Three-Parent Embryos: Gearing Up for the US Debate

On February 24, 2015 the House of Lords approved a law permitting mitochondrial replacement with its production of three-parent embryos to prevent maternal transmission of mitochondrial disease.

In October, the UK’s Human Fertilization & Embryology Authority will license the use of mitochondrial replacement for human clinical trials. The arrival of Britain’s first three-parent baby is expected by 2016.

The Consensus Study Committee held its first meeting in January 2015. It will convene again in March and May with the inclusion of public comment sessions, and will draft and finalize the consensus report during its last two closed-door meetings. If MR is approved by the FDA, American clinicians could submit an application and, if deemed eligible, could inaugurate the production of three-parent embryos in human clinical trials in the not-so-distant future.

Here, I argue two things. First, that the profound moral and social harm of MR outweighs the theoretical good of preventing a subset of mito-diseases. Second, that anyone interested in protecting human life, human dignity, human procreation, and the human genome should subscribe to the following four-step plan so that the voice of reason can be heard during the upcoming US debate on three-parent embryos.

I. Understanding the science of MR

Mitochondria are organelles—tiny “powerhouses” in our cells—that convert food into energy. These energy-generating structures are necessary to sustain life and support growth and, literally, make it possible for us to move and think.

Mitochondrial DNA (mtDNA) is the only DNA that we inherit exclusively from our mothers. Each mitochondrion contains 37 genes of its own DNA that are separate from the 20,000-25,000 genes found in the nucleus of our cells.

In a person with mitochondrial disease, the mitochondria are failing and cannot convert food and oxygen into life-sustaining energy. A subset of mitochondrial diseases is caused by mutations in mitochondrial genes, and women who carry such faulty mitochondria will transmit them to all of their children, male or female. Female offspring of each generation who conceive their children will, in turn, transmit the faulty mitochondrial genes to their children. Because nearly all cells of the body have mitochondria, mitochondrial diseases are usually complex, serious conditions that affect multiple organs of the body. Inheriting faulty mitochondria deleteriously affects organs that need high levels of energy—brain, heart, kidneys, muscles, and liver. A mitochondrial disease, once expressed, is inevitably progressive. In a pregnant woman it can cause miscarriage, stillbirth, or infant death and, in later life, it can trigger seizures, strokes, blindness, deafness, or heart and liver failure.

It is estimated that one in 5,000 to 10,000 people have a mitochondrial disease. But only 15 percent of these cases are likely to be caused by mutations in mtDNA. Only women of the 15 percent subset with a very high level of mito-mutations will be eligible for mitochondrial replacement (MR).

To prevent maternal transmission of this subset of mito-disease, the recently enacted UK law permits the use of two mitochondrial donation techniques—pronuclear transfer (PNT) and maternal spindle transfer (MST).

Pronuclear transfer involves the simultaneous creation of two IVF embryos. The first embryo is generated when the mother’s egg (containing faulty mitochondria) is fertilized in vitro, i.e., in a petri dish, by the father’s sperm. The second embryo is generated after the donor’s egg (containing healthy mitochondria) is fertilized in vitro by the father’s sperm. After the nuclear DNA of the second embryo is removed through a process called enucleation, the nuclear DNA of the first embryo is also extracted and transferred to the second enucleated embryo. As a result, the first embryo is intentionally destroyed so that the second embryo, now comprised of DNA from its three parents (nuclear DNA from Mama and Papa and healthy mtDNA from the donor) will, theoretically, be free of its mother’s mutated mito-genes and their associated mito-diseases. After the three-parent embryo develops in a petri dish to its blastocyst stage, it is transferred to the mother’s uterus for implantation and gestation.

