The Truth about Mitochondrial Replacement

Françoise Baylis disputes popular descriptions of mitochondrial replacement as much needed treatment to avoid the birth of children ‘born to suffer’.

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The United Kingdom’s House of Commons recently voted to amend the Human Fertilisation and Embryology Act 2008 to permit heritable genetic modification using a technology called mitochondrial replacement. This technology involves the creation of an embryo using the genetic material from three individuals: a man who contributes nuclear DNA; a woman who contributes nuclear DNA; and a woman who contributes mitochondrial DNA.

Usually, embryos are created using the sperm of one man and the egg of one woman. The sperm contains nuclear DNA and the egg contains both nuclear and mitochondrial DNA. Some women, however, have diseased mitochondrial DNA. If these women reproduce, they could pass their mitochondrial disease along to their children. This could mean serious health problems for these children including neurodegenerative disease, stroke-like episodes, blindness, and muscular dystrophy. To avoid the birth of children with these types of mitochondrial diseases, scientists want to replace the woman’s unhealthy mitochondrial DNA with healthy mitochondrial DNA from an egg donor, and then create a healthy embryo using IVF. The donated mitochondrial DNA would be passed on to the children, and the children’s children, and so on for generations. This vertical transmission of mitochondrial DNA from one generation to the next has given rise to the debate about the ethics of heritable genetic modification.

In the wake of the House of Commons historic vote (382 to 128 in favour of amending the Human Fertilisation and Embryology Act), Gillian Lockwood, the medical director of the Midland fertility clinic, maintains there is a need to educate those who still “have anxieties” about mitochondrial replacement technology. This is an interesting perspective given that for the past several years the UK public has had plenty of education (some would say indoctrination) by scientific and government organizations about the “need” for this technology so that families can have healthy genetically-related children free of mitochondrial disease.

"Ragged red fibres - gtc - very high mag" by Nephron

“Ragged red fibres – gtc – very high mag” by Nephron

To put this “need” in perspective, recent calculations suggest that mitochondrial replacement could benefit about 150 births per year in the UK. This would be the case if all women at risk of having a child with mitochondrial disease chose to reproduce using mitochondrial replacement and IVF. Quite clearly, however, it is highly unlikely that this number of women would choose to reproduce in this way – because of the risks to themselves and their potential offspring, as well as the costs involved.

First, women with mitochondrial disease who become pregnant are at increased risk of pregnancy complications including gestational diabetes, pre-eclampsia, and preterm delivery. Second, the short- and long-term risks to children born after mitochondrial replacement are unknown and may take years to identify. This is especially so as this new technology will be offered as a therapy, outside the context of a clinical trial where careful long-term follow-up to identify and deal with unintended consequences could be mandated. Third, mitochondrial replacement and IVF are not cheap. At this time, the cost of mitochondrial replacement is unknown. The cost of one IVF cycle is between £4000 and £8000, and a woman might need as many as four IVF cycles to become pregnant (the success rate of IVF in the UK is estimated at 25% per cycle). For these and other reasons, some women might take their chances with natural reproduction, some women might chose IVF with donated eggs, some women might choose adoption or foster care, and some women might remain child-free.

Why highlight these facts? Because the pursuit of all scientific and medical advances comes with opportunity costs. The time, talent, and energy devoted to possibly helping “less than 150 women per year” have healthy genetically-related children free of mitochondrial disease (when there are other available options) could be better spent on other public health goals that would benefit considerably more people.

In response to this claim, some might argue that mitochondrial replacement is not just about helping (less than) 150 women per year who have mitochondrial disease. Indeed, Shoukhart Mitalipov (the first scientist to clone human embryonic stem cells) has suggested that mitochondrial replacement might be useful in treating age-related infertility, which affects thousands of women per year in the UK and around the world.

As well, there are those who might insist that this technology is an important scientific breakthrough, the benefits of which cannot be known or anticipated. This may well be true, but just as we can’t know or anticipate the benefits, we can’t know or anticipate the harms.

If we are to have honest conversation about the possible future benefits and harms of mitochondrial replacement, we should start by acknowledging that discussions to date have been a distraction. Arguably, framing the science as primarily a benefit for families at risk of mitochondrial disease has been a sophisticated advertising campaign to garner public support for legislative change to ultimately allow human cloning for reproductive purposes. The real ethical issue is volitional evolution (the intentional genetic shaping of human purpose) about which considerable, informed ethical debate is both needed and warranted.

