The Obstetrician & Gynaecologist 2007;9:3:177-180
doi: 10.1576/toag.9.3.177.27338
Copyright © 2007 by the Royal College of Obstetricians and Gynaecologists.
Cloning
Alison Murdoch, MD FRCOG, Professor of Reproductive Medicine and Consultant Gynaecologist1
1. Newcastle Fertility Centre at Life, International Centre for Life, Times Square, Newcastle upon Tyne NE1 4EP, UK Email: a.p.murdoch{at}ncl.ac.uk
 |
Abstract
|
|---|
Key content:- Reproductive cloning is prohibited in the United Kingdom and there is legislation banning it in some other countries.
- The therapeutic potential of being able to grow unlimited supplies of functioning, differentiated cells of different types is immense.
- One possible application in gynaecology might be to use cell-based therapies to replace the endometrium and to treat myometrial scars and bladder wall or vaginal deficiencies.
- A licence to undertake somatic cell nuclear transfer for the derivation of stem cells was granted in the UK in 2004 and the first blastocyst described in 2005.
- One potential way of obtaining oocytes might be to ask women undergoing in vitro fertilisation to donate some of theirs.
Learning objectives:
- To learn about the moral and ethical issues surrounding human cloning.
- To be aware of the potential use of cloning in gynaecology.
- To be informed about the current research.
Ethical issues:
- How can oocytes be obtained without risk to the donor?
- Is it ethical to pay women to donate oocytes?
Please cite this article as: Murdoch A. Cloning. The Obstetrician & Gynaecologist 2007;9:177–180.
Keywords embryonic stem cells / Human Fertilisation and Embryology Authority / in vitro fertilisation / somatic cell nuclear transfer / therapeutic cloning
|
Introduction
|
|---|
Reproductive cloning is prohibited in the United Kingdom as a result of the Human Reproductive Cloning Act 2001 and there is also legislation banning it in other countries. Because the technology is inefficient and the risks to any potential children are great, the procedure cannot be justified.
In subsequent legislation, the UK Parliament approved procedures leading to nuclear reprogramming (therapeutic cloning), as a result of an amendment to the Human Fertilisation and Embryology Act 2001. The international situation is changing, as countries debate and reconsider their positions. At present only a few countries, albeit with strict regulation, support therapeutic cloning, including the UK, South Korea, India, China and Singapore. In most other countries it is a criminal offence to undertake such research.
Against this background, the UK has taken a world lead in what many consider to be the most exciting new medical science for many years. In August 2004 the first licence to undertake somatic cell nuclear transfer (SCNT), for the derivation of stem cells (therapeutic cloning), was granted by the Human Fertilisation and Embryology Authority (HFEA). The first blastocyst following SCNT was described in 2005.1
Arguments against embryo research, SCNT and therapeutic cloning are largely based on religious and moral beliefs relating to the status of the preimplantation embryo. Unfortunately, the explanation of early human development at a molecular level is so far from theological teachings that it seems unlikely that the two will be reconciled in the foreseeable future. Nonetheless, the majority of scientific and clinical opinion recognises the enormous potential of the technology. The open support that followed the HFEA decision to allow SCNT indicates that the UK public also wants this work to proceed. It is likely that the debate will continue until successful therapies develop, in which case international heath services and commercial lobbies will prevail, or the potential for the research will be proved to have been overestimated.
This article explores how gynaecologists are becoming directly involved in this exciting new science and asks whether it will be of benefit to our patients. First, however, the procedures involved are explained (Figure 1).
|
What are stem cells?
|
|---|
Everyone starts out as a single cell: a fertilised oocyte. This cell, called a ‘totipotent stem cell’, contains unique genetic information from which every single cell type in the body is made. Following a few further divisions, some cells differentiate to become the trophoblast and the remaining cells form an inner cell mass that may eventually form a fetus. There is a very small period of time when this inner cell mass contains just a few hundred cells with the full potential to become all types of cells of the body. These are called ‘pluripotent cells’ and they can be isolated and grown as a cell line. They are then known as ‘embryonic stem cells’.
Embryonic stem cells have the potential to differentiate into any cell type in the body; for example, nerve, bone, cardiomyocytes or islet cells. Although we know that, by definition, all cell types can be grown from embryonic stem cells, our understanding of how the process is controlled is limited. Many questions need to be addressed regarding the biology of stem cells. It takes little imagination to realise that the therapeutic potential of being able to grow unlimited supplies of functioning, differentiated cells of different types is immense. However, we must be cautious. The apparent simplicity of the concept belies the enormous amount of scientific work still needed to realise the potential. It is likely to be many years before such treatments are widely available.
