Issues Magazine

Stem Cells: Ethics Versus Patient Needs

By Natalie Seach, Veronica Shannon and Richard Boyd

What is the current status of stem cell research and the moral and ethical concerns associated with stem cell research and its clinical translation?

The isolation of the first human embryonic stem cell (ESC) line, just over a decade ago,1 provided a remarkable catalyst for a revolution in medical therapies that could treat a wide variety of debilitating clinical diseases. ESC technologies have since developed rapidly. While scientists caution that clinical trials are still several years away, patient expectations for badly needed treatments are high, placing increasing demands on the ethical and regulatory boundaries and leading to continual public debate and revision of legislation.

What Are Stem Cells?

Stem cells can be broadly classified into two types: adult and embryonic. Both are characterised by the capacity for prolonged self-renewal and the ability, albeit with varying degrees, to differentiate into distinct cell lineages that are specific to an organ or tissue.2

Adult stem cells (ASC) exist in many, if not all, post-natal tissues where they replenish, repair and maintain that resident tissue throughout life. They also exhibit a limited capacity to differentiate into other cell types. ASC-based therapies have already demonstrated clinical success (www.clinicaltrials.gov).

ESC are pluripotent – they can generate cells in the three primary germ layers from which all bodily tissues and organs are ultimately derived. ESC lines have thus enabled unique research into the mechanisms of human development and disease. The potential ability to differentiate into virtually any cell type has meant ESC have become the focus of not only researchers but also patients and their advocacy groups. Never before have there been such synergies between diverse groups of society in addressing the development of new clinical treatments.

How Are Embryonic Stem Cells Derived?

Unlike post-natal or adult stem cells, ESC derivation inevitably results in the destruction of an embryo. Thus, ESC research is subject to more complex moral and ethical issues centring on the embryo’s right to life, the provision of human eggs and the ethical concerns surrounding new cloning technologies.

Traditionally, ESC are derived from the inner cell mass of a blastocyst-stage embryo, which in humans is reached approximately four to five days post-fertilisation. This region contains undifferentiated pluripotent cells that, once removed, can be propagated in culture medium to obtain a self-renewing, pluripotent ESC line.2 The embryos used for ESC derivation are obtained from excess embryos resulting from assisted reproductive technologies such as in vitro fertilisation (IVF).

Recently, however, ESC have also been produced by a process called somatic cell nuclear transfer (SCNT), which involves the transplant­ation of a somatic cell nucleus into a previously enucleated, unfertilised egg (oocyte). The nucleus is subsequently reprogrammed by the oocyte cytoplasm and, when appropriately stimulated, develops into a blastocyst-stage embryo in culture. Cloned embryos generated by SCNT will contain a set of chromosomes that are identical to that of the person who donated the somatic cell nucleus, but will not be 100% genetically matched given the presence of maternal mitochondrial DNA in the oocyte cytoplasm. If the cloned embryo is implanted into the uterus and allowed to develop (a process termed reproductive cloning), a cloned animal may result.

Therapeutic cloning, on the other hand, involves the derivation of an embryo clone using SCNT, but instead of intrauterine implantation the blastocyst embryo is used to derive pluripotent ESC clones in vitro. Cloned ESC lines have been derived by SCNT from non-human primates,3 but so far no human ESC lines have been successfully produced using this technology.

Therapeutic Versus Reproductive Cloning

Human reproductive cloning is universally viewed as morally abhorrent. It is prohibited by law globally, and is punishable by imprisonment. There are major concerns that cloned humans would suffer psychologically due to social stigma and their lack of individuality. Some religious groups also believe that reproductive cloning violates the sanctity of marriage, the natural process of human generation and, ultimately, human dignity.4

Apart from moral concerns, mammalian studies demonstrate that cloned offspring produced via SCNT are invariably abnormal. Most do not survive gestation and those that do invariably die prematurely from numerous pathological abnormalities attributed to inadequate reprogramming of the donor somatic cell nucleus by the oocyte cytoplasm.5

Therapeutic cloning, however, holds great promise for the study of human development and disease and is supported by scientists and international legislation, including in Australia.6 For example, an ESC line could be cloned from a person with cystic fibrosis to produce an indefinite supply of cells, and therefore provide an invaluable in vitro platform for analysing a disease’s pathology and screening novel therapeutic drugs. SCNT technologies may also be used to grow new ‘immunologically matched’ cells or tissues for a patient and thus circumvent the need to find compatible organ donors.

