CBEL Report Volume 1, Issue 1

Tomohide Ibuki

Translated Article

A bioethical discussion of issues inherent to mitochondrial replacement and having “three
genetic parents” *Tomohide Ibuki(Tokyo University of Science)

Abstract
In February 2015, the U.K. became the first nation in the world to legalize the so-called“mitochondrial replacement” procedure for egg cells of patients with mitochondrial disease. Given
the possibility that Japan may also seek approval to use this technology, the present study aimed toorganize thoughts and discussion points put forth by previous studies concerning the ethical aspectsof mitochondrial replacement technology. One main consideration presented here pertains to theunique bioethical issue created by this technology; namely, the birth of children with “three genetic
parents.” I have added my thoughts and discussion points.
With regard to mitochondrial replacement technology, I conclude that the following four issues
should be taken into consideration: 1) safety, 2) the likelihood of further application, 3) the child’s
identity, and 4) “three genetic parents.” This paper takes a particularly close look at 4), as I consider
whether mitochondrial replacement would in fact create “three genetic parents,” and whether it
would even be ethically problematic if a child was born to “three genetic parents.”

Key words: mitochondrial replacement, three genetic parents, mitochondrial DNA, assisted
reproduction technology (ART), bioethics

1. Introduction
1-1. Background
Diseases caused by reduced function of
mitochondria, organelles that produce energy incells, are collectively named “mitochondrial
disease” 1-6. The pathology of mitochondrial
disease varies, with some affecting nerves ormuscles, others causing severe symptoms inorgans such as the heart, and some that can be
50

fatal.
In February 2015, the U.K. passed the firstbill ever to allow the use of egg cells in newtechnologies that would prevent mitochondrial
disease to be passed on genetically to thechildren of women with mitochondrial disease 7.
These new technologies can be described as
those that aim to prevent the onset of
mitochondrial
diseasebyreplacingA bioethical discussion of issues inherent to mitochondrial replacement andhaving “three genetic parents”

mitochondria in an egg cell from a mother who
could genetically pass on mitochondrial disease,with that donated by a third party. Collectively,
these technologies are known as mitochondrial
replacement or mitochondrial transplantation.
While mitochondrial replacement isanticipated by patients and their families to
bypass the possibility of mitochondrial disease
onset while still having a child with the same
genetic background as the parents, some voices
within the U.K. remain opposed to this. For
example, the Church of England has spoken out
against the technology, on the grounds thatmitochondrial replacement will lead to thegenetic alteration of the next generation 8.
According to a survey conducted in 2012,
the number of patients with mitochondrial
disease in Japan was reported to be 1087 9, but
given the difficulty of diagnosing this illness,some have estimated higher numbers 1. In the
U.K. and other Western nations, it is said that 1
in anywhere from several thousand to 10-20,000
patients is afflicted 1. Regardless, a goodnumber of those afflicted by or who are carriersof mitochondrial disease face the risk ofgenetically passing this disease on to theiroffspring. Thus, Japan may also seek to use thistechnology in the future.
As mentioned above, passage of the bill in
the U.K. was accompanied by an examinationof this issue by the Nuffield Council on
Bioethics (an independent council thatspecializes in debates on bioethical issues), andthe Human Fertilisation and Embryology
Authority (HFEA), the latter of which includes
laypersons. Thus, legalization was preceded by
years of cumulative arguments surrounding thismatter 10-12. If Japan is headed toward

CBEL Report Volume 1, Issue 1

considering the introduction of this technology,
then we anticipate that serious ethicalevaluation will become necessary. In addition,
close scrutiny over the ethical aspects ofmitochondrial replacement may help to shedsome light on issues that have not yet been
considered much in the field of bioethics. One
topic that will be discussed below is that ofpotential issues involved in creating a child with“three genetic parents.” In addition to
mitochondrial replacement presenting newissues to the field of bioethics, this issue also
simultaneously asks a question that cannot beignored or addressed by conventional
perspectives concerning the value of genetic
linkages in our society and the ideal relationshipbetween parent and child. In past ethicaldiscussions on assisted reproductive technology,
the arguments about genetic associations werebased on the nuclear DNA and its dissociation
within the lineage. However, mitochondrial
replacement technology brings into question
genetic associations based on mitochondrial
DNA as well as the significance/implications of
dissociation.
1-2. Present study objectives and methods
Against this backdrop, I conducted aliterature review and present a critical
discussion of ethical issues surrounding
mitochondrial
replacement
when
this
technology is used as a way to prevent thegenetic continuation of mitochondrial disease.
My specific aim with the present study was toclarify the following two points. First, I aimed
to understand and organize the main argumentsthat have been made thus far concerning ethicalissues with mitochondrial replacement. Building
51