Being honest about the past will better enable us to be honest about the future.

Addendum: In Canada, the use of mitochondrial replacement to create a human being is illegal. The Assisted Human Reproduction Act 2004 prohibits altering “the genome of a cell of a human being or in vitro embryo such that the alteration is capable of being transmitted to descendants.”

Listen to: 3-Parent babies: Genetic modification sparks debate on evolution – Feb 5, 2015

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Françoise Baylis is Professor and Canada Research Chair in Bioethics and Philosophy at Dalhousie University @FrancoiseBaylis

2 comments

  1. Michael Crawford · · Reply

    We are inherit three genomes – one each in the form of maternal and paternal chromosomal genomes, as well as a mitochondrial genome from our mother. Insofar as three parent embryos would be produced by the combination of three discrete and intact components (no genes altered) derived from gametes, the warning for potential abuse via human cloning seems a little overstated. Cloning from adult cells requires “conditioning” of the parental genome to acclimate it to behave like the genetic material carried by gametes. This is technically challenging: witness Dolly the sheep – she was the 277th attempt to get it right. Moreover, many of the failed attempts had adverse consequences upon the host mother. Who would want to bear the expense, risk, and liability?

    There are more compelling ethical and practical reasons to question the advisability of attempting three parent embryos.

    First, enucleating a donor egg to provide a cell with mitochondria is technically challenging and damages eggs. Mouse studies in which parental nuclei were placed into enucleated eggs had very low success rates (Davor Solter’s group). Moreover, there will presumably be leakage of cytoplasm during enucleation. What will be the consequences of this leakage to the host egg? Cytoplasm to nuclear volume ratios are critical to early cellular programming.

    Second, getting nuclei into an enucleated egg is no trivial matter… This was originally achieved by microinjection (potential for shearing and damaging genetic material). More recent technologies involve electrically shocking eggs, or of using an attenuated virus to merge genetic material with host eggs. How would this affect health prospects in an organism that might live 80 years? Who could afford or be willing to produce the hundreds of eggs necessary to reach technical success?

    Third, the new embryo could be contaminated during nuclear transfer by carry-over of mutant mitochondria from the afflicted mother. Although this carry-over would likely represent a very small number of mitochondria, either the mothers or their eggs originally carried a survivable mix of both normal and damaged mitochondria (they were heteroplasmic) – the damaged ones amplified more rapidly to achieve majority over their normal counterparts in the offspring’s cells. Admittedly, transfer contamination would add very small numbers of damaged mitochondria to the thousands present in the host egg, however small numbers of mutants could grow over time or generations to produce the same effect. For example it is conventional wisdom that only the mother contributes mitochondria to an embryo, however it is possible that the few dozen sperm (paternal) mitochondria actually make it into the embryo and can contribute (Ladoukakis ED, and Eyre-Walker A. Heredity (Edinb). 2004 Oct;93(4):321; refuted by Bandelt,H., Kong, Q., Parson, W., and Salas, A.. J Med Genet. 2005 Dec; 42(12): 957–960). One report has mitochondrial disease being transmitted from the father (Schwartz, M., Vissing,N Engl J Med, Vol. 347, No. 8 J. 2002, Aug 22).

    Until the risks that attend mitochondrial transfer and contamination during engraftment are known, inter-generational justice requires that we tread carefully. At this point we cannot say what the chances are that grandchildren, or great grandchildren will eventually be afflicted…

  2. Jacquelyn Shaw · · Reply

    Dr Baylis’ concern regarding the ‘opportunity costs’ of pursuing mitochondrial replacement fertility therapy seems likely to prove prophetic. At this point, more funding is needed for research on mitochondrial science generally (not simply in the context of fertility therapy) and seems far more appropriate, to allow us a greater ability to understand mitochondrial behaviour and anticipate any potential risks related to mitochondrial transfer. Not only are there (possibly grave) risks to the children who will be created by this new therapy, but there are also risks to young women, as mitochondrial replacement therapy may (if used broadly in treating age-related fertility problems) intensify the commodification of women’s reproductive capacity that we already see with global human egg markets. I suspect this new therapy is premature at best– only time will tell.

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