There remains the potential problem that cells derived from embryonic stem cell lines may be subject to immune rejection. For this reason, there is interest in deriving embryonic stem cell lines specific to each patient. This involves reprogramming the nucleus of their somatic cells. The nucleus of every cell in the body contains a full copy of the unique genetic code of that individual and when differentiating into, for example, a skin cell, the nucleus activates some genes and suppresses others. The goal is to change the gene expression first by ‘wiping the memory clean’ and then by switching on the gene expression to allow different cell types to develop. At present, the only method we have of reprogramming the nucleus is to place it in an enucleated, mature oocyte. The cell is then activated to form a blastocyst, from which the inner cell mass can be isolated and embryonic stem cells derived. The donated nucleus could come from any differentiated cell from the patient and requires minimal medical intervention. Cells grown from an embryonic stem cell line after SCNT would be genetically similar to the patient and, thus, not rejected. Using similar techniques, a stem cell line carrying a specific disorder could be derived so that the disorder could be studied in the laboratory. The supply of oocytes, however, is the major rate-limiting factor in the advance of this research. This puts gynaecologists in a central role.
|
Obtaining a supply of oocytes
|
|---|
Considering this process, the role of the gynaecologist is clear. Until we find an alternative source of oocytes, the gatekeeper to the success of SCNT is the woman who donates her oocytes. As gynaecologists, particularly those who work in reproductive medicine, we have the knowledge and skills to induce superovulation in women and retrieve the oocytes. If stem cell biology is to achieve its full therapeutic potential in an ethically acceptable environment, it is going to be essential for some gynaecologists to become involved in this work. The welfare of the donor must be our priority.
Initial hopes were that oocytes from in vitro fertilisation (IVF) treatment that fail to fertilise would be appropriate for this research. They are available without any additional risk to the donor, as they would otherwise be discarded. Disappointingly, it has been shown that these oocytes are not suitable for SCNT and only freshly aspirated oocytes can reprogramme the nucleus.1 Other research2 has shown that these oocytes have a high rate of abnormality: information which has been confirmed by our further work.3
Subsequently, our research team have developed a strategy to recruit more donors of fresh oocytes. We asked women undergoing superovulation for IVF treatment to donate two of their oocytes if 12 or more were aspirated. We estimated that this would not reduce the pregnancy rate and this resulted in the donation of 66 fresh oocytes to our research within 7 months.4 Although this was an improvement, these numbers are not sufficient to permit rapid progress in this field.
Risks of oocyte donation
An important consideration is to ensure that donors are fully informed of the risk inherent in participation in the research. Donation of oocytes requires the donor to undergo superovulation and the minor operative procedure of ultrasound-guided oocyte retrieval. This is not a pleasant procedure. It carries a small risk of morbidity and deaths have been reported. Ovarian hyperstimulation syndrome (OHSS) occurs in 1–2% of women who are superovulated. The risk is related to age and the number of follicles that develop. Young women are ideal oocyte donors and if they develop > 20 follicles, the risk of OHSS is higher (14%).5 This has resulted in a debate regarding the most appropriate donors. It is generally accepted that oocyte donors must be subject to the same protection and regulation as the subjects of any other medical research, including consideration of payment.6 Whereas in some countries it is considered acceptable to pay women to donate oocytes, it is not an acceptable practice in the UK.7
Oocyte sharing schemes
There is a good argument to support an oocyte-sharing scheme since these women are already accepting the risk of OHSS as part of their own IVF treatment. Egg sharing involves asking women undergoing IVF treatment to donate some of their oocytes to research in return for a reduced price for IVF. The National Health Service (NHS) currently refuses to fund the majority of the IVF needed in the UK, so an oocyte-sharing scheme could be an acceptable option for couples having difficulty finding funds for their own treatment. Pregnancy rates in appropriately selected cases may not be reduced after treatment. This is an attractive option, as the risk of OHSS to the donor would not be any higher than that that from her own treatment. The HFEA has recently initiated a public consultation exercise examining the wider issues of oocyte donation for research and the protection of donors and subsequently agreed that this is an appropriate practice.8
|
How will stem cells benefit gynaecology?
