A limitation of the use of embryonic stem cells is that they
are immunologically foreign to the person receiving them, and
are therefore potential targets for immune destruction. In the
case of diabetes, treatment is achieved by encasing the cells in
a membrane that is impermeable to the host’s immune cells.
However, this strategy is not applicable when transferred
cells must be integrated into the structure of an organ. A poten-
tial solution is the conversion of adult cells into embryonic
stem cells.
The changing of adult cells to those resembling the embryo
is called “induced pluripotency”. The discovery that a small
number of key molecules determine the pluripotent state of
the inner cell mass has allowed scientists to force the expression
of these factors in adult cells. Remarkably, this has resulted in
some adult cells resuming the characteristics of embryonic stem
cells.
The potential of these cells for regenerative medicine is being
fully investigated, but perhaps the most striking discovery is
their ability to convert into either sperm or oocytes. In mouse
models, gametes produced from induced pluripotent stem cells
are fertile and can produce viable offspring. Obvious questions
regarding the safety of using gametes created from converted
adult tissue must be addressed before any thought should be
given to it as a treatment for infertility.
Induced pluripotent stem cells allow the development of
banks of cells from people with known genetic conditions.
These can be induced to differentiate into tissues of interest ,such as nerve cells in cases of neurodegenerative disease, and
serve as powerful tools for the investigation of disease mecha-
nisms and for drug screening. Induced pluripotent cells can
also be used to test the toxicity of new chemicals.Unexpected Long-term Consequences
of Working on Embryos
All of these exciting advances in embryo-based therapies may
be associated with unexpected biological risks. A new field
called epigenetics points to the important role of the early
embryo in setting the program that determines the timing and
level of expression of key regulators of homeostasis throughout
life. A host of stresses experienced by gametes and early embryos
can adversely change these settings.
The technologies used to create and manipulate the embryo
in vitrogenerate stress responses in the embryo that alter epige-
netic settings. When this is sufficiently severe, it leads to early
embryo death.
It is chastening to realise that after 30 years of developing
these techniques, only around 25% of the embryos created have
the capacity to develop to term. The vast majority die within
the first week or so after IVF. Those that survive have an
increased risk of epigenetic changes in gene expression patterns
throughout life, which causes an increased incidence of hyper-
tension, poor glucose control and a range of other chronic
diseases. Animal modelling shows that the more extreme the
manipulations of the embryo, the greater the stress response
and epigenetic disturbance.
These studies point to a need for a greater understanding
of how environmental conditions disturb the process of epige-
netic programming in the gametes and early embryo, as well as
the development of strategies to mitigate their maladaptive
effects.Conclusion
The confluence of our new molecular understanding of embry-
ology and an increased capacity for the microsurgical and genetic
manipulation of the embryo provides a panorama of new oppor-
tunities for alleviating human disease. Each of these new oppor-
tunities suggests questions about their safety and the possible
unintended consequences for future generations.
The potential benefits are such that many are certain to be
fully explored, but it is equally important that the long-term
safety of any new treatments receives equal attention. It is
unlikely that the market will attend to these needs, and this
market failure will mandate institutional intervention.
Chris O’Neill is Professor of Reproductive and Developmental Medicine at the Kolling
Institute for Medical Research and Sydney Medical School, President of the Society for
Reproductive Biology, and a past member of the National Health and Medical Research
Council’s Embryo Licensing Committee.16 | JAN/FEB 2016
Current Status of Assisted
Reproductive Technologies
The egg (oocyte) is approximately 80 μm in diameter – about the
thickness of a fine hair. Fertilisation triggers cell division,
producing an embryo containing around 80 cells after 5 days.
During this period, the embryo is in a free-floating state, so
surgery on the oocyte and embryo is feasible in the test tube.
The direct microsurgical injection of sperm into the oocyte
allows for fertilisation by sperm that are incapable of swimming
or are misshapen. Fertilisation via sperm injection is even possible
with sperm collected after a man dies, although this is not legal in
many jurisdictions.
The only remaining form of male infertility is a complete loss
of sperm production, but even that may be treatable eventually.
Normal fertility and the success of assisted reproduction
decline rapidly with advancing female age. Improvements in
cryopreservation techniques now allow ovarian tissue to be stored
at a younger age for later use. This has particular relevance for
girls and women who are about to have treatments that reduce or
prevent normal ovarian function, such as chemotherapy. This
treatment is early in its development phase and should not be
seen as a cure-all for the female biological clock just yet.