken ... kids who were killed because they were crying and that would attract an enemy and that’s the example of prevention to secure the wellbeing of the group. So at some stage ... the child’s life is not as highly valued as the ... group.102

I know that the way that our, from my understanding of traditional culture, that the way that society had to operate in order to survive was to make sure that the collective right was the paramount right and if you look at the way that it was structured, that’s what it was based on. It was the whole idea of everyone goes on that consensus decision-making ... the

way that our communities operated were based on collectivity, not individualists, whereas opposed to the Pakeha, it’s actually the individual, individualisation to land, individual title, individual, you know everything is individual. And now we’ve got to the point where the right of the individualist is paramount to the right of the collective.103

The overriding principle of the collective good over that of the individual led to decion-making processes based on similar notions:

It’s difficult ... as soon as you start looking at the pattern individualist approach, it gets difficult because families do things for family reasons and cultures do things for cultural reasons as opposed to, you know we get born and think, what is my individual purpose in life and why was I born and why didn’t you do this and why didn’t you do that? We are very egocentric in that regard and, although I think that’s part of the human nature, I don’t necessarily believe that fundamental fixation, obsession with the individual was the leading, was the determining factor, in the way that Mäori society made their decisions.104

Individual rights, in relation to the good of the collective, are troubling notions to reconcile in contemporary Western society. While it is undeniable that traditional Mäori society saw the collective good as paramount over individuals and as such made decisions accordingly, there remain inherent difficulties in maintaining such collective responsibilities today. One participant acknowledges this notion:

I don’t know that Mäori society is unified enough to be too prescriptive in this regard, in that we do live as individuals. I think that it’s a breakdown in our society, I think a more community approach is definitely the way to go if we want to keep our culture alive, but the fact that “what happens in your home, is your business” kind of mentality doesn’t help that, and it also means that our power to influence the individual home or the individual as a community, basically they can just turn around and say “hmm nah, we’re out of here”, you’ve got no control over that. So when then do you start looking at the survival of the collective, or the right of the collective over the individual?105

While our report recognises that notions of collective responsibility by individuals have been degraded, we still argue for the incorporation of culturally aware processes and procedures for those willing to utilise them. This imperative is related to broader issues surrounding Mäori ability to exercise kaitiakitanga and tino rangatiratanga.

The implementation and recognition of collective rights and decision-making are ultimately about Mäori exercising tino rangatiratanga. Control is a crucial component of indigenous people’s role in decision-making regarding pre-birth genetic testing.

These tensions need to be addressed for Mäori to exercise their right as kaitiaki. In doing this, recognition must be given to the status of whakapapa and the fact that it is collectively not individually held. Processes and procedures that recognise the influence this technology may have on collective groups, and that recognise Mäori decision-making, must be put in place. Whether participants argued for or against pre-birth genetic testing, they all strongly asserted Mäori need to exercise kaitiaki and rights to assert rangatiratanga over their cultural practices. The issue is less about ownership of human genetic material and decision- making authority and rights, and more about ensuring that the integrity (mana) of all being impacted is maintained.

Decision-making processes based on individual and collective rights provide a unique challenge when dealing with pre-birth genetic testing. A number of participants outlined the influence this technology may have particularly on whanau. Whanau as a collective group have a number of values and processes upon which they function and organise themselves. The utilisation of technology such as pre-birth genetic testing provides a number of concerns for whanau groups regarding their unique decision-making dynamics not currently catered for under the current Human Assisted Reproductive Technology regulatory regime.

Whanau in its original reference was to refer to a set of siblings (brothers and sisters) born to the same parents. Today, however, whanau generally refers to a ‘large family group comprising several generations and parent-child families related by descent from a recent ancestor’.106 While whanau structures experienced decline and decay under British cultural tradition since 1840, Mäori whanau structures are still apparent today. Whanau as a collective group have a number of values and processes upon which they function and organise themselves. The utilisation of technology such as pre-birth genetic testing provides a number of concerns for whanau groups, regarding their unique decision-makingdecision-making dynamics not currently catered for under the current Human Assisted Reproductive Technology regulatory regime.