|
|---|
Ironically, gynaecology is not one of the fields in medicine quoted as obviously benefiting from stem cell medicine. However, we should watch for the possibility of using cell-based therapies to replace the endometrium and to treat myometrial scars and bladder wall or vaginal deficiencies. The making of new gametes may be possible but this is only likely to be a research benefit in the foreseeable future. Nevertheless, opportunities for research into the earliest stages of human development are providing more immediate benefit. Funding for research related to human fertilisation and early embryo development has traditionally been very difficult to find. Following recognition of its close links to stem cell biology, it is now more readily available. If SCNT is to be reproducible and efficient in humans, we need to study the physiological processes from meiosis in human oocytes to fertilisation and early cleavage. Failure of these processes is fundamental to many problems that a gynaecologist faces: infertility, miscarriage and fetal abnormalities. Many of these problems are age related, which is a major current concern as the age of first conception is rising. There are clear and exciting new opportunities related to stem cell biology for the next generation of clinical and academic gynaecologists.
|
Conclusion
|
|---|
As our understanding of the science grows, we are beginning to see ethical issues in a different light. The principal ethical objections to embryonic stem cell derivation arise from the totipotency of the fertilised oocyte, i.e. its potential to form a new individual if implanted into a uterus. On this basis, each totipotent cell is given a unique status protected by UK law. Reproductive cloning shows us that every somatic nucleus is also totipotent, since it has the potential, if reprogrammed and implanted, to be a new individual. No one would seriously argue that every totipotent somatic cell nucleus should have legal protection: billions of such nuclei are shed by everyone each day.
Bioethical arguments will continue and, for some with deeply held beliefs, no consensus is likely. Ultimately, however, the success of science will determine the views of society and politicians. A successful embryonic stem cell-based therapy will not be denied to a sick patient because it was originally derived from a totipotent nucleus.
It is important to set a realistic timescale so that inflated expectations do not result in perceived failure. It has taken 30 years for IVF to develop from the first successful birth to its current position, in which 1.6% of all babies born in the UK are the result of assisted conception and the National Institute for Health and Clinical Excellence (NICE) have recommended that it should be offered as a mainstream, NHS-based treatment. Somatic cell nuclear transfer and therapeutic cloning is just at the beginning of that process. A likely timescale is at least 5–10 years before clinical trials could start. Despite the great potential, we need to be cautious so that women, their families and society are not disappointed.
|
References
|
|---|
- Stojkovic M, Stojkovic P, Leary C, Hall VJ, Armstrong L, Herbert M, et al. Derivation of a human blastocyst after heterologous nuclear transfer to donated oocytes. Reprod Biomed Online 2005;11:226–31.[Medline]
- Lavoir M-C, Weier J, Conaghan J, Pedersen RA. Poor development of human nuclear transfer embryos using failed fertilised oocytes. Reprod Biomed Online 2005;11:740–4.[Medline]
- Hall VJ, Compton D, Stojkovic P, Nesbitt M, Herbert M, Murdoch A, et al. Developmental competence of human in vitro aged oocytes as host cells for nuclear transfer. Hum Reprod 2007;22:52–62. doi:10.1093/humrep/del345[Abstract/Free Full Text]
- Choudhary M, Nesbitt M, Leary C, Murdoch AP. Donation of fresh oocytes for nuclear transfer research – a new approach. Reprod Biomed Online 2006;13:301–2.[Medline]
- Jayaprakasan K, Herbert M, Moody E, Stewart JA, Murdoch AP. Estimating the risks of Ovarian Hyperstimulation Syndrome (OHSS) during egg donation for research. Hum Fertil (Camb) In press
- The Hinxton Group: An International Consortium on Stem Cells, Ethics & Law. [wwwhinxtongroup.org].
- Human Fertilisation and Embryology Authority. SEED Report: A Report on the Human Fertilisation & Embryology Authority's Review of Sperm, Egg and Embryo Donation in the United Kingdom. London: HFEA; 2006. [www.hfea.gov.uk/cps/rde/xbcr/SID-3F57D79B-34FED032/hfea/SEEDReport05.pdf].
- Human Fertilisation and Embryology Authority. Donating Eggs for Research: Safeguarding Donors. London: HFEA; 2006. [ww.hfea.gov.uk/cps/rde/xbcr/SID-3F57D79B-B4AEA87B/hfea/donating_eggs_for_research_safeguarding_donors_consultation_FINAL.pdf].
TOP
Abstract
Introduction
