Human Reproduction Vol.21, No.4 pp. 857–863, 2006
doi:10.1093/humrep/dei430
Advance Access publication December 16, 2005.
OPINION
Embryonic stem-cell gametes: the new frontier in human reproduction
Zubin Master
W. Maurice Young Centre for Applied Ethics, University of British Columbia, Vancouver, British Columbia, Canada
To whom correspondence should be addressed at: W. Maurice Young Centre for Applied Ethics, University of British Columbia,
6356 Agricultural Road, Room 227, Vancouver, British Columbia, Canada V6T 1Z2. E-mail: [email protected]
As infertility increases and gamete donations decline, an alternate source of sex cells may prove valuable for research
and infertility treatment. This article examines the social and scientific value of gametes derived from the differentiation of established human embryonic stem (ES)-cell lines (ES-cell-derived gametes) and customized gametes created
using nuclear transfer technologies to contain a haploid set of genes creating children genetically related to parent(s).
ES-cell-derived gametes may be valuable as a resource for biomedical research, instruction and training in assisted
reproductive technologies and perhaps for creating children. The creation of children by ES-cell-derived and customized gametes may not result in psychological harm to children but customized gametes may lead to physical harm to
children or an accumulation of gene mutations in a population. Although the creation of new types of children using
ES-cell gametes provides more reproductive choices to both fertile and infertile individuals, the risk or physical harm
to children from customized gametes may be so severe that the scope of reproductive liberty must be limited. Further
scientific and ethical analysis of the creation of children by ES-cell gametes is required.
Key words: assisted human reproduction/embryonic stem cells/nuclear transfer/reproductive liberty/scientific and social value
Introduction
Human gametes (oocytes and sperm) are a valuable resource for
research, infertility training and treatment by assisted human
reproduction. Ova from female donors have become increasingly valuable, given the decline in fertility rates in the USA
since the 1960s due to many women choosing to have children at
later ages (Mathews and Hamilton, 2002) and to the increase in
the causes of infertility such as chlamydia infection in women
(National Center for Health Statistics, 2004). Currently, the rate
of gamete donations is low and may decline due to social policy
no longer permitting anonymity in some nations (Human Fertilisation and Embryology Authority, 2005). Owing to these various social and environmental factors, the demand for gamete
donation, primarily ova, is at an all-time high.
In the last few years, several reports have shown that mouse
embryonic stem (ES)-cells can differentiate into sperm (Toyooka et al., 2003; Geijsen et al., 2004) and ova (Hubner et al.,
2003) and that human ES cells can also differentiate into germ
cells in culture (Clark et al., 2004; Lacham-Kaplan et al., 2005).
Gametes may be created through the differentiation of currently
established human ES-cell lines and are herein referred to as
ES-cell-derived gametes. It may theoretically be possible to create ‘customized gametes’ by using nuclear transfer technology
to derive ES cells cloned from an embryo. These cloned ES
cells may differentiate into either sperm or ova which contains a
haploid set of genes from the individual. This article analyses the
social and scientific value of ES-cell-derived and customized
gametes by examining the harms and benefits of their potential
applications. Amongst several ethical concerns raised in the use
of ES-cell gametes in human reproduction (Testa and Harris,
2005), this article focuses on the reproductive liberty offered to
individuals who use ES-cell gametes and the potential physical
and psychological harm to children born from them. I argue that
ES-cell-derived gametes may be tremendously valuable for biomedical research and infertility training and possibly even to
create children. It is doubtful that the use of either ES-cellderived or customized gametes will affect the psychological
development of children. However, the molecular technologies
used to create customized gametes may result in gene mutations
in gametes or may accumulate in a population over time.
Although the use of ES-cell-derived and customized gametes to
create children offers greater reproductive choices to individuals, this reproductive liberty must be weighed relative to the
potential risk of physical harm to the child. Further research on
the medical, ethical, legal and social implications of using EScell gametes to create children should be performed in order to
adequately understand the harm and benefits of these technologies in human reproduction.
