YSM Issue 87.4

IMAGE COURTESY OF ACCELERATING SCIENCE
Mitochondrial diseases are passed on from mother to child in the
embryo. Though sperm do have mitochodria (they need energy to
propel themselves to the egg), paternal mitochondria—along with all
mitochondrial DNA—is usually lost immediately after fertilization.
The mother’s egg, on the other hand, contains a multitude of
mitochondria that become an intrinsic part of the embryo, and
eventually a part of the mature organism. Mitochondria are matrilineal,
meaning that they pass from mother to daughter completely
unaltered for generations. This is unfortunate for women afflicted
with Leigh syndrome, because they cannot naturally conceive healthy
children. This is where mitochondrial replacement comes into play.
Scientists in the U.S. and abroad are testing several methods of
mitochondrial replacement to create three-parent embryos and allow
mothers with mitochondrial diseases to have their own biological
children. One procedure, pronuclear transfer (PNT), completes invitro
fertilization using the two primary parents’ gametes. At the
same time, the father’s sperm is used to fertilize a donor egg with
healthy mitochondria. Pronuclei, or the nuclei from the cells involved
in fertilization, are removed from the primary parents and deposited
into the second embryo. The embryo is eventually transferred to the
mitochondrial replacement
is legalized and is successful
‘‘If
in clinical trials, [it] will likely
come to the surface as the
safest and most effective way
to prevent mitochondrial
disease from passing through
successive generations.”
mother with the hope of a successful birth of a disease-free baby.
Two additional methods of mitochondrial replacement include
Maternal Spindle Transfer and Nuclear Genome Transfer, both
of which utilize the mother’s nuclear DNA directly from the egg.
The donor egg’s nuclear DNA is removed, and the mother’s nuclear
DNA replaces the discarded donor DNA. The new egg with healthy
mitochondria and the mother’s nuclear DNA is fertilized with sperm
from the father in-vitro, and the egg is then transferred to the mother.
If mitochondrial replacement is legalized and is successful
in clinical trials, one of these three methods—PNT, Maternal
Spindle Transfer, or Nuclear Genome Transfer—will likely come
to the surface as the safest and most effective way to prevent
mitochondrial disease from passing through successive generations.
Of course there are a multitude of risks for women receiving invitro
fertilization after mitochondrial replacement. First and foremost,
pregnancy and delivery of a child is not guaranteed. The general
in-vitro fertilization treatment is not entirely safe, and the addition
of chemicals used in mitochondrial manipulation is speculated
to increase the risk of harmful effects for the mother. Because
mitochondrial replacement has yet to be tested in humans, scientists
are unsure if the mother’s body will react negatively to the implanted
three-parent embryo. Moreover, the three-parent child may not be
perfectly healthy, and may instead be born with damaged physiology.
While it is true that three-parent children would avoid
inheriting Leigh syndrome, they could potentially face other lethal
complications. It is possible that birth defects and other negative
reactions to the reagents used in the procedure will occur. In fact,
mitochondrial replacement might even result in mitochondrial disease
as a result of incomplete mitochondrial transfer or incompatibility.
A variety of diseases can also be caused by epigenetic changes that
occur during mitochondrial replacement. These modifications do not
affect DNA directly, but instead modify DNA expression through
chemical reactions such as DNA methylation. Unfortunately, such
detrimental epigenetic changes can be passed on to future generations.
Governments around the globe prohibit genetic modifications in
humans for ethical reasons. Even the limited germ line modification
entailed by mitochondrial replacement has caused disputes. On
one side, opponents of the new therapy argue that if scientists
can modify DNA in the embryo, there is nothing stopping them
from creating “designer babies.” But in general, opposition to the
three-parent embryo remains relatively quiet for now; proponents
are looking ahead to the potential of mitochondrial replacement in
helping patients of mitochondrial diseases live more fulfilling lives.
www.yalescientific.org
October 2014
Yale Scientific Magazine
31