Of mice and human embryos: is there an ethically preferred order of preclinical research on new assisted reproductive technologies?

It is widely acknowledged that the responsible introduction of new assisted reproductive technologies (ARTs) requires preclinical safety research, including the use of animal models and human embryos. However, the moral sensitivity of human embryo research has led to regulations and guidance stating that human embryos may only be used for research that cannot also be conducted with animals. We call this the 'use animals first' (UAF) rule. In the field of ART research, this translates into the notion of an ideal chain of consecutive preclinical research steps, where research using human embryos may only be considered as a further step after promising results have been obtained in animals first. This may lead to research ethics committees requiring animal studies that are in fact a waste of time and money, while exposing animals to an infringement of their wellbeing for no good purpose. In this paper, we explore the possible moral arguments behind the UAF-rule and test their validity. We conclude that there are no convincing grounds for upholding this rule and recommend replacing it.

Double-effect reasoning and the conception of human embryos.

Some commentators argue that conception signals the onset of human personhood and that moral responsibilities toward zygotic or embryonic persons begin at this point, not the least of which is to protect them from exposure to death. Critics of the conception threshold of personhood ask how it can be morally consistent to object to the embryo loss that occurs in fertility medicine and research but not object to the significant embryo loss that occurs through conception in vivo. Using that apparent inconsistency as a starting point, they argue that if that embryo loss is tolerable as a way of conceiving children, it should be tolerable in fertility medicine and human embryonic research. Double-effect reasoning shows, by contrast, that conception in vivo is justified even if it involves the death of persons because the motives for wanting children are not inherently objectionable, because the embryo loss that occurs in unassisted conception is not the means by which successful conception occurs, and because the effect of having children is proportionate to the loss involved. A similar outcome holds true for in vitro fertilisation in fertility medicine but not for in vitro fertilisation for research involving human embryos.

Pluripotency of spermatogonial stem cells from adult mouse testis.

Embryonic germ cells as well as germline stem cells from neonatal mouse testis are pluripotent and have differentiation potential similar to embryonic stem cells, suggesting that the germline lineage may retain the ability to generate pluripotent cells. However, until now there has been no evidence for the pluripotency and plasticity of adult spermatogonial stem cells (SSCs), which are responsible for maintaining spermatogenesis throughout life in the male. Here we show the isolation of SSCs from adult mouse testis using genetic selection, with a success rate of 27%. These isolated SSCs respond to culture conditions and acquire embryonic stem cell properties. We name these cells multipotent adult germline stem cells (maGSCs). They are able to spontaneously differentiate into derivatives of the three embryonic germ layers in vitro and generate teratomas in immunodeficient mice. When injected into an early blastocyst, SSCs contribute to the development of various organs and show germline transmission. Thus, the capacity to form multipotent cells persists in adult mouse testis. Establishment of human maGSCs from testicular biopsies may allow individual cell-based therapy without the ethical and immunological problems associated with human embryonic stem cells. Furthermore, these cells may provide new opportunities to study genetic diseases in various cell lineages.

Complicity in stem cell research: the case of induced pluripotent stem cells.

Many who object to human embryonic stem cell (hESC) research because they believe it involves complicity in embryo destruction have welcomed induced pluripotent stem cell (iPSC) research as an ethical alternative. This opinion article aims to show that complicity arguments against hESC research are prima facie inconsistent with accepting iPSC research as it is currently done. Those who oppose hESC research on grounds of complicity should either (i) oppose iPSC research as well, (ii) advocate a radical change in the way iPSC research is done, (iii) demonstrate that complicity arguments against iPSC research are weaker than those against hESC research or (iv) reject complicity arguments against both hESC and iPSC research, either by adopting a more limited conception of complicity that allows acceptance of some hESC research, or by accepting that destroying embryos for important scientific research is not wrong.

A libertarian perspective on the stem cell debate: compromising the uncompromisible.

The present paper attempts to forge a compromise between those who maintain that stem cell research is out-and-out murder of young helpless human beings and those who favor this practice. The compromise is predicated upon the libertarian theory of private property rights. Starting out with the premise that not only the fetus but even the fertilized egg is a human being, with all rights thereto, it offers a competition between those who fertilize eggs for research and those who wish to adopt them. If and only if the former win this competition will they be allowed to use these very young human beings for the purposes they have constructed them. This is justified on grounds of avoiding child abuse.

Regulatory issues for personalized pluripotent cells.