Mikaere107 outlines the importance of whanau through the relationship between whakapapa:

The strength of the whanau lay in the tapu status of whakapapa that connected whanau members to one another, to past and future generations, to the gods and through them to the environment. The principle of balance was of vital importance, for it ensured the continued integrity of the group. The very survival of the whole was absolutely dependent upon everyone who made it up, and therefore each and every person within the group was important. They were all part of the collective; it was therefore a collective responsibility to see that their respective roles were valued and protected.

There are a number of roles and functions for individuals within the whanau context. From children to kaumatua, all have a role that is complimentary to the function of the group as a whole. ‘Front’ roles within whanau such as kai korero (speech makers), kai karanga (callers) and kai-whakahaere (directors of proceedings) are usually filled by the most senior descendants of the whanau most suited to the role. Similarly the whanau group is usually led by kaumatua (either male or female). The eldest sibling of the most senior generation has a special status in the whanau as te kai-pupuri i te mana - ‘the one that holds the mana’ on behalf of the collective. In many whanau groups several kaumatua form a collective leadership group with the matamua acting as coordinator and spokesperson.108

An example of the differing manner in which decisions are made to contemporary Western nuclear families is through child care. Decision-making in the whanau context with regard to child care was not always made by the parents. According to Mäori way of thinking, parents do not necessarily have exclusive right to bring up their children or even to choose alternative care-givers. Up until the 1950s, and to a certain degree even today, kaumatua often made decisions about who would raise the children of the whanau. From the 1950s, with the advent of urban migration and economic independence, this practice has decreased. Nevertheless, Mäori today generally recognise the rights grandparents have in decision-making regarding mokopuna (grandchildren), and play an important role as advisors, negotiators and the bearers of knowledge regarding parenting.109

The emerging themes on Mäori and pre-birth genetic testing uncover a number of issues that need to be addressed if the utilisation of pre-birth genetic testing is to take into consideration Mäori cultural, ethical and spiritual concerns. Regulation of pre-birth genetic testing needs to consider the broader context of whakapapa, decision-making, and collective responsibility. While there are a number of potentially positive effects for pre-birth genetic testing discussed at the start of this section, there are still concerns surrounding termination of embryos and foetuses, equity and access, but most critically the balancing of individual and collective rights and cultivation of an environment through which this can be achieved.

The first two parts of this chapter are written by Bevan Tipene-Matua and Victoria Guyatt. They would like to thank all researchers on this project for their support and many stimulating discussions.

Tenei au, tenei au, tenei au te hokai nei i taku tapuwae, Ko te hokai-nuku, ko te hokai rangi, ko te hokai

The tauparapara (chant) of Täne’s journey to the uppermost heavens represents a powerful link for Mäori between the spiritual, physical, cultural and the ancestral. All knowledge was brought forth and retrieved by Täne. It is from the sacred knowledge contained in Ngä Kete o te Wänanga (baskets of knowledge) that Täne performed the karakia whakatö tamariki (recitation to bring about conception). This knowledge and understanding facilitated the beginning of the ira tängata, into Te Ao Marama, the world of light and being.

The word ira means ‘life principle’ and can be used more specifically to mean ‘gene’,110 while tängata means human. Ira tängata hence refers specifically to a human life that has inherited a collection of genes from the parent(s). The genes are more than biological elements, however. There is a godlike and spiritual quality to all of them because as human beings, ira tängata descend from ira Atua, the Gods.111

The following draws together material that have been gathered primarily from a literature review undertaken for this project. It is not intended to be definitive, nor is it a representation of all Mäori views, but it is an introductory guide to assist in the formulation of policy or guidelines in relation to preimplantation genetic testing (PGD) or, more generally, human assisted reproduction technology. Some of the concepts, beliefs or principles may be mentioned in other parts of this chapter but are included below with additional details.

This part of the chapter raises the question: what are the needs, values and beliefs of Mäori? An exploration of this question, which may assist decision-makers in the exercise of powers or functions pursuant to the Human Assisted Reproductive Technology Act 2004 (the HART Act), involves a discussion of Te Ao Mäori (Mäori world view) and the system of Mäori values, needs and beliefs.

The first section of this part attempts to identify values and beliefs that may help provide guidance in giving effect to section 4(f) of the HART Act which states:

All persons exercising powers or performing functions under this Act must be guided by each of the following principles that is relevant to the particular power or function:

(f) the needs, values, and beliefs of Mäori should be considered and treated with respect.