The science of creating ES-cell-derived and customized
gametes
Several cell and molecular techniques were used to demonstrate the in vitro differentiation of mouse ES cells into sperm
© The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
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Z.Master
or ova (Hubner et al., 2003; Toyooka et al., 2003; Geijsen
et al., 2004; Lacham-Kaplan et al., 2005). ES cells can spontaneously differentiate into ova which could undergo meiosis
(Hubner et al., 2003; Lacham-Kaplan et al., 2005) or differentiate into male germ cells which display proper erasure of
methylated genes (Geijsen et al., 2004). Interestingly, ova may
be created from the differentiation of male ES-cell lines
(Hubner et al., 2003), which suggests that ES cells containing
X and Y chromosomes may be genetically sufficient to create
both male and female gametes. These studies demonstrate that
ES-cell-derived gametes display similar biological characteristics to gametes derived from germ cell precursors.
Although the creation of ES-cell-derived gametes may be a
relatively simple process of in vitro spontaneous differentiation, the creation of customized gametes would theoretically be
much more labour intensive involving multiple steps. The
creation of customized gametes involves somatic cell nuclear
transfer (SCNT) technology that creates a cloned embryo
(Figure 1). SCNT involves injection of a diploid nucleus into
an enucleated oocyte and the initiation of embryonic development by parthenogenesis. Cloned ES cells can be derived from
the embryo and differentiated into either sperm or ova in vitro
(Figure 1). Customized gametes of the opposite sex may also
theoretically be created. For example, SCNT of a male nucleus
and the derivation of male ES cells can differentiate into ova.
Although ova have been shown to form from X- and Ychromosome-containing ES cells, a nucleus from a woman
may not be able to differentiate into sperm, given that women
do not carry Y-chromosome-specific genes. The transient or
stable expression of human DAZ genes (Vogt and Fernandes,
2003) that function in male gamete formation may induce ES
cells to differentiate into sperm. Clearly, there are several additional technological barriers impeding the actual creation of
customized gametes of the opposite sex for women.
The creation of customized gametes in general is theoretically possible because human ES cells have been cloned from
individuals (Hwang et al., 2004) and human ES cells have been
shown to differentiate into germ cells (Clark et al., 2004).
However, what has not been demonstrated is the differentiation
of sperm or eggs from cloned ES cells in order to derive customized gametes. The efficiency of creating cloned ES cells
after autologous transfer of a somatic cell nucleus from a
woman into her own oocyte is between 3 and 5% (Hwang
et al., 2004). The creation of customized gametes would be a
less efficient process because additional factors, such as the
age of a woman or heterologous nuclear transfer, may interfere
with normal embryonic development. The creation of customized gametes may therefore require further research and development to become an efficient process, and rapid advances in
molecular technologies and ES-cell biology may soon be able
to create customized gametes.
The benefits of ES-cell-derived gametes
There are two major benefits for ES-cell-derived gametes. EScell-derived gametes may be used in the near future as a
resource for both basic and applied scientific research (Dennis,
2003; Vogel, 2003c; Westphal, 2003; Surani, 2004; Testa and
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Figure 1. The creation of customized gametes. Customized gametes
could theoretically be created using somatic cell nuclear transfer
technology. A nucleus from a skin cell from Parent 1 can be transferred into an enucleated oocyte and begin embryonic development
by parthenogenesis. Parthenogenic activation of an oocyte could be
provided by an electrical impulse or by chemical induction.
Between day three to five of embryonic development, cells from the
inner cell mass (ICM) of the resulting blastocyst are harvested to
derive ES cells. Diploid ES cells could then differentiate into haploid oocytes (shown here) or sperm (not shown). The oocyte from
Parent 1 could be fertilized with the sperm from Parent 2 through
standard IVF procedures. Those embryos that are selected as best
suitable for further embryonic development will be transferred to
surrogates who will carry the child to term. Images are not drawn to
scale. N, the sets of chromosomes, 1N, haploid; 2N, diploid; ICM,
inner cell mass; ESC, embryonic stem cell; ET, embryo selection
and transfer. The oocyte, embryo and blastocyst images were
adapted from the Colour Atlas of Clinical Embryology (Moore
et al., 2000).