CBEL Report Volume 1, Issue 1

Tomohide Ibuki

upon this, I aimed to evaluate specifically the
discussion thus far concerning the creation of achild with “three genetic parents” and thebioethical ramifications unique to thetechnology of mitochondrial replacement. I alsopresent my own opinions and thoughts on thismatter. The current reality in Japan is that very
little ethical discussion has occurred
surrounding mitochondrial replacement. As
such, the ultimate objective of article below is
to pave the way for discussions to progress on
the pros and cons of mitochondrial replacementin Japan.
To this end, I must first acquire an accurate
understanding of mitochondrial disease and thetechnology of mitochondrial replacement. The
following chapter presents an overview of thistechnology and a basic explanation of
mitochondrial disease.
2. Mitochondrial disease, mitochondrial
replacement, and alternative measures
Genes of the several hundred proteins that
reside in mitochondria are encoded by nuclear
DNA, but each mitochondrion also houses 5-10
mitochondrialDNA(mtDNA).
The
mitochondrial genome is roughly 16.6 kbp inlength and encodes 13 types of proteins 2-6 i.
Mitochondrial disease can be caused by genetic
mutations in nuclear DNA as well as
qualitative/quantitative abnormalities in mtDNA.
Some also suspect an interaction between
nuclear DNA and mtDNA.
At the time of fertilization, mitochondria
within the father’s sperm either never enter theegg or are destroyed in the process of doing so.
i

Details related to mitochondrial disease below aresummarized from References 2-6.

52

Consequently,
mitochondria
withinanindividual’s cells originate from the maternal
egg cell, and each mature egg typically contains
several hundred mitochondria. However, theproportion of mitochondria with abnormalities
differs even between eggs from the same
mother; therefore, even fertilized eggs from thesame mother vary in the likelihood for
mitochondrial disease onset.
Representative mitochondrial diseases
includechronic
progressive
external
ophthalmoplegia(CPEO);
mitochondrial
encephalopathy, lactic acidosis, and stroke-like
episodes (MELAS); myoclonus epilepsy
associated with ragged-red fibers (MERRF),
and Leigh’s disease. The pathology andprogression of mitochondrial disease vary
widely, but many forms of the disease result inthe onset of disorders in emotional, cognitive, or
muscular development; MELAS and Leigh’s
disease in particular can be fatal. With the
exception of CPEO, the diseases mentioned
above involve specific mutations in mtDNA,
and it is known that a mutation in mtDNA isinvolved for CPEO as well. Curative treatments
are not currently available for these diseases,
and thus treatment focuses on supportive
measures.
Onset of mitochondrial disease brought
about by mutations in mtDNA might beprevented
byreplacingthemutatedmitochondria within the egg cell with healthy
mitochondria. The two specific mitochondrial
replacement methods approved for use in the
U.K. include maternal spindle transfer (MST)and pronuclear transfer (PNT)13 ii. In MST, theii Descriptions hereafter on methods of mitochondrial
replacement are based on explanations from ReferenceA bioethical discussion of issues inherent to mitochondrial replacement andhaving “three genetic parents”

spindle that contains nuclear DNA is removed
from an egg donated from a third party, and thespindle extracted from the intended mother’s
egg cell is transplanted into the donor’s egg.
Sperm from the intended father is then used tocreate a fertilized egg through in vitro
fertilization. In PNT, the egg from a donor
undergoes in vitro fertilization with sperm fromthe intended father to create a fertilized egg,
from which the two pronuclei (the nuclei fromthe sperm and the egg that have not yet fused
after fertilization) are removed. Meanwhile, thetwo pronuclei harvested from a fertilized egg
from the intended parents are transplanted into
the enucleated fertilized egg (created by thedonor and father). iii
Aside from mitochondrial replacement,
preimplantation genetic diagnosis (PGD) or
prenatal diagnosis (or elective abortions) may
also prevent mitochondrial disease from being
genetically transmitted to future generations.
Using an egg donor is certainly possible, but
this approach would mean that the intended
mother would have no genetic link to the child.
Needless to say, each of these alternativetechnologies comes with its own unique set of
ethical challenges.
3. Ethical concerns with mitochondrial
replacement
The main ethical issues about mitochondrial
replacement as highlighted by previous studies
are 1) safety, 2) the likelihood for further
13.
iii
Therefore, while the present paper cannot provide
details on this, as one fertilized egg is destroyed
through the process of mitochondrial replacement incases of PNT, issues emerge concerning the moral
status of the fertilized embryo.