The second section, which relates to the HART Act and Preimplantation Genetic Diagnosis Guidelines formulated by NECAHR, looks into responses from a Mäori focus group held in November 2004 that raised several issues about PGD.

The third section sets out a tikanga Mäori framework that is premised on a model provided by Professor Hirini Moko Mead.

Culture . . . constitutes a resource which we create and on which we draw, consciously and unconsciously, to comprehend our social and physical environments and our place in them. It shapes the ways in which we see and experience our world. Culture defines the way in which we see, understand and respond to physical and social phenomena.112

Any society’s beliefs and practices are shaped by that society’s culture and can only be usefully analysed in its terms. The values that underpinned traditional Mäori society113 shaped and informed Mäori systems and cultural practices, and continue to do so. Concepts derived from traditional society, such as tapu and makutu are still important to Mäori in understanding illness, disease or genetic disorders.

In the early nineteenth century Mäori encountered new agricultural methods and medical practices via missionaries, whalers and colonial settlers. Ethnographic materials, missionary journals and manuscripts are an invaluable source of information about this period of New Zealand history. Mäori interactions, whether of a collaborative nature or otherwise, with Päkehä involved a decisive era of change for the indigenous and settler cultures.

...the Mäori response to western contact was highly intellectual, flexible and progressive, and also highly selective, aiming largely to draw upon the strengths of the west to preserve the Mäori people and their resources from the threat of the west itself, and to enable them to enjoy its material and cultural riches with the Westerners.114

The deeds of Mäori ancestors (Ngä mahi a ngä tüpuna) during this time continue to inspire the current generation of Mäori thinkers, practitioners and researchers. Mäori practices, law and values evolved from the deeds of the ancestors and developed over subsequent generations for Mäori society.115

If men are unable to perceive critically the themes of their time, and thus intervene actively in reality, they are carried along in the wake of change. They are submerged in that change and so cannot discern the dramatic significance.116

The use of human assisted reproductive technology to biopsy embryos and diagnose genetic disorders requires Mäori to explore the efficacy and relevance of traditional concepts in an ever-changing contemporary world. The following is an exploration of the concepts of tapu, makutu and karakia (charm, spell, incantation) in relation to preimplantation genetic diagnosis and Mäori attitudes to illness.

Mate Muaori is a term used to describe illness believed to be due to Mäori causes and for which there is no remedy other than that which is uniquely Mäori, as distinct from diseases introduced by the Päkehä or “Mate Päkehä”.117

Pre-contact Mäori society was described as healthy, virile and relatively unaffected by serious disease.118 Mäori had rational procedures for treating minor, curable conditions, but faced with the serious, they had to resort to the “supernatural” because such disease was thought to be the result of an atua, or spirit.119 The causes of disease or illness were attributable to a transgression of tapu or makutu.120 It seemed to Mäori that there was a class of illness which was impervious to European medical procedures. Such illness was termed mate Mäori, indicating a malady caused by some spiritual disturbance.121

The definitions of health (hauora) and illness (mate), the boundaries between the two conditions, and markers which indicate we have moved from one condition to another are provided by culture and learnt experience.

Tapu had a spontaneous origin in the fear of the supernatural, but was moulded by experience or what was believed to be experience; and the belief is fortified by suggestion which produces death or disease when tapu is broken.122

The importance of culture is reflected in the ways in which people recognise and articulate symptoms of illness or disease. In relation to a genetic disorder Mäori may still view their illness as a transgression or a punishment, or a sign of personal weakness and therefore may not seek treatment. Historically, the violation of tapu or a committed hara may have resulted in an illness which the tohunga or the wider collective may have resolved.