Maternal spindle transfer uses a donor egg containing healthy mtDNA and an egg from the mother containing faulty or mutated mtDNA. The nuclear DNA of the donor egg is removed, leaving behind the normal mtDNA in the cytoplasm of the egg. Then, the nuclear material from the mother’s egg is removed and transferred to the enucleated donor egg. The hybrid mother/donor egg is then fertilized in vitro by the father’s sperm and the resultant embryo, because it is genetically composed of nuclear DNA from its mother and father and healthy mtDNA from a donor, has three parents and is also, theoretically, mito-disease free. After the three-parent embryo develops in a petri dish to its blastocyst stage, it is transferred to the mother’s uterus for implantation and gestation.

The principal difference between the two techniques is this: in maternal spindle transfer (or MST) the nuclear DNA is moved before the mother’s egg has been fertilized (when the egg’s nuclear DNA is attached to a structure called the spindle, hence its name). Whereas in pronuclear transfer (or PNT) the DNA is moved after the mother’s egg has been fertilized (when the nuclear DNA is contained in two structures called pronuclei, hence its name).

One of the best resources for the science of MR technology is the Center for Genetics and Society, for those interested in reading more about the subject.

II. Recognize the moral case against MR

The PNT technique of MR involves the intentional destruction of a human embryo.

When the PNT technique is used, the first embryo (with faulty mtDNA) is dismantled or destroyed when its nuclear DNA is removed. The sole purpose of producing the first embryo is for the sake of its nuclear DNA, the nuclear genome that will guarantee the child’s biological relationship to his parents. The sole fate of the first embryo is its destruction through its dismantlement. The healthy (second) embryo is only obtained by means of the intentional killing of the unhealthy (first) embryonic human being. What kind of twisted logic is it, then, that would bring life to one embryonic human being by deliberately killing another?

Using the PNT technique of MR reduces the three-parent embryo to an experiment in human genetic modification. In doing that, this crass use of human embryos wields a blow against the dignity and equality of all human beings, born and unborn.

But the intentional destruction of embryonic human life does not end with the completion of the MR process. The UK protocol for PNT or MST seems to encourage clinicians to produce multiple three-parent embryos so that each can be genetically tested to ensure that only those carrying significant amounts of healthy mitochondria are transferred to their mother’s uterus. Although not explicitly stipulated, the implication is that those embryos will be destroyed who either have unacceptable amounts of mutated mtDNA in their cells or who might have sufficient amounts of healthy mtDNA but whose transfer risks high-order pregnancy complications.

Both MR techniques sunder the unity of marriage.

The one-flesh union of husband and wife grounds the unity of their marriage. As part of the marriage vow, the husband promises his wife he will be father only to her children and the wife promises her husband she will be mother only to his children. The third person in MR, the female who donates the mtDNA of her egg toward the production of the resultant embryo, disrupts the bond of unitive love that is of the essence of the parents’ marriage and their procreative endeavors. This third-party intrusion only serves to add insult to the fundamental moral injury of the IVF production of a three-parent embryo: the decision to generate a child outside the marital act of love.

Both MR techniques distort the meaning of parenthood and human procreation, deny the IVF child its basic right to life and to be loved unconditionally, and contradict the child’s fundamental equality with his parents.

The three-parent embryo is produced in vitro—in a petri dish in a laboratory—outside its mother’s body and outside a loving act of sex between its mother and father. Because our secular world has, for the past 37 years, uncritically accepted IVF as an ethical reproductive technology, it is difficult at this juncture to objectively assess the morality of using it for MR. Contrasting IVF with natural conception is the best way forward in this assessment process.

Consider, on the one hand, the child conceived within his parents’ loving act of sexual intercourse. He is not the object of his parents’ making, but the fruit of their love. The parents recognize their desire is not the only cause of their child’s existence and their desire’s goal is to respect the child as a gift freely given by God. The intentionality exercised in their conjugal act, then, is that of unconditional love for the baby. It would make no sense for such a child to say to his parents: “I exist because, and only because, you desired me.” The parents accept and love their child unconditionally—just because he exists—and value the goodness of his existence independently of their desires, their will, or their love. It would make perfect sense for the child naturally conceived to say to his parents, in effect: “I exist because you desired to make a gift of yourselves within a bodily act of union that was engraved with your deep desire for a baby; I came to be as the gift of God and the fruit and the crown of your act of self-giving love.”