Ethics of stem cells, cloning and assisted reproduction
Harris, 2004; Newson and Smajdor, 2005) and for instruction
and training in assisted human reproduction. It is unlikely that
customized gametes will be used as a resource for basic
research because their creation involves additional technical
steps that would cost more and serve as additional variables to
control for in experiments.
ES-cell-derived gametes may be used for both basic and
applied scientific research as a new resource, and as a new bioassay
system to study stem-cell development (West and Daley, 2004).
Further experiments need to be performed with ES-cell-derived
gametes to ensure that they are morphologically and functionally similar to gametes derived through germ-cell differentiation. ES-cell-derived gametes may be used in several areas of
basic scientific research to study ES differentiation, gametogenesis, X-chromosome inactivation, fertilization, early
embryonic development, germ-cell tumours and imprinting
(Surani, 2004; West and Daley, 2004; Lippman et al., 2005;
Newson and Smajdor, 2005). One of the most likely applications of ES-cell-derived ova may be to further develop SCNT
technology to advance patient-specific therapies and create cell
lines for studying the biology of degenerative disorders and
diseases (Vogel, 2003c; Surani, 2004; Testa and Harris, 2004;
Hwang et al., 2005; Newson and Smajdor, 2005; Pickering
et al., 2005). Moreover, ES-cell-derived gametes may also be
used for applied research in understanding the causes of infertility or for creating new, or for improving existing, assisted
reproductive technologies (ARTs) or methods of contraception
(Westphal, 2003; Surani, 2004; Testa and Harris, 2004; Newson
and Smajdor, 2005). ES-cell-derived gametes are of tremendous potential scientific value as a new resource and assay system for society.
An additional source of human sperm and ova may have
immediate social benefit as a resource to train individuals in
human reproduction and for the practice of ARTs. Currently, in
most cases, animal semen and ova are used for practical purposes, but in some instances it will be unavoidable to use human
sperm and ova. For example, ova could be used to train technicians performing various ARTs that involve a degree of technical
mastery. Intracytoplasmic sperm injection (ICSI) is a technically
challenging ART used to treat male infertility, which involves
holding the oocyte steadily in suspension while injecting a needle into the rigid oocyte membrane to allow a single sperm cell to
enter. Furthermore, a new source of sperm and oocytes from ES
cells may be used to train infertility specialists to recognize
proper morphological development of human embryos to select
the ones best suited for transfer. Thus, ES-cell-derived gametes
provide an excellent training tool for infertility technicians,
researchers and obstetricians and gynaecologists and are also a
valuable resource for scientific and medical research.
Physical harm to children created by customized gametes
Many pregnancies achieved through the use of ARTs have
been known to result in multiple gestations, with infants being
born with low birth weights (Yu, 1998; Bonduelle et al., 2002;
Olivennes et al., 2002) as well as other birth defects such as
retinoblastoma (Cruysberg et al., 2002; Moll et al., 2003),
the imprinting diseases Beckwith–Wiedemann syndrome and
Angelman syndrome (Cox et al., 2002; DeBaun et al., 2003;
Gicquel et al., 2003; Maher et al., 2003; Maher, 2005), chromosomal abnormalities (Bonduelle et al., 1998; Meschede
et al., 1998; Bonduelle et al., 2002; Kurinczuk, 2003) and various other congenital defects including cerebral palsy (Sutcliffe
et al., 1995; Ferraris et al., 1999; Anteby et al., 2001; Roesch
et al., 2001; Hansen et al., 2002; Stromberg et al., 2002).