Tapu is a principle which acts as a corrective and coherent power within Mäori society. It acts with a system of prohibitory controls, effectively acting as a protective device. Tapu and makutu were applied to control human behaviour.123

The laws of tapu affected all areas of life – conception, birth, marriage, sickness, death, burial, exhumation; all industries; and no person in the community was exempt from its stringent rules. Tapu came originally from the gods or the mediums of the gods, who were impregnated with tapu.124 Examples of infringements of tapu included: used weeds, stones or water from tapu

places for the purposes of cooking; taking tapu objects into cooking houses or any common place, or interfering with them; defecating or spitting on any sacred object or depositing cooked food there; trespassing on any tapu spot, or handling any tapu object and not having the tapu removed from one’s person by being made noa or common.125 Punishment could take any number of forms such as minor skin ailments or serious illness. An example is provided below to illustrate the point of how traditionally a serious illness could have been treated.

Te Moananui, a Ngäti Kahungunu rangatira, was afflicted by an unknown disease. Two tohunga took the chief to a stream before dawn, immersed him in the water and conducted several rituals. The object of the incantations was to absolve the patient from all wrongs and act as an appeal to the gods; at birth, a chief would have certain rites performed and particular gods were given control over him to protect him from the dangers of war, misfortune, ailment or witchcraft.126 The tohunga then proceeded to recite a healing charm, followed by a ritual to compose, tranquillize and relieve the patient of their fears and to cause him to have faith in the efficacy of the procedure. Finally, the last ritual appealed to the superior beings to bestow health. The chief recovered from his serious illness.127 A similar procedure would have been utilised to treat a patient affected by makutu albeit with different karakia.

Intimately connected with the superstition respecting things tapu is the belief as to the cause of disease, namely, that a spirit has taken possession of the body of the sufferer. The belief is that any neglect of the law of tapu, either wilful, accidental or even brought about by the act of another person, causes the anger of the Atua of the family who punishes the offender by sending some infant spirit to feed on a part of his body - infant spirits being generally selected for this office on account of their love of mischief and, because not having lived long enough on earth to form attachments to their living relatives, they are less likely to show them mercy. When, therefore, a person falls sick, and cannot remember that he has himself broken any law of the tapu, he has to consult a matakite (seer) or a tohunga to discover the crime and use the proper ceremonies to appease the Atua; for there is in practice a method of making a person offend against the laws of tapu without his being aware of it. This method is a secret one called makutu. It is sufficient for a person who knows this art, if he can obtain a portion of the spittle of his enemy, or some leavings from his food, in order that he may treat it in a manner sure to bring down the resentment of his family Atua. For this reason a person would not dare to spit when in the presence of anyone he feared might be disposed to injure him, if he had a reputation for skill in this evil art. With such a belief as to the cause of all disease it will not be wondered at that the treatment of it was confined to the karakia of a tohunga or wise man.128

Tohunga were the repositories of tribal knowledge, history and esoteric lore. They were perceived as the spiritual head of the community. Tohunga performed a diagnostic role in relation to sickness by formulating a case history and family history via the patient’s dreams and activities prior to becoming ill. The tohunga also investigated the role of the family to discover the hara (infringement) which caused the disease. The next step was to propose a treatment plan to remove the offending spirit. This may involve the family with the requisite ritual performed by the tohunga. The treatment plan could conclude with a period of rehabilitation for both the individual and the family.

The role of tohunga in the twentieth century changed dramatically. The Tohunga Supression Act 1907 prohibited tohunga from practising traditional Mäori medicine and Mäori spirituality by imposing fines on tohunga who practised and maintained traditional knowledge. Tohunga did continue to practise but the Act sufficiently restricted cultural practices. The Act was repealed in 1962.

In 1977, Mason Durie explored contemporary issues of Mäori attitudes to sickness, doctors and hospitals.129 Durie maintained that tapu continued to enable the social life of the community to be upheld – it was the basis of law and order and its respect ensured the survival of the community. The laws of tapu had direct application to matters of health and sickness. The concepts of tapu and the perception of illness as an infringement against tapu are central to much of the anxiety and depression which surround the Mäori patient while in hospital. Family involvement at times of illness is likewise a very traditional and culturally necessary attitude which must be recognized in the management of the whole patient and not just his impaired organ.130 Durie considered that mate atua – sickness – was an infringement of tapu and therefore an interference with the particular atua.