This child has an existential appreciation for the fact that his parents freely provided the occasion and the gametic material so that God, according to his good design, chose to bring him into being. The parents, in turn, relate to their child as someone who is their equal, a rationally intelligent and self-determining person who desires to be loved in and for himself, just because he exists.

Consider, on the other hand, the IVF baby. The actions of the IVF technique of MR—the technical simulations of the merely procreative structure of the marital act—sunder the link between the baby’s procreation and his parents’ act of sexual love. These actions deny the IVF child the reciprocal self-giving act of its parents’ marital love. Separated from the interpersonal communion of spousal love, the fertilization of an embryonic human being in a petri dish becomes nothing more than a rational, productive action oriented to a goal. The parents’ intention to generate a child by means of IVF treats the child as a product and reduces him to the object of their production.

For this reason, IVF parents make the life of their child depend on their desires, on their will, and, therefore, on their power. Such power sets the IVF parents over against their child, creating a relationship riddled by gross inequity. The IVF child could think and, in effect, say to his parents: “I came to be only on the condition that your desires for a baby would be satisfied.” But this sort of existential dependence would contradict the child’s fundamental equality with his parents and with all other human beings.

As the product of his parents’ will, the IVF baby becomes a mere means, an instrument, for the satisfaction of their desire for children. There is no other way to put it: the IVF parents use the child as an instrument to fulfill their desires.

So, in its normative practice, the IVF technique of MR (with its ancillary practices of the deliberate destruction of human embryonic life) is a chosen mode of action by which parents and doctors intentionally deny the child not only his fundamental right to be loved unconditionally, i.e., to be conceived, gestated, and born into marriage, but also the child’s basic right to life.

MR promotion exploits the women who donate their mitochondria.

Women who donate their eggs for IVF techniques like MR risk adverse health events. Ovarian Hyperstimulation Syndrome is the most immediate and, in the short and long term, memory loss, bone ache, seizures, risk of stroke, organ failure, infection, cancer, and even loss of fertility. Since no agency within the IVF industry is systematically tracking the rate at which any of these health risks occur, the women who donate their eggs are hampered in giving a truly informed consent to the procedure.

Many predict the great need for eggs for MR will only lead to increased exploitation of prospective donors. And if, like egg donors in the UK, US donors are offered generous compensation from IVF clinics, they could also become victims of psychological exploitation. How can prospective female donors—especially the economically disadvantaged who are frequently targeted—make prudent medical decisions when the “carrot” of financial reimbursement and healthcare discounts is dangled in front of them?

Furthermore, the UK law stipulates that the identity of mitochondrial donors will be kept anonymous, even though anonymous egg donation is prohibited in Britain. It seems discriminatory to treat women who donate their mitochondria differently than women who donate their entire egg. The mito-donor’s name should be available so that three-parent children could, at the minimum, identify the woman who shared her mtDNA for the benefit of their health.

MR endangers the human genome.

Even if, theoretically, this technology might prevent mitochondrial diseases in some people (and some reputable scientists think that is a big if), “the bottom line is that there is an equal or arguably greater chance that it will tragically produce very ill or deceased babies,” as Paul Knoepfler, MD, stem cell researcher at the University of California Davis School of Medicine, put it. And, because MR constitutes germline genetic engineering—genetic modification of the germ cell of the egg or the whole embryo—any or all genetic errors that occur as a result of MR will be inherited, that is, passed on through child-bearing females of one generation to the male and female children of the next. The moral tragedy of risking genetic errors is that there is no way for those who use MR today to be accountable to those in future generations harmed by unsuccessful modifications of their predecessors.

MR represents a new form of eugenics.