The development of personalized pluripotent stem cells for research and for possible therapies holds out great hope for patients. However, such cells will face significant technical and regulatory challenges before they can be used as therapeutic reagents. Here we consider two possible sources of personalized pluripotent stem cells: embryonic stem cells derived from nuclear transfer (NT-ESCs) and induced pluripotent stem cells (iPSCs) derived from direct reprogramming of adult somatic cells. Both sources of personalized pluripotent stem cells face unique regulatory hurdles that are in some ways significantly higher than those facing stem cells derived from embryos produced by fertilization (ESCs). However, the outstanding long-term potential of iPSCs and their relative freedom from the ethical concerns raised by both ESCs and NT-ESCs makes direct reprogramming an exceptionally promising approach to advancing research and providing therapies in the field of regenerative medicine.

Cybrid human embryos--warranting opportunities to augment embryonic stem cell research.

The recent vote in the British Parliament allows scientists in principle to create hybrid embryos by transferring human somatic cell nuclei into animal oocytes. This vote opens a fascinating new area of research with the central aim of generating interspecific lines of embryonic stem cells (ESCs) that could potentially be used to understand development, differentiation, gene expression and genomic compatibility. It will also promote human cell therapies, as well as the pharmaceutical industry's search for new drug targets. If this approach is to be successful, many biological questions need to be answered and, in addition, some moral and ethical aspects must be taken into account.

Artificial reprogramming of human somatic cells to generate pluripotent stem cells: a possible alternative to the controversial use of human embryonic stem cells.

Recent findings showed certain specific factors had the ability to reprogram in vitro human somatic cells, which in turn could generate pluripotent stem cells. Remarkably, somatic cell-derived pluripotent stem cells recapitulated the features of human embryonic stem cells, as demonstrated independently by two groups of investigators. The reprogramming of somatic cells may represent an alternative to the controversial use of human embryonic stem cells in transplantation therapy and in a variety of other applications, such as generation of cellular models for human diseases and for drug research and development. However, the intrinsic expression of epigenetic reprogramming factors in somatic cells requires the use either of lentiviral- or retroviral-mediated gene transfer, which may cause insertional mutagenesis-induced malignancies. In summary, the recent achievements for the in vitro reprogramming of human somatic cells to a pluripotent state can be considered an important advancement in stem cell research. As for future clinical applications in regenerative medicine, it is necessary to tackle the issue of insertional mutagenesis, which is associated with all types of integrating gene delivery systems. Another critical issue is the control of the tumorigenic potential of somatic cell-derived pluripotent stem cells. As it stands, the newly developed technology can be used to engineer useful models for the study of human diseases and development of novel therapeutics.

Fearing a non-existing Minotaur? The ethical challenges of research on cytoplasmic hybrid embryos.

In this paper we address the ethical challenges of research on cytoplasmic hybrid embryos, or "cybrids". The controversial pronouncement of the UK's Human Embryology and Fertilisation Authority of September 2007 on the permissibility of this area of research is the starting point of our discussion, and we argue in its favour. By a rigorous definition of the entities at issue, we show how the terms "chimera" and "hybrid" are improper in the case of cybrids, and how their use can bias the debate creating moral prejudices. After analysing the scientific aspects of cybrids research and sketching out current alternatives, we enter the ethical debate, starting from the premise that research on early human embryos is ethically permissible under some circumstances. We emphasise how research on cybrids has positive consequences in terms of scientific and therapeutic applications, since it allows the derivation of human embryonic stem cells genetically tailored to the somatic cell donor. Such cell lines offer a unique in vitro model both for studies of human pathogenesis and for drug screening and discovery. Research on cybrids also circumvents the problem of the scarcity of human oocytes and their ethically dubious donation. Finally, we object to the most common arguments against cybrids research, that is, moral repugnance, the slippery slope argument, the appeal to "nature", and the unfair distribution of economical resources.

Reproductive cloning in humans and therapeutic cloning in primates: is the ethical debate catching up with the recent scientific advances?

After years of failure, in November 2007 primate embryonic stem cells were derived by somatic cellular nuclear transfer, also known as therapeutic cloning. The first embryo transfer for human reproductive cloning purposes was also attempted in 2006, albeit with negative results. These two events force us to think carefully about the possibility of human cloning which is now much closer to becoming a reality. In this paper we tackle this issue from two sides, first summarising what scientists have achieved so far, then discussing some of the ethical arguments in favour and against human cloning which are debated in the context of policy making and public consultation. Therapeutic cloning as a means to improve and save lives has uncontroversial moral value. As to human reproductive cloning, we consider and assess some common objections and failing to see them as conclusive. We do recognise, though, that there will be problems at the level of policy and regulation that might either impair the implementation of human reproductive cloning or make its accessibility restricted in a way that could become difficult to justify on moral grounds. We suggest using the time still available before human reproductive cloning is attempted successfully to create policies and institutions that can offer clear directives on its legitimate applications on the basis of solid arguments, coherent moral principles, and extensive public consultation.