However, the current notions of tapu may have changed. The elders have intimated that it is very difficult for most people of this generation to become tapu because we lack the commitment to maintain conditions by which a person becomes tapu.131 It is difficult for most Mäori today living in suburbia to observe and adhere to tapu. The knowledge of what is prohibited and restricted requires experience and contact with repositories such as kaumatua or tohunga. Historically, everything was regarded as tapu. Individuals and groups continue to have responsibilities and obligations to abide by the norms of behaviour and practices established by the ancestors.132 In summary, the primary purpose of tapu is to protect – through recognizing the whakapapa between ira atua and ira tängata, and adhering to tikanga.

The following karakia (ritual) whakatö tamariki was recited by Täne over Hine-titama in order to cause her to conceive.133 It was used to implant a human embryo. The word whakatö means to be pregnant or to conceive or to plant.

The karakia discusses the drawing forth of a genetic line of descent so a being forms, develops and grows. At line 8 the ritual refers to the forming of the head, limbs and body of the embryo. In pre-contact the karakia whakatö tamariki was performed by the tohunga, by virtue of their mana.134 The tohunga would instruct a prospective parent (mother) as to reproductive rituals

and procedures that would cause them to conceive. In some cases a mother would insert something into her which would be returned to the tohunga who would then recite the karakia while immersing the object in sacred water. The karakia would be dedicated to Rongo-mä-täne (if a female was desired) or Tümatuenga (if a male). There are also examples of sacred places where rites and incantations were performed in the hope that the couple may conceive. Elsdon Best documents several sites of reproductive significance where tohunga would perform rites over the woman while she held a tree or stood in a particular sacred place to conceive.

The wairua (spirit) of a child is, according to several of my authorities, implanted by the male parent during coition. “I think,” said a worthy friend of mine, “that the wairua is implanted during sexual connection. We do not know where this spirit comes from, but I think the spirit (wairua) of an ancestor may thus be implanted in a child, because see how often a child resembles a grandparent or ancestor.135

However, it is also noted that since the arrival of Päkehä (contemporary) the effectiveness of these rituals may have declined. The place of karakia whakatö tamariki may no longer be relevant, but District Health Boards, for example Waitemata Health and the Otago District Health Board, have policies and practices in place to meet the potential requirements of Mäori. The Waitemata Health DHB is an example of how tikanga Mäori and the principles of the Treaty can be incorporated into the provision of health services.136 The “Tikanga Best Practice Policy” models provide the patient or consumer (türoro) access to new technology and health care in a culturally appropriate way that respects and protect their needs. This accords with the obligations of DHB’s under section 4, New Zealand Public Health Disabilities Act 2000.

The kaihau waiü refers to the rights a child inherits at birth. A child is born into a kinship system which is already in place and has been for many generations. The whakapapa of a child affects access rights to land, resources and establishes their place in society. The mätämua or first born inherits a tapu in recognition of the law of primogeniture and the associated rights of being born first. Many of a person’s prospects in life depend on parents and the legacy they pass on: genes, social standing, economic position, education and within some tribal groups this continues to be the case:

... tapu pertained to everything connected with birth. Some first born children were kept strictly tapu from birth, and not allowed to carry food or to perform any labour whatever. This would apply to first born male and female children of a chief ’s family.137

~ Mätämua - first born and the order of birth are important in terms of a child’s whakapapa and the associated privileges;

~ Tuakana138 / Teina139 - status in relation to another family member and the associated responsibilities (but also consider reciprocity of position - the elder and younger have an obligation to look after each other)

There are several historical examples of how Mäori pre-determined the gender of the child. These may involve the way the baby moved in the womb, or a whe (praying mantis) found upon a woman was a sign she had conceived and, depending on the type of mantis, whether it was a boy or girl.

Several customs existed in relation to becoming pregnant or wanting a child of a particular sex. For example, a prospective mother could attend the birth of another member of the community and she would stand over the afterbirth (whenua) and stand (piki) over it in the hope of having a child of the same gender. She could also have a tohunga perform karakia over the placenta of another woman’s afterbirth in the hope that she would conceive too.140 The same custom could be used for infertile women. Tohunga could also prevent conception by reciting a karakia whakapä.141

A woman is considered most tapu when she is pregnant. When a woman was closer to giving birth, she was taken to the whare kohanga away from the rest of the hapü. Separating women from the rest of the tribe ensured two things. Firstly, it removed most of the duties a woman would have had to perform, letting her rest and stay strong while carrying the child. Secondly, by remaining separate from the rest of the hapü, the risk of sickness and disease was greatly reduced; hence the mother avoided any unnecessary duress during pregnancy. The tapu of the woman in this context ensured the survival of as many children as possible, to keep the hapü strong.142