CBEL Report Volume 1, Issue 1

application of this technology, 3) identity of thechild created by this technology, and 4) “three
genetic parents.” Below, I organize some simple
argument points.
3-1. Issues related to the safety of
mitochondrial replacement
When applying a novel medical technology
to humans, the first issue to emerge is safety.
Mitochondrial replacement is no different, andvoices of concern have been raised about thesafety of this technology. Baylis organizedconcerns about the dangers of mitochondrial
replacement in the following four categories: 1)
harm toward the egg donor, 2) harm to the childor future generations, 3) harm to selectindividuals
withspecialinterests
inmitochondria-based lineage research, and 4)
harm to society 14. While 1) represents a
problem that resides in the entire area ofassisted reproductive technology that requires
egg donors, 2)-4) are issues unique tomitochondrial replacement.
It is not necessarily clear how the child bornfrom mitochondrial replacement will be affected,
if at all, and whether the effects (if any) will beobserved in their own children. This concern forharm to the child or future generations is at theheart of 2) and has become a major focal pointof the discussion in the U.K.. There is someconcernthattheoriginal(mutated)
mitochondria are not eliminated completely,
which would allow for the development of
mitochondrial disease, or that the complexitiesof the mutual interactions between nuclear
DNA and mtDNA will create some other effects
beyond what could be anticipated 11. Various
effects have been reported in experiments using
53

CBEL Report Volume 1, Issue 1

Tomohide Ibuki

mouse models 15.
The individuals noted in 3) with special
interests in this matter include genealogicalresearchersandhistorical/anthropologicalresearchers of human migration, for whom
mitochondrial replacement technology thatsevers the mtDNA of the maternal line may
disrupt their research. Baylis acknowledges that
this risk is extremely low, but still questions
whether obstructing their freedom in research isacceptable, especially if there are alternate ways
around the use of this technology (e.g., PGD).
Japan is considering the possibility of using
autologous transplantation of mitochondria as
infertility treatment 16, but there are so manyother applications of mitochondrial replacement
technology to which this could lead, and theeffects on society from some of these would not
be small—this is concern 4): harm to society. In
section 3-2, I discuss the effects of thistechnology on other technologies and point out
that perhaps I should be spending human andfinancial resources on more highly prioritizeddiseases affecting a greater number of patients
14.
Some have argued that the concerns
described above are significant enough to keep
this technology from moving forward 14, 17. On
the one hand, some would argue that new
medical technology is going to accompany risk,
and what is needed is not so much a prohibition
altogether, but rather an extremely carefulapproach to research 18, 19. The U.K. Department
of Health and the Nuffield Council have called
for careful execution of the procedure andfollow-up with children born using thistechnology, acknowledging that its safety
cannot be guaranteed 100% 13, 20.
54

3-2. Concerns that this technology will leadto further applications
As noted above, in addition to the risk to thechild created by this technology, other concerns
remain about the possibility of mitochondrial
replacement leading to the application of othertechnologies as well. One example is using thistechnology as an infertility treatment (seeabove), but of the various applications, thebiggest concern is its use in genetic engineering
10, 14, 21. Even though the contribution of mtDNA
to phenotype is small, we are certainly
manipulating and changing genetic informationthat is to be inherited by the next generation(s).
The first question is whether or not an importantmoral
difference
existsbetweenthe
manipulation or engineering of mtDNA versus
that of nuclear DNA. The British Department of
Health and some others have established thatthe two are clearly different issues 20.
Bredenoord et al. state that, from theperspective of “the child’s right to an open
future,” there is no critical or moral differencein manipulating mtDNA versus nuclear DNA 22.
The argument is ongoing among medical
specialists about whether or not a delineation
should be made between diseases involving
mtDNA and those that do not 23. Clearly, thequestion about whether manipulation of mtDNA
differs from that of nuclear DNA is not easily
answered.
In addition, even if a delineation could be
made, some concern remains about thepossibility that permitting mitochondrial
replacement would pave the way for genetic
engineering of nuclear DNA as well. Even if
mitochondrial replacement does not serve theA bioethical discussion of issues inherent to mitochondrial replacement andhaving “three genetic parents”

purpose of genetic enhancement or engineering,
the aim of disease prevention alone—as an
attempt to manipulate the next generation’s
genetic characteristics—opens up the possibility
for genetic engineering of the next generation,
as well as enhancement-type interventions suchas designer babies or the practice of eugenics 10,
14, 21, 24.
The concerns described thus far do not deem
mitochondrial replacement as unethical, butrather represent some hesitancy to open the door
to other potentially unethical acts that would beenabledbypermitting
mitochondrial
replacement—in other words, it is a slippery
slope argument. In general, for a slippery slope
argument to become validated, the validity ofthe speculative theory and the unethicality ofthe premise become important 25. While I will
not argue the validity of the speculative theoryof the present argument, I do wish to point out
the importance of knowing whether or not theunethicality of the premise is clear. In otherwords, mitochondrial replacement to increase
the chances of getting pregnant, genetic
engineering of nuclear DNA, enhancement
interventions and (new) eugenics practices are
all technologies that could be argued both forand against, and we may not be able to state
firmly that any one of these is necessarily
unethical. Because of this, the unethicality ofthe premise may not always be obvious, and theslippery slope approach may present insufficientgrounds for this argument. At the very least, thiswarrants a discussion centered on the ethics ofmitochondrial replacement and careful scrutinyof the practice of technologies that involve thesematters.