The scourge: moral implications of natural embryo loss.

It is often claimed that from the moment of conception embryos have the same moral status as adult humans. This claim plays a central role in many arguments against abortion, in vitro fertilization, and stem cell research. In what follows, I show that this claim leads directly to an unexpected and unwelcome conclusion: that natural embryo loss is one of the greatest problems of our time and that we must do almost everything in our power to prevent it. I examine the responses available to those who hold that embryos have full moral status and conclude that they cannot avoid the force of this argument without giving up this key claim.

Commentary: "re-programming or selecting adult stem cells?".

The recent observations that embryonic stemness-associated genes could assist in the "de-differentiation" of adult skin fibroblast cells to "embryonic-like stem cells", using the "somatic cell nuclear transfer" techniques, have been interpreted as indicating a "re-programming" of genes. These reports have demonstrated a "proof of principle" approach to by-pass many, but not all, of the ethical, scientific and medical limitations of the "therapeutic cloning" of embryonic stem cells from embryos. However, while the interpretation that real "re-programming" of all those somatic fibroblastic differentiation genes might be correct, there does exists an alternative hypothesis of these exciting results. Based on the fact that multipotent adult stem cells exist in most, if not all, adult organs, the possibility exists that all these recent "re-programming" results, using the somatic nuclear transfer techniques, actually were the results of transferred rare nuclear material from the adult stem cells residing in the skin of the mouse, monkey and human samples. An examination of the rationale for this challenging hypothesis has been drawn from the hypothesis of the "stem cell theory of cancer", as well as from the field of human adult stem cells research.

Resolving the "egg supply problem" in human embryonic stem cell derivation through technical means--a legal and ethical analysis.

This paper seeks to briefly discuss the legal and ethical problems connected to scientific developments in the field of human embryonic stem cell derivation aimed at solving the "egg supply problem" in stem cell research. The legal situation is discussed in respect of the UK's current regulatory regime, proposed reform and the Oviedo Convention. The scientific developments which are examined are chimeric embryos, in vitro maturation of oocytes, derivation of stem cell lines in connection with pre-implantation genetic diagnosis and the derivation of oocytes from existing stem cell lines.

Ethics and embryonic stem cell research: altered nuclear transfer as a way forward.

Ethical controversy in stem cell research arises because current methods to produce embryonic stem cell lines require the destruction of living human embryos. For this reason, there is increasing interest in developing alternative, non-embryonic sources of pluripotent stem cells. This effort is especially important in the US due to the prevailing policy against federal funding of embryo-destructive research. Altered nuclear transfer (ANT) is one of several potential methods to develop alternative sources of pluripotent stem cells. This approach employs the technique of somatic cell nuclear transfer, but the somatic cell nucleus or egg cytoplasm (or both) are first altered before the somatic cell nucleus is transferred into the oocyte. This alteration precludes the coordinated organization and developmental potential that is necessary for the resulting biological entity to be an embryo, but it still allows the entity to generate pluripotent stem cells. Proof-of-principle for one variant of ANT has been established in mice by silencing the functional expression of the gene Cdx2 in the somatic cell nucleus prior to its transfer into an enucleated egg. From the resulting non-embryonic laboratory construct, fully functional pluripotent stem cells were procured. Other more recent studies have suggested the possibility of achieving the same results by preemptively silencing maternally derived Cdx2 messenger RNA in the egg before the act of nuclear transfer. The procedure would produce the equivalent of a tissue culture of pluripotent stem cells. In contrast to the use of embryos 'left over' from clinical in vitro fertilization, ANT could produce pluripotent stem cell lines with an unlimited range of specifically selected and controlled genotypes. Such flexibility would greatly facilitate the study of disease, drug development, and toxicology testing, and may allow the production of therapeutically useful pluripotent stem cells that are immune-compatible. If developed to the point of scientific reliability, ANT would be a valuable research tool for the study of other aspects of cell development and differentiation, including gene expression patterns, imprinting, and cell-cell signaling. ANT would also help to clarify definitions and boundaries that distinguish true organisms from 'biological artifacts' and, thereby, provide moral precedent to guide future progress in developmental biology.