The term whare ngaro implies the death of all children of a couple. The term is not applied to lines of descent broken through infertility of women, or by a person not marrying. This affliction of a whare ngaro, is attributable to the dead or ancestors, or caused by witchcraft

- makutu.143 If parents lost their first child, a tohunga would be asked to perform the tu ora rite over the next child so that the whare ngaro (lost house) might be averted, and the child survive.144

In the Rua-tahuna district, of late, several women, whose children had died in infancy, and hence who feared a whare ngaro, were not allowed to eat of any food which had come from Rua-toki, inasmuch as the infliction is thought to have had its origin at that place. These women were afterwards taken to Rua-toki, where some rite was performed over them, in order that the cause of the children’s death might be destroyed (ka tahuna ana mate e te tohunga - the tohunga destroyed those afflictions).145

E ahua tangata ana te pakeke o te wahine. He whakatipu tängata taua mea. (The pakeke of a woman is a sort of human being, it is a person in embryo).146 Best discusses menstruation and says that the pakeke has no wairua although tapu.

According to the Lore of the Whare Kohanga, Mäori believed that premature birth was caused by some infringement of the laws of tapu. When a woman wanted to abort the fetus herself, she would deliberately infringe tapu, for example, by passing cooked food over the head of an elder; or she may take cooked food to a tapu place and eat it. The aborted fetus is termed an atua kahukahu and has the potential to develop into an unwanted spirit. If an abortion was to take place the fetus needed to be properly buried so that an animal wouldn’t unearth and eat it. Karakia would be performed over the fetus when buried to nullify the effects of the spirit.

In June 2003, the Minister of Health gave approval in principle to the use of PGD in New Zealand, and requested that NECAHR develop guidelines on the use of this technology. NECAHR’s draft guidelines on PGD were disseminated to fertility clinics, District Health boards, professional organisations, consumer groups, government agencies and interested individuals in October 2004. The guidelines were subsequently approved by the Minister of Health in March 2005 and are deemed to be guidelines issued by the Advisory Committee on Assisted Reproductive Technology (ACART) pursuant to interim arrangements under the HART Act: see section 83(2)(1). Category 1 of the guidelines has, since then, been declared by Order-in-Council to be established procedures under section 6(1) of the Act. It is worth reiterating that the transitional provisions under the Act ensure that the guidelines which were developed by NECAHR remain effective until such time when ACART issues new guidelines.

In November 2004 a Mäori Focus Group raised several key issues and concerns about PGD. The purpose of the Mäori focus group was to provide a forum to discuss, from a Mäori perspective, issues that were of interest and/or concern arising from the proposed guidelines. The following is a discussion of some of these key messages.

At the heart of the requirement of informed decision-making is the need to ensure that Mäori perspectives are known and understood. But this is a two-way process. It is equally important for Mäori to be informed. Proper and adequate consultation is an important part, however, consultation is the end point not the starting point. The starting point is the development of constructive relationships that will lead to a real knowledge and understanding of all of the points of view of all parties.147

The courts and the Waitangi Tribunal have variously outlined the requirements of genuine consultation with Mäori, and these have been well tested over the years through a number of legislative avenues. In the case of Air New Zealand Ltd v Wellington International Airport Ltd 148, Justice McGechan noted that: “Consulting involves the statement of a proposal not yet finally decided upon, listening to what others have to say, considering their responses and

then deciding what will be done.” In addition, the broad principles established by the courts in relation to consultation should be kept in mind.

The focus group was concerned about how Mäori are consulted on these issues. Members of the group noted that the Treaty of Waitangi and the principles of the treaty were missing from the Guidelines. Furthermore, the group stipulated that the Crown and Mäori, in partnership, should decide on the introduction of new technologies. In short, genuine consultation did not happen. The group asked how could they have input into the Guidelines to protect a Mäori view or perspective? The ability of Mäori to make informed decisions about PGD is impaired by the Crown. The principle of partnership is a two-way process; in this case, the interests of Mäori in PGD have not been adequately protected.