CBEL Report Volume 1, Issue 1

3-3. Mitochondrial replacement and identity
issues in a child screated by this technology
Another issue is the identity of the childborn as a result of mitochondrial replacement.
In other words, can a child born from anembryothat
underwent
mitochondrial
replacement embody the same identity as if s/he
had not undergone mitochondrial replacement?
According to the Nuffield Council, 99.9% of thegenetic characteristics of a child are determinedby nuclear DNA, so mtDNA would not
influence an individual’s identity 13.
In the above argument, the debate focuseson the issue of numerical identity—i.e., identity
in the sense that at two separate points in time,
one’s existence remains the same. However, as
the Nuffield Council has widely discovered,
there is great diversity in the concept of identity.
Therefore, if, for example, an individual’s
identity is determined by the world in whichs/he lives, or by their own personal narrative
rather than by their genes (i.e., narrative
identity), then we could conclude that theiridentity would be changed by the presence orabsence of mitochondrial replacement 14. This isbecause the raw narrative of Child α born from
Mr. A’s sperm and Ms. B’s egg versus that ofChild α’ born from Mr. A’s sperm, Ms. B’s egg
nucleus, and Ms. C’s mitochondria will bedifferent, particularly with regard to thepresence of mitochondrial disease, whether anon-parent third party was involved in theirbirth or not, and issues with the disclosure ofthese facts.
Of course, some questions remain as towhether this sort of influence on identity isalways unethical or not 26. To use an example ofsomeone undergoing an organ transplant, as
55

CBEL Report Volume 1, Issue 1

Tomohide Ibuki

long as receiving a transplanted organ will not(figuratively, at least) render an individual as adifferent existence, then we cannot conclude
that one’s numerical identity has undergone achange before and after the transplant. On theother hand, if the individual’s life narrative andworld are changed dramatically by undergoing
the transplant or not, then we would conclude
that the narrative identity is changed by thetransplant. Generally speaking, this type ofchange in narrative identity is not considered torender transplant medicine unethical. If asimilar argument can be made for mitochondrial
replacement, then trying to decree that thistechnology is unethical due solely to changes innarrative identity would be difficult.
3-4. Issues with “three genetic parents”
As described above, a child born as a resultof mitochondrial replacement has nuclear DNA
from the sperm, nuclear DNA from the intended
mother’s egg, and mtDNA from the donor. This
has led to the criticism that mitochondrial
replacement is the first technology ever tocreate a child with “three genetic parents” 27.
The term “three genetic parents,” or “tri-parent”
has become commonplace among the press both
domestically and abroad, when commenting on
mitochondrial replacement 7, 28, 29. The U.K.
Department of Health and the Nuffield Council
have criticized the use of this term, however,opining that it is inappropriate 13, 20.
At least two thoughts must be consideredwhen offering the criticism that “mitochondrial
replacement creates a child with three genetic
parents.” The first is the obvious matter ofwhether or not mitochondrial replacement does,in fact, create a child with “three genetic
56

parents.” Second, even if we can affirm that it
does give rise to a child with three genetic
parents, is this in it of itself unethical? As
discussed in section 1-1, these points are newissues that have been presented to the field ofbioethics by the arrival of mitochondrial
replacement technology. They are alsoquestions that should be considered from
non-conventional angles with regard to thevalue of genetic linkage and the ideal
relationship that should exist between parent
and child. For the remainder of this paper, I will
focus the discussion on these two specificpoints.
4. “Three genetic parents,” the value ofgenetic linkage, and the implications ofsevering this4-1. Does mitochondrial replacement lead tothe birth of a child with “three genetic
parents?”
As discussed above, the U.K. Department of
Health and the Nuffield Council have expressedsome negative opinions pertaining to the term,“three genetic parents”:“Genetically, the child will, indeed, have
DNA from three individuals but all available
scientific evidence indicates that the genes
contributing to personal characteristics andtraits come solely from nuclear DNA, which
will only come from the proposed child's
motherandfather.
The
donatedmitochondrial DNA will not affect thosecharacteristics.” (U.K. Department of
Health, 2014, page 15).
As reflected in this excerpt, the U.K.