Although SCNT would obviate the need for IVF embryos, some believe it is still ethically repugnant to deliberately create an embryo simply to destroy it to produce a stem cell line. These people are also concerned by the ‘slippery slope’ effect – that the legalisation of therapeutic cloning will eventually lead to the technology for successful human reproductive cloning, even if it remains illegal.4

Another complication of SCNT technology is the need for large numbers of donor human oocytes. The procedures associated with oocyte donation are not without significant psychological and medical risks to the female donors.7 Other fears are that SCNT research may lead to a black market in illegal oocyte trade or paid egg donations targeting certain lower socio-economic groups.

In an attempt to overcome the ethical and physical restrictions of human oocyte donation, interspecies SCNT has been proposed in which an enucleated animal oocyte could effectively substitute for a human oocyte to reprogram a donor human somatic nucleus. Many scientists believe that these hybrid embryos may provide a plausible alternative for the study of early human development and perfection of human therapeutic cloning techniques, without the use of human oocytes. Applications for the use of human–animal cytoplasmic hybrid embryos have recently been approved by the Human Fertilization and Embryology Authority in the UK.8 This practice is currently not permitted in Australia.6

Alternative Sources of Embryonic Stem Cells

New technologies for ESC lines are being developed to alleviate the need for embryo destruction. Single-cell biopsy of the embryo in utero, as used for pre-implantation genetic diagnosis testing, may allow the generation of ESC lines9 without embryonic destruction although it still poses an implicit risk to the developing foetus.

Recently there has been a major breakthrough in the induction of pluripotency in adult cells. The introduction of specific ESC-related genes into the genome of a somatic cell can reprogram the cell to give it stem cell-like qualities.10 These induced pluripotent stem cells (iPS) are believed to functionally mimic ESC and thus remove the need for embryos. Despite their enormous promise, the techniques used to induce pluripotency currently preclude their use in humans due to the risk of tumorigenesis.11 However, dynamic iPS research may soon overcome these limitations.

Although these new avenues of research provide the potential for alternative ESC-line generation without the destruction of embryos, they are relatively new techniques with unproven safety profiles. Most scientists believe that future research should continue in parallel with traditional ESC research.

Should We Destroy Embryonic Life for Therapeutic Research?

The definition of life is wide-ranging throughout religious and political sectors. Many evangelical Protestants, Roman Catholics and some Orthodox Jews believe that life morally begins at conception.12 Therefore, they argue that the embryo has full rights and interests and, just like a child or adult, cannot be used in research that is not to its own benefit, nor without consent. Because ESC derivation ultimately destroys the embryo’s potential for life, ESC research, whether from discarded IVF or therapeutically cloned embryos, is rigorously opposed by such groups.

Others hold a developmental or gradualist view of life. They consider that the moral status of the embryo grows as it develops in utero, the full rights and interests being achieved when the embryo takes on a human-type form and is capable of feeling and thinking.12 The fact that the early embryo is capable of either twinning and that two separate embryos can fuse to form one at this stage in its development would support the view that it is not yet an individual.

Although many oppose embryonic destruction for ESC research, some groups justify the use of discarded IVF embryos since the embryos are earmarked for destruction. Similarly, some support the use of existing ESC lines on the basis that the embryo has already been destroyed and that the potential future therapeutic benefits should not be foregone.

Australia joins a growing list of countries, including the UK, China and Japan, that allow the generation of ESC lines from surplus IVF embryos. However, some governments oppose ESC research. In the USA, under the former Bush administration, federal funding was prohibited for the derivation of new ESC lines but was available for existing lines derived before August 2001.

It is very likely that important clinical treatments will evolve from future ESC research; indeed, the first clinical trials are imminent. Should people from countries opposing this research be able to partake of the treatments?

Where to Next?

The unprecedented levels of excitement and expectation that the revolution of stem cell technologies has brought raise both hope and alarm. The rapid advances create a push from the research bench and a corresponding pull from patients to bring these new discoveries into clinical trials. However, the challenges lie in balancing tantalising results with the clinical reality of shallow evidence and unproven safety profiles.

The non-profit International Society for Stem Cell Research has recently released guidelines for the clinical translation of stem cell technologies encompassing ‘scientific, clinical, regulatory, ethical and societal issues’.13 It emphasises the need for continual stem cell research but cautions that many therapies are still years from the clinic and wants to ensure against unnecessary marketing of unproven treatments, especially for monetary incentives facilitated by a desperate and vulnerable patient population.

The task remains to manage the unquestioned needs of the patients while simultaneously developing the legislative framework for research within sensible and necessary ethical boundaries. The hope is that the appropriate balance will be achieved and that we may one day unravel the aetiology of human disease, and perhaps even cure serious illness and injury.

Reproduced from Chemistry in Australia, March 2009 (www.raci.org.au/chemaust), and adapted with permission. Reference details are available from the authors (natalie.seach@med.monash.edu.au).