The Te Wanaka O Otautahi Research Team has advocated for legislative amendment to the Act to include the Treaty of Waitangi. The focus group sought to include the Treaty of Waitangi in the PGD guidelines. The inclusion of a Treaty of Waitangi clause would require committees to act reasonably and in good faith, and to make informed decisions that actively protect Mäori interests. An example of an appropriate statutory provision is section 8 of the Hazardous Substances and New Organisms Act 1996, which states:

All persons exercising powers and functions under this Act shall take into account the principles of the Treaty of Waitangi (Te Tiriti O Waitangi)

It is also advocated that a statutory Mäori advisory committee be established. The committee would be required to provide advice and assistance, as sought by the other committees constituted under the Act, on matters relating to policy, process and applications. This advice would be given from a Mäori perspective as described within Terms of Reference set by the committees.

Genetic counselling149 provides information and support to an individual or to a family about genetic disorders.

The Mäori focus group highlighted the important role that whänau could play in a couple’s decision-making process. In particular, concern was expressed that the whänau may not be aware that the couple is experiencing infertility issues or that they (or future children) may be susceptible to a genetic disorder. It was emphasised that for Mäori the process around options for the couple began at home. However, it was also recognised that the individual(s) may be separated from whänau. The group clearly expressed the view that counselling may be achieved by whänau and that genetic counsellors would involve kaumatua or whänau.

A possible solution may be that providers of genetic counselling services in collaboration with Mäori develop culturally appropriate qualifications or incorporate mätauranga Mäori into existing programmes of study. Alternatively when counselling, kaumatua or appropriate person(s) with relevant skills and expertise could be included or advised at the information stage during counselling.

One of the first points raised by the focus group related to health. There are a number of health priorities for Mäori. The bullet points below highlight areas of concern for Mäori health and wellbeing:

~ Te Puawaitanga: Mäori Mental Health National Strategic Framework states that mental health problems are now the number one health concern for Mäori.150

~ Health providers such as District Health Boards rationalize health expenditure and prioritise investment. For example the Otago District Health Board in collaboration/ partnership with Kai Tahu have identified health and disability services as its number one priority. Reproductive Technologies do not feature on an extensive list of health priorities set by Ngäi Tahu

~ Relatively recent advances in medical technology may make some genetic changes possible but such developments will only affect a very small section of the population.151

~ The direction of Mäori health policy and research is generally focused on reducing inequalities and supporting Mäori families to achieve maximum health and well-being.152

~ In terms of causes of lost healthy life years, and causes of disparity in life expectancy between Mäori and non-Mäori, the Clinical Research Trials Unit in Auckland has identified tobacco as the single most important risk factor and cardiovascular disease as the most important disease category.153

Mäori may have greater health concerns and priorities. This does not preclude Mäori from engaging in PGD and the associated services offered by assisted reproductive technology or diagnostic testing for genetic disease.

Tikanga are essentially a set of ethics expressed as customs and traditions that have been handed down through many generations and accepted as a reliable and appropriate way of achieving and fulfilling certain objectives and goals.

In 2004, Mere Roberts in collaboration with Lincoln University conducted and completed an extensive survey of Käi Tahu to collect their views on biotechnology.154 The project involved 22 interviews and focus groups involving a total of 91 people who affiliated themselves with Käi Tahu. The interviewees were questioned about xenotransplantation, stem cell research, cloning, genetic modification, and bioprospecting.155

The overwhelming feedback was one advocating tino rangatiratanga (self-determination) and kaitiakitanga (guardianship). Participants were concerned at the perceived lack of involvement and control by Mäori in the existing risk assessment and decision-making processes. In their view, a Treaty of Waitangi framework should form the basis for Mäori involvement in biotechnology. Most participants believed that Article II guaranteed them

their rights and responsibilities to participate as partners in the policy setting and approval processes surrounding research on novel biotechnologies. These rights and responsibilities, inherent in tino rangatira, provide the mandate for kaitiaki and the practice of kaitiakitanga. This concern led to a range of suggestions that a more culturally appropriate process should include a political/pragmatic approach based on Article II rights, and a spiritually-based approach centred on culturally specific values. The concerns raised in the Roberts study are consistent with the concerns raised by the NECAHR Mäori focus group.156 This adds impetus to developing initiatives for cultural decision-making frameworks.