A bioethical discussion of issues inherent to mitochondrial replacement andhaving “three genetic parents”

Department of Health and the Nuffield Council
consider it problematic to label a mitochondrial
donor as a ‘parent,’ given the low power of
influence that mtDNA has on an individual’scharacteristics and form. At a workshop
targeting individuals from the general publicthat was conducted by the HFEA as part of theprocess of policy-making, participant responses
were consistent with this opinion, as
demonstrated by the high number of those who
felt that the term “three genetic parents” wasinappropriate, based on the little amount thatwould be contributed genetically to the childfrom the donor’s mtDNA 30. However, whileboth the U.K. Department of Health and the
Nuffield Council have these opinions
concerning genetic linkages, they also do notnecessarily deny the presence of emotional
linkages altogether. Actually, that which
partially protects a child’s right to know their
origins (albeit in a limited manner fromanonymous information, etc.) offers medical
benefits in addition to the emotional linkages.
Baylis rebuts this from the perspective of
narrative identity 14. Specifically, she argues
that Child α, born as a result of Mr. A’s sperm
and Ms. B’s egg, will constitute an entirely
different individual from Child α’, born from
Mr. A’s sperm, Ms. B’s egg, and Ms. C’s
mitochondria. In so far as Child α and Child α’
are different individuals, it can be said that there
are three parents, including the mitochondrial
donor Ms. C. iv
iv

In cases for which the mitochondrial donor is fromthe same maternal lineage as the egg donor (e.g., amother or sister), they will have similar if not the same
mtDNA. Thus, in actuality, there will be two genetic
parents. However, most of these cases do not allow for
the possibility of bypassing mitochondrial disease, so I

CBEL Report Volume 1, Issue 1

Indeed, while the contribution of mtDNA toan individual’s phenotype is low, there are cases
in which mtDNA plays a decisive role in thedevelopmentof
mitochondrial
disease.
Therefore, in some cases, an entirely different
life could be anticipated as a result of theinfluence of mtDNA; naturally, a different
personality and identity would also develop 22.
That said, even if Child α and Child α’ were
to have different identities, this is not a valid
reason to conclude that mitochondrial donor Ms.
C should be labeled as a parent to Child α’. At
the very least, most would generally bereluctant to call her a genetic parent, primarily
because if Ms. C should be considered a genetic
parent in these instances, then there are others towhom the same label should be applied.
However, labeling the mtDNA donor as aparent in some of those cases may force us tomake some conclusions that would generally goagainst our intuition.
Such cases would include those of somatic
cell cloning with the aim to reproduce (hereafter,
reproductive cloning). In reproductive cloning,
mtDNA has a different origin from that of thenuclear DNA, unless the woman uses her own
egg cell or another egg donor such as hermother or sister with the same maternal genetic
background. Therefore, if the mitochondrial
donor in mitochondrial replacement is labeled agenetic parent, then the egg donor in
reproductive cloning should also be labeled assuch, to avoid inconsistencies. However, within
the context of reproductive cloning, those who
would consider a mtDNA donor (i.e., an egg
donor) as a parent are certainly not in thehave excluded them from my present discussion.
57

CBEL Report Volume 1, Issue 1

Tomohide Ibuki

majority.
Of course, with reproductive cloning,
dramatic differences in phenotype are notanticipated simply due to differences inmitochondria. In this regard, one may argue thatan important moral difference exists between
reproductive cloning and mitochondrial
replacement. Conversely, perhaps some would
advocate that egg donors in reproductive
cloning are labeled parents as well. However,(while this is doubtful given the argument
trajectory thus far), even if a child were to beborn with “three genetic parents” throughmitochondrial replacement, we could notconfidently conclude that something unethicalhas occurred. If this is true, then the simple factthat a child is born with “three genetic parents”
cannot be the sole reason to deem mitochondrial
replacement an unethical procedure.
4-2. Revisiting the ethics of creating a childwith “three genetic parents”
Let us open up the discussion anew withregard to whether there are any ethical issues
with creating a child who would be born to“three genetic parents.” First, unless we feel theneed to adhere so tightly to the original
definition of the term “genetic,” then it could besaid that many children in modern-day society
have three or more people whom they could call‘parents’ 31. For various reasons andcircumstances, there are some children forwhom their so-called biological/genetic parents
differ from those who raised them (i.e., social or‘adopted’ parent). For example, the couple thatgave birth to the child may encounter a situationin which they are forced, for whatever reason,
to leave the child to be raised by another couple.
58