Stuart Newman, New York Medical College Professor of Cell Biology and Anatomy, unmasks MR’s “correctionist” brand of eugenics:

One factor in placing these [MR] procedures on the social agenda seems to be the conflation of biological modification of people who do not yet exist with medical treatment of actual sick people. The attempt to improve future people is not medicine, however, but a new form of eugenics. In its willingness to risk producing damaged offspring by modifying embryos’ genomes, this “correctionist” eugenics goes even beyond the “selectionist” version of the forced sterilization programs for criminals and others considered biologically inferior conducted in the United States and Europe throughout most of the 20th century (and brought to an extreme in Nazi Germany). Activities that are clearly covered by the Nuremberg Code prohibiting nonconsensual human experimentation are recast by proponents of gene-altering technologies [like MR] as within the alleged rights of parents to exert proprietary control over the characteristics of their prospective offspring. It must be emphasized that such hypothetical rights are not at all the same as the inviolable commitment of parents to the health and well-being of their existing children. The genetic design of future offspring, even with the limited objective of making these future children more “normal,” will open the door to attempts to pick and choose other characteristics, because definitions of normality will vary, as will access to technology to take risks with future lives.

III. Refute misrepresentations of MR

The following arguments are based in large part upon Jessica Cussins’ “Eight Misconceptions about ‘Three-Parent Babies.’”

“MR will eliminate mito-diseases in future children.”

Even if MR were to work perfectly, it could not guarantee the three-parent children will be free of mito-disease, since the majority of mitochondrial diseases are caused by mutations in nuclear DNA, not in mtDNA.  

“MR will be in great demand because one in 200 babies is born with mitochondrial diseases.”

The UK’s Human Fertilization & Embryology Authority (HFEA) fails to make clear that this statement, repeated on the agency’s website, is not referencing the incidence of persons suffering from mito-diseases, but rather the incidence of mitochondrial mutations in the general population. Estimates for the number of individuals who do have mitochondrial disease is one in 5,000-10,000 people. And, as already noted, only 15 percent of these cases are caused by mutations in mtDNA. Of the 15 percent, only women with a very high level of mutation would be eligible for MR. The HFEA has estimated that, in the UK, around 10 women a year would be eligible for the procedure.  

“MR will save lives.”

Although the chief medical officer for Britain, Dame Sally Davies, described MR as a “life-saving treatment that will save around 10 lives a year,” the fact is MR is not a treatment for any person currently suffering from mito-diseases. Its goal (if it works) is not to save anyone’s life but to prevent a mother from transmitting her faulty mtDNA to her biological, IVF-generated child.

“MR has been adequately studied in animals and, therefore, is safe.”

In the 1990s there were a number of studies using PNT in mice. When the UK’s HFEA required its Newcastle University researchers to test PNT on a non-human primate model, the researchers failed to comply. And when the Oregon Health and Science University research team tried PNT on macque monkeys, they eventually abandoned it because the three-parent embryos died early in their development. In response to the failed Oregon macque experiments, the HFEA simply withdrew its requirement for PNT testing on non-human primates.

Reputable scientists argue the Achilles heel of doing MR in 2015 is this: it is an attempt to use a technique that involves mtDNA before geneticists have thoroughly studied the mitochondrial genome and before they have sufficiently understood the complex interactions between the mito-genome and the nuclear genome. As Knoepfler wrote in his open letter to the UK Parliament, “A scientific reality often passed over in this discussion is that while mitochondria have been studied for decades, the field of studying the mitochondrial genome is in its infancy and is far too new to support a major human intervention that involves the mitochondrial genome. The interactions between the mitochondrial genome and the nuclear genome are also only poorly understood today. It would be rash and premature to proceed with human mitochondrial transfer now given how primitive our knowledge is in this area at this time.” Given our ignorance and given the intergenerational risks, these scientists contend it is irresponsible to pursue MR especially when, given the big margin for genetic error, mistakes can never be erased.

“A majority of the public supports MR.”