These outcomes demonstrate that children born using various
ARTs may be physically harmed because the technology
bypasses natural mechanisms of selecting out embryos containing genetic abnormalities (Engel et al., 1996; Baschat
et al., 1996; Johnson, 1998; Kim et al., 1998). However, it has
been suggested that some reproductive technologies such as
ICSI may also cause de novo gene mutations due to the extensive
micromanipulation involved (Bonduelle et al., 1998;
Bonduelle et al., 2002; Kurinczuk, 2003).
The micromanipulation of cells during SCNT has also been
shown to adversely affect spindle formation (Simerly et al.,
2003; Simerly et al., 2004), telomere length (Lanza et al.,
2000; Tian et al., 2000; Wakayama et al., 2000; Betts et al.,
2001; Miyashita et al., 2002), X-chromosome inactivation
(Eggan et al., 2000; Wrenzycki et al., 2002), imprinting and
other epigenetic changes (Dean et al., 2001; Humpherys et al.,
2001; Kang et al., 2001; Humpherys et al., 2002; Kang et al.,
2002) and also fails to activate key embryonic genes (Boiani
et al., 2002; Bortvin et al., 2003). The cause(s) of these genetic
and epigenetic changes is thought to explain the low success of
viable embryos after nuclear transfer and why many animals
born using SCNT technology display physical defects that result in their death by multiorgan failure (Rideout et al., 2001;
Cibelli et al., 2002; Ogonuki et al., 2002; Wilmut, 2002;
Edwards et al., 2003; Hochedlinger and Jaenisch, 2003; Vogel,
2003a). It is possible that these genetic and epigenetic changes
alter genome integrity such that a high number of attempts may
be required for the successful birth of a single cloned offspring.
Since the creation of customized gametes involves SCNT, it is
possible that the mutations resulting from the use of this technology to create cloned embryos may occur in the creation of
customized gametes. The use of customized gametes in combination with other ARTs may result in an accumulation of
genetic mutations in a population. At present, it remains
unknown to what extent micromanipulation of cells causes
aberrant de novo genetic or epigenetic changes using various
technologies. Based on evidence of the physical problems of
offspring born either from ARTs or from SCNT, the risk of
creating de novo genetic and epigenetic mutations from creating
customized gametes should be evaluated.
Can children be psychologically harmed?
Claims have been made that children created from ES-cell-derived
gametes have either ES-cell lines as parents (Vogel, 2003b;
Newson and Smajdor, 2005) or no parents (Weiss, 2003), suggesting that children may be psychologically harmed from the
knowledge that they were created in an artificial manner (Newson
and Smajdor, 2005). Similar claims have also been made that
genetically related children created from same-sex couples
may face psychological harm or alter their childhood experience
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Z.Master
(Newson and Smajdor, 2005). Others on the other hand have
claimed that overcoming biological barriers to create children
from two same-sex individuals using customized gametes may
be a way to further democratize human reproduction in society
(Testa and Harris, 2005). I will argue that the claims that children born from ES-cell gametes may have altered childhood
experiences or suffer psychological harm are not true and that
such claims may be problematic as they precipitate notions that
non-traditional families may be harmful to the child’s psychological development or that ES-cell-derived ‘artificial’ gametes
themselves may be harmful because they are created by different biological means than gametes collected from adults.