In this case, this child would have four adults
that could be considered “parents.”
However, in the case described above, thechild may not necessarily have three (or more)parents from the stage of birth and beyond. On
the one hand, mitochondrial replacement
necessitates that three human beings are
involved in the child’s birth. However, inmodern-day assisted reproductive technology,
similar circumstances can emerge in several
cases. One typical example would be the case inwhich a sperm or egg is donated from a third
party in order to have a child 31. In this case, thechild would have the two adoptive parents thatraised him/her in addition to the genetic parent
that is the donor for one of the spouses,
resulting in a total of three or more parents. In
cases involving surrogate mothers, one may
even argue that multiple individuals could beconsidered parents to this child 32. Admittedly,
opinions are quite split in Japan with regard to
the technology requiring a third-party egg or
sperm donor and surrogate mothers. The
problems embodied by this technology thatwould likely overlap with problems inherent tomitochondrial replacement include confusion
about family values or discrimination toward
children born through this technology. However,whether or not these demerits are so severe as tooutweigh the alternative of the child not existing
requires further discussion. In the context of
mitochondrial replacement, if Child α and Childα’ were to embody different numerical identities,
then Child α’ would essentially be non-existent
if this technology was not employed. If different
numerical identities are not assumed for Child α
and Child α’, then Child α (= Child α’) would
benefit from being able to avoid the serious

A bioethical discussion of issues inherent to mitochondrial replacement andhaving “three genetic parents”

disease that is mitochondrial disease, throughthe application of mitochondrial replacement.
Johnson opines that the ability to avoid
mitochondrial disease in this manner, or, at thevery least, to have the potential to do so,
outweighs the demerits associated with having
three parents 18.
In sum, if we do not adhere too tightly to thesemantics of the term “genetic” whendescribing parents, we must acknowledge theexistence of quite a few children with three (ormore) adults who could be called ‘parents,’ andthat this is not unique to mitochondrial
replacement. However, when considering athird-party egg or sperm donor through thesame lens, having three parents frommitochondrial
replacementisethically
problematic in cases for which A) the demerits
are so severe that it would be better if the childdid not exist, or B) the demerits far outweighthe merits associated with the ability to bypass
mitochondrial disease. That said, it is notalways obvious that the demerits associatedwith having three parents far outweigh themerits of being able to avoid mitochondrial
disease.
4-3. The value of mtDNA linkage and nuclear
DNA linkage
Thus far, I have delved into the twoargumentsofwhether
mitochondrial
replacement will give rise to the birth ofchildren with three genetic parents (section 4-1),
and whether or not giving birth to a child withthree genetic parents is, in fact, ethicallyproblematic (section 4-2), both issues of which
are related to the existence of “mitochondrial
donors” and “genetic parents.” Consider,

CBEL Report Volume 1, Issue 1

however, how the “mitochondrial recipient,” i.e.,
the woman or couple requesting the transplant,
might view this issue. As mitochondrial
replacement would involve a female seeking a
nuclear DNA linkage, some might view this as atechnology that (in the opposite manner) severs
the mtDNA linkage. Thus, as a final argument,
we will discuss issues with mitochondrial
replacement and genetic parents as viewed fromrecipients of the mitochondrial replacement
technology. However, given my limited ability
to discuss this matter thoroughly, I will only
briefly point out a few argument points todiscuss the value of both mtDNA and nuclear
DNA linkages, as well as the implications ofsevering each, ideally in a manner that
contributes to future discussions on this topic.
Several infertility treatment technologies(e.g., in vitro fertilization for infertility, or
pre-implantation genetic diagnosis to avoid
habitual abortions) incorporate the practice of
seeking a nuclear DNA linkage with the child.
In other words, if nuclear DNA linkage was not
so persistently sought after and a couple ishaving difficulty becoming pregnant, then theiroptions would be to give up on having children,
adoption, fostering, or using an egg donor. The
same would apply to mitochondrial replacement
12. Of course, some also view these desires for anuclear DNA linkage and the technology thatevokes this desire in some individuals withskepticism 33. Even so, it is difficult to conclude
that the desire to have a child with nuclear DNA
linkage in its entirety is unreasonable orpreposterous, or that such a desire is completely
socially constructed 34. If that is the case, at thevery least, the possibility exists that our society
does, in fact, perceive some form of value in59

CBEL Report Volume 1, Issue 1

Tomohide Ibuki

nuclear DNA linkage, despite the myriad ofproblems inherent to this.
What can we conclude about mtDNA
linkage? One characteristic of mtDNA is that it
is shared all along the maternal lineage; is itproblematic to sever this linkage? Very few
discussions are ongoing concerning this point,either within or outside of Japan, and Japan
must also revisit this discussion and conduct
bioethical research studies to this end. However,as stated in section 3-3, if mtDNA is responsiblefor 0.1% or less of phenotype, and the primaryconcern is to have a child who (phenotypically)
resembles the parents, then the nuclear DNA
linkage should be sufficient and mitochondrial
replacement (which would sever mtDNA
linkages while maintaining nuclear DNA
linkages) should not be problematic to perform.
5. Conclusions
In the present paper, I have attempted toorganize arguments from previous studies whileproviding a critical discussion of the ethicalramifications of allowing mitochondrial
replacement to address the genetic issues of egg
cells in women with mitochondrial disease. I am
likely the first group from Japan to haveexamined the ethical aspects of mitochondrial
replacement, particularly with regard to the
ethical implications of giving birth to children
with “three genetic parents.” I was
unfortunately unable to discuss all arguments infull, simply because I aimed to represent as
many issues as possible that will serve as thefoundation for future discussions in Japan. As
mentioned in Section 4 above, a societal-level
discussion is needed to evaluate the worth of
mtDNA linkages and what it means to sever60

