Mitochondrial transfer and three-person IVF: What's in a name?

In 2012, the Human Fertilisation and Embryology Authority (HFEA) undertook a publicity campaign and public consultation on the
subject of mitochondrial transfer, or, to use its more sexy name, 'three-person
IVF'.

This emotive description may conjure up
some unnerving perceptions of the consequences, and, as this concept challenges
our very notion of parenthood and conception, may be met in the public arena
with discomfort; a general 'yuk' factor. However, the potential of this
technique to help treat a number of serious diseases that affect multiple
organs in the body means it is worthwhile considering some of the fundamental
aspects of this approach.

In order do this, it's worth starting with
the role of mitochondria, a type of subcellular component, or organelle. The vast
majority of cells contain mitochondria; notable exceptions include red blood
cells and cells of the retina. They are often known as the cellular power
stations, since their principle role is the generation of adenosine
triphosphate, the energy currency of life.

In addition to this pivotal responsibility,
mitochondria have a second important job as 'cell executioners', since they
play a vital role in the initiation of programmed cell death (apoptosis).

Since nearly all cells have mitochondria,
mitochondrial diseases are usually complex serious conditions that affect
multiple organs in the body. Like many other characteristics, we inherit our
mitochondria, but only from our mother — Dad's mitochondria, packaged in the
midpiece of the sperm, are discarded as soon as the sperm has successfully
fertilised the egg.

We can, of course screen for such diseases
and inform potential parents of the likelihood of an embryo having damaged
mitochondria, but now we have the opportunity to begin testing new techniques
that may enable us to avoid mitochondrial diseases entirely.

There are currently two approaches that
offer promise for prevention of mitochondrial disease; spindle transfer or
pronuclear transfer. These names describe the process much more accurately than
mitochondrial transfer, since the proposed techniques do not actually transfer
the mitochondria! Instead, an egg is required from a donor who does not carry
mitochondrial mutation, and the nuclear material is removed from that egg, in a
process called enucleation. In parallel, the nuclear material from the woman whose
eggs carry mutated mitochondria is removed by a very fine needle and replaced
into the donor egg.

The key difference between the two
approaches (spindle or pronuclear transfer) is the stage at which this transfer
is performed. In pronuclear transfer, a woman who carries damaged mitochondria
has her eggs fertilised in vitro. However, as soon as fertilisation is
confirmed successful, as indicated by the formation of two structures call
pronuclei, these are collected from the zygote, and injected into the
enucleated donor egg.

By contrast, in spindle transfer, the donor
egg, with the healthy mitochondria receives the nuclear component from the egg
carrying the diseased mitochondria and this is then fertilised. In either case,
if successful, a one-cell embryo, containing the nuclear DNA from the mother
and father is created and this can be transplanted back into the uterus,
hopefully to produce a healthy baby. However, because the egg that carried the
nuclear material came from a healthy donor, the child will have inherited
mitochondria free of disease.

The technology to enable this is a result
of many years of research, but there is much that we still do not know. Whilst
it may not be accurate to refer to this technique as 'three-parent IVF' it is
true that offspring generated in this way possess DNA from three sources; over
99.9 percent from Mum and Dad but also with some DNA from the mitochondria
inherited from the egg donor (since mitochondria have their own genome). It is
this very concept that enables the prevention of mitochondrial disease.

In order for this approach to work, the
mitochondria need to interact successfully with the nucleus from a different
individual. All research to date shows that this is safe, but we need to
increase our understanding of this process. It may also be important to consider
matching mitochondrial subgroup between egg donor and egg recipient, in much the same way that blood donors must be
matched according to blood type. One further important consideration is that if
the child born after mitochondrial transfer is a girl, all of her eggs, and
consequently any children that she has, will contain mitochondria descended
from the original egg donor.

To begin to answer the outstanding
questions surrounding this technological breakthrough, more research is needed.
In the UK, we are truly fortunate in having a very open and permissive research
environment, and whilst funding is very tight, the opportunity exists to
perform groundbreaking research using early embryos from animal models and in
the human. We have generous donors too — the unsung heroes of this type of
research are the people who, after IVF, present scientists with the amazing
gift of their surplus embryos which are not required for treatment and would
otherwise be discarded.

This resource allows us to learn much about
development of humans and investigate the effects of techniques such as
mitochondria transfer. Uniquely, we in the UK have a guardian of such important
research; the HFEA, who oversee research on human embryos, ensuring that
researchers adhere to strict standards, enshrined in law. The public
consultation on research on mitochondrial transfer,
serves as an illustration of the way on which the HFEA conducts its business.

Finally, the UK is home to some of the
world leaders in the understanding of human embryo development all of whom work
to the highest standards of scientific conduct and adhere to the conditions of
HFEA research licences. And it is for these reasons that we in the UK are
uniquely empowered, and arguably have a duty, to perform the vital research to
necessary to evaluate the importance and potential of mitochondrial transfer
for the avoidance of mitochondrial disease.