Parents who use ES-cell gametes may contribute to the
genetic make-up of the child, socially by rearing the child, or in
some cases surrogate women may carry the child during pregnancy to term. It is unlikely that children created with one EScell-derived gamete and raised by a single social parent, such
as a single mother, will exhibit any greater childhood psychological problems than a child raised socially by a single heterosexual mother. For example, children in fatherless families
experience a closer relationship with their social mother and
are more dependent on them than children from father-present
families (MacCallum and Golombok, 2004). Although children in fatherless families seem not to be affected negatively
from the absence of a social father, mothers raising children
without a father reported had increased severity in disputes
with their children than mothers in father-present families
(MacCallum and Golombok, 2004). However, the psychological development and personality characteristics of children in
families headed by a single mother would depend heavily on
economic factors (Golombok, 2005). Children created using EScell-derived sperm and raised by a single mother may not display behavioural differences when compared to children raised
in heterosexual two-parent families. Empirical research on the
gender identification and development of school children
raised by single lesbian social mothers found no differences
compared with children raised by a heterosexual single social
mother (Golombok et al., 1983). Similarly, the emotional and
gender development of children raised by two lesbian social
mothers, where the child was created through donor insemination did not differ in their psychological development when
compared with children raised in heterosexual families who
naturally conceived a child (Brewaeys et al., 1997). These
studies show that the psychological development of a child is
dependent on socio-economic factors and how the parent(s)
raise their children than on whether a single social mother or a
same-sex couple are the social parent(s). It is unlikely that creating genetically related children from same-sex couples using
customized gametes, or children raised by single parents using
ES-cell-derived gametes, would display any greater psychological problems than children conceived naturally.
Claims that children created from ES-cell-derived gametes
may suffer psychological harm from knowing they were created
by ‘artificial’ means is also unlikely to occur as ES-cell-derived
gametes may be considered just as artificial as other ARTs.
The psychological behaviour of children created from IVF and
donor insemination was similar to that of children conceived
naturally and raised in heterosexual families (Golombok et al.,
860
1995; Colpin and Soenen, 2002). Assessment of the psychological wellness of adolescents born from IVF were found to function similar to adoptive or naturally conceived children based
on standardized interviews and questionnaires (Golombok
et al., 2001). What is so artificial about creating gametes from
ES cells when compared to ‘natural’ gametes obtained from
humans? Would the differentiation of germ-cell precursors into
mature germ cells be different inside the human body than the
differentiation of ES cells into mature germ cells in vitro? It is
likely that the in vitro differentiation of ES-cell-derived gametes (artificial gametes) is regulated by similar molecular pathways as the creation of sperm and oocytes naturally through
germ-cell development. If being born from artificial means
could pose psychological harm to children, then the ART
known as in vitro maturation where immature sperm or ova are
collected and allowed to mature in vitro before fertilization
would also result in children facing psychological harm which
has not been the case. Subtle differences in the extent of artificiality as that which deviates from natural conception is found
throughout all ARTs and thus it would be difficult to accept
that ES-cell-derived gametes are more artificial than other
ARTs and that this knowledge would some how harm or alter
the child’s psychological development.
Exercising reproductive liberty and the creation of
children using ES-cell gametes
The freedom to control ones own reproductive capability to
have or avoid having children by coital or non-coital reproduction can be defined as reproductive liberty (Robertson, 1994).
If an individual is granted the moral liberty to control their
reproduction and the agency to exercise choice, others should
not interfere unless competing interests are affected such as the
welfare of the child (Harris, 2005). One of the major benefits
offered by ES-cell-derived and customized gametes is to
provide more reproductive choices to individuals, allowing
them to create genetically related children. For example, EScell-derived gametes may be used by fertile single parents who
desire to create a child with a gamete from a non-living person.
Customized gametes can be used to create children genetically
related from two men or two women. Both ES-cell-derived and
customized gametes offer new ways of procreation to both fertile and infertile individuals, creating different genetic relationships with their children. The desire to have a child that is
genetically related to the parent because of religious practices
or social or cultural norms is a deeply cherished value for many
(Buchanan et al., 2000). The scope of reproductive liberty
should allow for the use of ES-cell-derived and customized
gametes for all types of reproduction and should not be limited
to individuals with infertility as the moral right to reproduce
and to have genetically related children applies equally to both
fertile and infertile individuals.