these, in a manner that incorporates deeper
bioethical research studies and pays attention to
the various stakeholders involved. In addition,in the event that mitochondrial replacement is
implemented in Japan, it would likely begin as aclinical study, so a framework with research
regulations must be organized for thistechnology. If the present paper could be used
to help pioneer this discussion, then I havesufficiently accomplished my objectives.

References
1. Japan Intractable Diseases Information
Center: Mitokondoria byou (Byouki no kaisetsu(Ippan riyousha muke)) (Mitochondrial disease:
A disease commentary (for laypersons)). 2015:
http://www.nanbyou.or.jp/entry/194(Last
accessed January 15, 2016)
2. Shunji Kita, Yu-ichi Goto. Mitokondoria
byou (Mitochondrial disease). Journal of
Clinical Rehabilitation 2010; 19(12):1192-1196.
3. Yu-ichi Goto. Mitokondoria byou no chiryou
to kea no saishin jouhou (Latest updates ontreatment and care options for mitochondrial
disease). Home Health Care for the People with
Intractable Diseases 2012; 18(6):28-30.
4. Yoshimitsu Fukushima, supervising editor.
Iden igaku yasashii keitoukougi 18 kou (18basic systematic lectures on genetic medicine).
Medical Sciences International, 2013.
5. Yoshikuni Mizuno, ed. Shinkei naika
handobukku—Kambetsu shindan to chiryou,
Dai 4 ban (Neurology Handbook: Differential
diagnosis and treatment, 4th edition).
Igaku-Shoin, 2010.
6. Geoffrey Cooper, Robert E. Hausman(Translated into Japanese by Kazuo Sutoh,A bioethical discussion of issues inherent to mitochondrial replacement andhaving “three genetic parents”

Toshiaki Katada, Yasufumi Emori, Hiroyuki
Adachi, and Michio Tomishige). The Cell: A
molecular approach. 4th Edition. Tokyo Kagaku
Dojin, 2008.
7. Gallagher, J. U.K. Approves Three-person
Babies. BBC news website 24 February 2015:
http://www.bbc.com/news/health-31594856(Last accessed January 15, 2016)
8. The Church of England. Statement from
Revd Dr Brendan McCarthy on Mitochondrial
Replacement Therapy. 30 January 2015:
https://churchofengland.org/media-centre/news/
2015/01/statement-from-revd-dr-brendan-mccar
thy-on-mitochondrial-replacement-therapy.aspx(Last accessed January 15, 2016)
9. Japan Intractable Diseases Information
Center. 2014. Mitokondoria byou (Shitei
nambyou sentei iinkai shiryou 2014 nen 10
gatsu (Mitochondrial disease (Selection
Committee
Resourcesfor
DesignatedIntractable
Diseases,
October2014).
http://www.nanbyou.or.jp/entry/3663 x (Last
accessed January 15, 2016)
10. Ishii, T. Potential Impact of Human
Mitochondrial Replacement on Global Policy
regarding Germline Gene Modification.
Reproductive BioMedicine Online 29: 150-155,
2014.
11. Dimond, R. Social and Ethical Issues in
Mitochondrial Donation. British Medical
Bulletin 115: 173-182, 2015.
12. Yuri Hibino. Eikoku ga mitokondoria
teikyou no rinshou ouyou o kettei (United
Kingdom approves clinical application of
mitochondrial donation). Sanka to Fujinka
2015; 82(12):1440-1445.
13. Nuffield Council on Bioethics. Novel
Techniques for the Prevention of Mitochondrial