Tikanga - as what is ethically correct, right and socially appropriate. An essential part of wise decision-making because it contains cultural integrity – “In all things there are tikanga, principles, process and guidelines [for] preventing and managing that which is desired as good ... Violation [can] come about when [this] does not happen”157

The purpose of looking into a tikanga framework in the context of this report is to provide a prospective mother or family with a means of assessing the risks/benefits of PGD in a culturally appropriate way. The framework discussed is premised on the model provided by Professor Hirini Moko Mead. Professor Mead defines tikanga as:

A means of social control – tikanga controls interpersonal relationships, provides ways for groups to meet and interact, and even determines how individuals identify themselves. Tikanga has a place in any social situation. Ceremonies relating to life itself – birth marriage, sickness and death – are firmly embedded in tikanga Mäori.158

Professor Mead’s reference refers to a tikanga Mäori position is sometimes also referred to as a framework of assessment. It provides a method for assessing a situation or event that challenges our thinking and values. The key point is that the framework provides a position not the position. The following provides a checklist of matters and questions to consider as part of an attempt towards developing a tikanga Mäori framework for PGD.

Tapu is a complex concept that acts as a code for social conduct so people can keep safe and avoid risk. The starting point of Professor Mead’s framework is to subject the ethically controversial issue to the tapu test. In this case the first question that could be asked is:

Mäori are inherently tapu by virtue of their whakapapa. The removal of an embryo from the whare tängata (womb) for diagnostic purposes does breach the tapu of the mother, the embryo and by implication the whakapapa of the wider family. The second test below is linked to the first.

Every living thing has a mauri. The mauri test is essentially a test of the risks to the life of the subjects of PGD. This may involve asking further questions and analysing the risks to the future child, mother, father and family. For example:

Professor Mead concludes that most of the concerns will probably be focused on the moral and social issues rather than risks to mauri. The concern would be for the life of the new being and for the long term prospects of the future child.

If a breach of tapu or mauri is established or is an issue, the next step is test 3.

The take issue is necessarily concerned about the breach of tapu or mauri. The take has to be accepted by all parties as a legitimate cause - there has to be recognition that tapu has been breached (or will be) and the reasons are canvassed and debated. The difficulty is reaching a mutual agreement about the breach or wrong committed.

~ Have the parties involved assessed the likelihood of damage to the well-being of the people who will use the new technology?

The final, desired state is that of ea, a state of satisfaction where a sequence has been successfully closed, relationships restored, etc.

Test 4 involves a search for precedents. In Te Ao Mäori, an event or tradition might help people understand the issue or help frame a response to it. The creation of life and the role of atua, tohunga gives a clear indication that whakapapa is inherently tapu. See the examples of traditional reproductive practices and the discussion of Te Ao Mäori above.

Whanaungatanga creates an obligation of support and assistance if the person seeking help is a blood relative - irrespective of whether it was supported by tikanga Mäori or not. In the context of a couple wanting to use PGD the wider family are obliged to support their decision.

Manaakitanga underpins all tikanga Mäori - it focuses on positive human behaviour and encourages people to rise above their personal attitudes and feelings towards each other and towards the issues they believe in. The aim is to nurture relationships and respect the mana of other people. The value is often expressed as “acting like a rangatira”.

A decision to use PGD should not damage the mana of a patient, a consumer, nor anyone associated. Ideally, mana should be enhanced. For example: doctors who perform abortions are often targeted or denigrated. The role of the doctor complies with the principle of manaakitanga but their personal mana is put at risk.

Noa - reaching a state whereby a new idea is accepted, incorporated into the thinking of people and is no longer a controversy - an informed public? People need to know the harms and benefits of PGD.

The success of tikanga depends on public acceptance. The basic question to ask is whether PGD is tika, that is, ethically, culturally, spiritually or medically right. The answer should be, yes, it is tika and right to participate in new technology.

New Zealand Law Foundation Research Reports

Human Genome Research Project --- "Choosing genes for future children: the regulatory implications of preimplantation genetic diagnosis" [2006] NZLFRRp 1