Although ES-cell gametes in general provide more reproductive choices to individuals to have children, if their use in
assisted human reproduction proves harmful to children, then the
scope of reproductive liberty should be limited and used only
when proven safe. The potential physical harm caused by EScell gametes must be placed in context since as a society, we do
Ethics of stem cells, cloning and assisted reproduction
accept some risks to children created using ARTs, or by natural
conception (Testa and Harris, 2005), for the benefit of existence
to the child and the reproductive autonomy granted to parents. If
ES-cell-derived or customized gametes were unsafe to children,
as a society how much risk are we willing to accept in order to
create children and exercise parental reproductive autonomy? A
decision to accept the risks of physical harm to children using
ES-cell gametes will depend on the frequency and magnitude of
harm to the child, the extent of correctable intervention(s)
needed and the liberty provided to parents to take extensive risks
in having children (Robertson, 2004). Increasing parental freedom
at the expense of posing severe risk of physical harm to children
may be unfair to the child and violates a principle of parental
responsibility (Steinbock and McClamrock, 1994). The risk of
physical harm in using customized gametes may resort to ‘devastating’ harm where the harm to children renders life beyond
a minimal standard of decency (Steinbock and McClamrock,
1994; Cohen, 2000; Pence, 2004). Several forms of physical
harm that require major surgery for correction with risk of death
or permanent disability may be considered devastating. The
assessment of physical harms to offspring from customized
gametes will require thorough scientific investigation using
appropriate non-human primate models (Hewitson, 2004) prior
to the use of customized gametes for the creation of human children. Along with scientific investigation of the physical harm to
offspring, the meaning of reproductive liberty provided from
creating and using ES-cell-derived and customized gametes for
individuals and society requires further ethical discourse.
Summary and conclusions
Gametes derived from the spontaneous differentiation of ES-cell
lines could be created and cultured in large quantities using bioreactors in the near future (Dang et al., 2004; Gerecht-Nir et al.,
2004; Bauwens et al., 2005). ES-cell gametes should be made
relatively inexpensive and may be scientifically and socially
valuable for biomedical research and for training infertility specialists. Both ES-cell-derived and customized gametes may
prove socially valuable as they offer new reproductive choices
to individuals who desire to have children. However, the freedom to exercise the reproductive choice to use ES-cell-derived
and customized gametes will depend on several medical and
ethical concerns; one extremely important issue is the potential
physical or psychological harm to children born from them. It is
doubtful that psychological harm to children born from ES-cell
gametes will occur due to feelings of being born in an artificial
manner or from being created by two same-sex parents because
children born from other ‘artificial’ ARTs or who have samesex social parents do not display any psychological differences.
Although it remains to be tested, the potential physical harm
to children created from ES-cell gametes may also be minimal
since other ARTs such as in vitro maturation uses similar procedures for maturing gametes in culture as would ES-cellderived gametes. However, the creation of customized gametes
using extensive microsurgical procedures such as SCNT may
create de novo genetic mutations or epigenetic changes. These
gene mutations may manifest as physical harm to children or
accumulate in a given population over time, having unknown
effects in the future. Other important moral concerns not discussed explicitly in this article also deserve attention when creating customized gametes. For example, the creation of customized
gametes treats human embryos only as a means to deriving ES
cells and not as an end in itself (Master, 2005). This moral conflict is inherent in therapeutic cloning and ES-cell research, and
many nations have social policies which prohibit the practice of
therapeutic cloning and the use of embryos for research or other
purposes (Pattinson and Caulfield, 2004). Physical harm to the
mother, the technocratic control of human reproduction and the
medical and ethical implications in using customized gametes to
bypass biological boundaries of sexual reproduction by ES-cell
gametes require further discussion and debate.
Acknowledgements
Salary support was provided through the Canadian Institutes for
Health Research (CIHR) Ethics of Health Research and Policy program and the Stem Cell Network, a Network Centre of Excellence. I
would like to thank members of the Novel Technologies Ethics team,
colleagues at the Department of Bioethics, Dalhousie University and
the Centre for Applied Ethics at the University of British Columbia
for valuable feedback. Thanks to Dr Kathy Hudson at the Genetics
and Public Policy Center for inspiration. This article is dedicated to
Mrs N. Patel and Dr D.J. Dumont.
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Submitted on 14 July, 2005; resubmitted on 12 October, 2005; accepted on
15 November, 2005
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