CBEL Report Volume 1, Issue 1

DNA Disorders: an Ethical Review. 2012:
http://nuffieldbioethics.org/wp-content/uploads/
2014/06/Novel_techniques_for_the_prevention_of_mitochondrial_DNA_disorders_compressed.pdf (Last accessed January 15, 2016)14. Baylis, F. The Ethics of Children with Three
Genetic Parents. Reproductive Biomedicine
Online 26(6): 531-534, 2013.
15. Dunham—Snary, K. and S. Ballinger.
Mitochondrial-nuclear DNA Mismatch Matters.
Nature 349: 1449-1450, 2015.
16. Mainichi Shimbun, December 12, 2015.
Nissanpu
ranshiwakagaeri
shouninmitokondoria chuunyuu. (Japan Society of
Obstetrics
andGynecology
approves
mitochondrial insertion to rejuvenate eggs ofolder
women).
http://mainichi.jp/articles/20151213/k00/00m/0
40/071000c (last accessed January 15, 2016)17. Bredenoord, A. and P. Braude. Ethics ofMitochondrial Gene Replacement. BMJ 342:
87-90, 2010.
18. Johnson, M. Tri-parenthood—a Simply
Misleading Term or an Ethically Misguided
Approach? Reproductive Biomedicine Online
26(6): 516-519, 2013.
19. Mitalipov, S. and D. Wolf. Clinical andEthical Implications of Mitochondrial Gene
Transfer.
Trends
Endocrinology
andMetabolism 25(1): 5-7, 2014.
20. Department of Health. Mitochondrial
Donation: Government response to theconsultation on draft regulations to permit theuse of new treatment techniques to prevent thetransmission of a serious mitochondrial diseasefrommothertochild.
July
2014:
https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/332881/Consult
61

CBEL Report Volume 1, Issue 1

Tomohide Ibuki

ation_response.pdf (Last accessed January 15,
2016)
21. Darnovsky, M. A Slippery Slope to Human
Germline Modification. Nature 499: 127, 2013.
22. Bredenoord, A., W. Dondorp, G. Pennings,
and G. De Wert. Ethics of Modifying the
Mitochondrial Genomes. Journal of Medical
Ethics 37(2): 97-100, 2011.
23. Biesecker, B. Social and Behavioural
Research in Clinical Genetics. Clinical
Genetics77: 10-17, 2010.
24. Murray, T. Stirring the Simmering“Designer Baby” Pot. Science 343: 1208-1210,
2014.
25. Satoshi Kodama. Yuukou na suberizaka
ronhou towa nanika? (What makes a slipperyslope
argument
valid?).
In:
Seimei/kankyou/kagaku gijutsu rinri kenkyuu V(Ethical Research studies on Life, Environment,
and Scientific Technology. V). 83-92, 2000.
26. DeGrazia, D. Enhancement Technologies
and Human Identity. Journal of Medicine andPhilosophy 30:261-283, 2005.
27. Szebik I. Response to “Germ Line Therapy
to Cure Mitochondrial Disease: Protocol andEthics of In Vitro Ovum Nuclear
Transplantation” by Donald S. Rubenstein,David C. Thomasma, Eric A. Schon, andMichael J. Zinaman (CQ Vol 4, No 3).
Cambridge Quarterly of Healthcare Ethics 8:369-374, 1999.
28. Yomiuri Shimbun, February 26, 2015. Ei,
ranshi no kaku ishoku gouhouka… “3 nin nooya” Idenshi uketsugu akachan umareru? (U.K.
legalizes nuclear transfer—will this create
babies with genetic material from “threeparents”?)
29. Asahi Shimbun, February 25, 2015. Taigai
62

jusei “oya ga 3 nin” no shingijutsu Ei de ninka
shingi (U.K. deliberating over new “3 parent”
technology for in vitro fertilization).
30. Human Fertilization and Embryology
Authority. Review of Scientific Methods to
Avoid Mitochondrial Disease 2014. 16 October
2014: http://www.hfea.gov.uk/8807.html (Last
accessed January 15, 2016)
31. Cohen J. and M. Alikani. The Biological
Basis for Defining Bi-parental or Tri-parental
Origin of Offspring from Cytoplasmic andSpindle Transfer. Reproductive Biomedicine
Online 26(6): 535-537, 2013.
32. Atsuko Kobayashi. Seishoku iryou wa hito oshiawase ni surunoka—seimei rinri kara
kangaeru. (Does reproductive medicine makepeople happy? Bioethical perspectives).
Kobunsha Shinsho 2014.
33. Azumi Tsuge. Seishoku gijutsu—funinchiryou to saisei iryou wa shakai ni nani omotarasuka? (Reproductive technology: What
does society gain from infertility treatment andregenerative medicine? Misuzu Shobo 2012.
34. Yoshie Yanagihara. Dairi shussan o meguru“Ko o motsu yokkyuu” (The “desire to have achild” in the context of surrogacy). Shiseigaku
kenkyuu 2012; 17:116-141.

*

This article was originally published inJapanese as below:
IBUKI, Tomohide, Mitokondoria chikann
niokeru “3 ninn no oya” no mondai nituiteno
seimeirinrigakuteki kousatsu (Mitochondrial
replacement and the problem of “three genetic
parents”). Journal of the Japan Association for
Bioethics 2016; 26(1):124-133.