On March 20, 2013 the HFEA put out a press statement indicating they had received broad support for MR from the general British public. But that seems to contradict the fact that a majority of those who participated in the online questionnaire (the line of public feedback that HFEA, by its own admission, described as most important) indicated disapproval of the introduction of either pronulear transfer or maternal spindle transfer.

“Except through MR techniques, women with mutated mtDNA have no other family-building option.”

A woman who does not wish to pass on faulty mtDNA to her offspring has other options to family building. She and her husband can adopt children, take in foster children, or mentor troubled children. As Humanae Vitae #10 teaches, this couple would be morally justified—for the serious reason of wanting to prevent transmission of mito-disease to their children—in using a natural system of family planning to avoid a pregnancy indefinitely. The benefits to the couple of pursuing adoption, foster care, or mentoring at-risk children—bringing the couple’s love to its perfection by giving life to other people’s children—are that these options completely avoid the moral evil of destroying embryonic human life, disrupting the unity of their marriage, depriving the child of their unconditional love, and harming the human genome.

“MR will not lead to more controversial practices; the slippery slope argument is exaggerated.”

Pete Shanks has written the best deflection of the exaggerated slippery slope allegation, published here.

Based on precedent, in the world of assisted reproductive technology, doing A has concretely led to doing the more controversial B, C, and D. Doing IVF for infertility using husband’s sperm and wife’s egg led to doing IVF for infertility using extra-marital donor gametes, which led to doing IVF for sex-selection, which led to doing IVF to identify and eradicate embryos with genetic diseases. Given this history, if doing IVF for MR appears to work, what precisely would stop advocates from wanting to use IVF to replace nuclear DNA to prevent transmission of nuclear DNA mito-diseases? And if that would work, what would stop proponents from using nDNA modification for the eugenic purpose of producing children with the “good genes” of whatever attributes and characteristics—physical prowess, beauty, intelligence—appeal to parents’ desires?

“The genetic contribution of the mito-donor is inconsequential.”

The best response to this claim is that of New York Medical College’s Stuart Newman (quoted here):

If mutations in different mitochondrial genes affect different organs (which they do), how can it possibly be maintained that mitochondrial genes only help produce mitochondria? Impairment of mitochondria impairs development—that’s how the diseases are produced. Genetic variation (even within a normal range) leads to phenotypic variation. The inescapable conclusion is that normal variations in mitochondrial genes must have differential effects on developmental outcomes.

In other words, mtDNA affects phenotype or the external characteristics of a person as it can impact cognition, aging, cancer, adult onset diabetes, and deafness. It follows then that the MR technique is much more complex than swapping out a bad car battery for a new one.

“Mito-donation is no more dangerous or controversial than organ donation.”

The donation of mtDNA is completely different from ordinary organ donation by the fact that the donated mito-genome: 1) changes every part of the recipient’s existence with its continuous interaction with nuclear DNA; 2) can have unforeseen complications on the recipient later in life; 3) changes the recipient’s genetic identity which is then transmitted—for better or worse—to successive generations; and 4) presumes the recipient’s consent.

IV. Let the voice of reason be heard!

Armed with: (1) an adequate knowledge of the science of MR; (2) the ability to identify and correct misrepresentations from MR advocacy groups; and (3) a comprehensive grasp of the moral case against MR, compose a succinct, cogent statement explaining your opposition to MR and its production of three-parent embryos and present it to the Institute of Medicine.

The IOM Consensus Committee will hold 2015 meetings open for public comment on March 31 (8:30 AM – 5 PM) through April 1 (8:30 AM until noon) and on two dates in May, to be announced. If you live in the DC area and wish to present your position statement orally, simply show up at the Institute of Medicine on those dates (500 Fifth St NW). If at a distance, submit your comments either by email (MitoEthics@nas.edu) or by US mail (Attn.: Michael Berrios; Institute of Medicine; 500 Fifth St NW, Washington, DC 20001).