Last month, the UK government announced it would move toward human trials of a risky and controversial technique known as “mitochondria replacement” or “three-parent IVF.” The technique would combine the nuclear DNA from one woman, the mitochondrial DNA from another woman and the sperm from a man in a novel attempt to try to prevent passing on mitochondrial disease to a future child. The technique is currently prohibited by law in the UK (and in dozens of other countries) because it modifies the human germline (these genetic changes - and any unintended consequences - would be passed on to future generations,) so final approval requires a legislative change. With another round of public consultation pending prior to such a change, here are the top misconceptions proliferating about the efficacy, safety, public support, and societal implications of mitochondria replacement.
Misconception 1: Mitochondria replacement “will save lives."
It’s troubling when media accounts sloppily represent these techniques as “saving lives.” It’s worse when scientific and government officials mislead in this way. But it’s been far too common. Chief Medical Officer for England Dame Sally Davies, for example, claims that mitochondria replacement is a “life-saving treatment” and “will save around 10 lives a year.”
Fact: Mitochondria replacement will not save any lives; it is not a treatment for any of the people who are currently suffering from mitochondrial disease. Its aim is rather to create a prospective child who would be genetically related to a mother affected by the condition, and who would (if the new technique worked) be healthy.
Misconception 2: Mitochondria replacement techniques will eliminate mitochondrial disease in future children, which no other technique can achieve.
Fact: Both aspects of this premise are misleading. First, even if the techniques were to work perfectly, they wouldn’t be able to guarantee a child free of mitochondrial disease because in the majority of cases, the conditions are caused by anomalies in nuclear DNA. They can also occur due to spontaneous mutations or with age. Furthermore, the HFEA acknowledges that mitcohondria replacement may not even be effective at removing all of the mutated mitochondria from a future child. Annex VIII of its final report states:
"The panel recommends that any female born following MST or PNT should be advised, when old enough, that she may herself be at risk of having a child with a significant level of mutant mtDNA, putting this child or (if a female) subsequent generations at risk of mitochondrial disease. Thus, we recommend that any female born following MST or PST is advised that, should she wish to have children of her own, that her oocytes or early embryos are analyzed by PGD in order to select for embryos free of abnormal mtDNA." (page 5)
That leads to the second point – there is already a safe available technique (preimplantation genetic diagnosis or PGD) that allows carriers of mtDNA mutations the ability to have healthy children of their own. If the HFEA recommends that girls born after mitochondria replacement use the technology, then why wouldn’t a woman simply use it in the first place? Even women with high levels of mutations in their own mitochondria can produce eggs with very low levels in most cases; PGD can find those embryos and (with a high rate of success) implant them back into a woman to produce a healthy child.
Misconception 3: This technique would be in high demand because one in 200 babies is born with mitochondrial disease.
Many news articles (particularly early on) bought into this, likely because the HFEA’s website states that, “Around one in 200 children are born each year with a form of mitochondrial disease.”
Fact: This is an extremely misleading way to discuss the incidence of mitochondrial disease. The HFEA seems to be relying on findings that around one in 200 people in the general population have mutations in their mitochondrial DNA, but most of these people will not experience any negative impact. Estimates of the number of people who actually have mitochondrial disease run around one in 5,000-10,000. Their conditions run the gamut from very minimal to quite debilitating. But only about 15% of these cases are likely caused by mitochondrial DNA: the majority of mitochondrial disease is caused by interactions with nuclear DNA. Of this greatly reduced subset, it is only women with a very high level of mutations who would be potential candidates for using mitochondria replacement rather than PGD to have a genetically related healthy child. Officials at the UK’s Human Fertilization and Embryology Authority and at its Department of Health – both agencies that are advocating moving forward with mitochondria replacement – have estimated that perhaps 10 women a year would consider the procedure.
Misconception 4: The techniques have been proven to work in animals.
For example, the Guardian states here that “The procedure has been shown to work in animals.”
Fact: There were a number of studies done mostly in the 1990s using one kind of mitochondria replacement technique (pronuclear transfer or PNT) in mice (see footnotes 3 – 6). However, the HFEA required that researchers at Newcastle University test PNT on a non-human primate model, which they never did. A research team in Oregon did try PNT on macaque monkeys, but found it to be unsuccessful, with embryos failing early, and thus abandoned PNT. They have shown success using another kind of mitochondria replacement (maternal spindle transfer or MST), although the monkeys are still young and no further generations have been studied. This knowledge has not deterred Newcastle,or the HFEA, from pushing for human trials of PNT. The HFEA’s response to the failed macaque experiments was to drop the requirement (see page 21) for non human primate testing.
Misconception 5: There is broad public support for mitochondria replacement techniques.
The HFEA put out a press statement on March 20 which cited “broad support for permitting mitochondria replacement” as the general conclusion of its public consultation on the techniques. This was consequently repeated by nearly every media report on the consultation.
Fact: By far the largest number of people (over 1,800) who took part in any of the different “strands” of the HFEA’s consultation were involved with the online open questionnaire. The majority of these participants wrote to say that they disagree with the introduction of either mitochondria replacement technique (PNT or MST.) In its past consultations, the HFEA has presented this strand, as the only portion which is open to everyone, as the most important. In this case, the HFEA is downplaying it.
For more on the numerous ways in which the HFEA has misrepresented its own data by claiming “broad support” from the public, see this blog post.
Misconception 6: The genetic contribution of the donor of mitochondrial DNA is inconsequential.
This is another claim that has been made repeatedly. For example, Doug Turnbull, Professor of Neurology at Newcastle University said, "Mitochondrial genes only help produce mitochondria. They have absolutely no role in any other characteristics.”
Fact: This statement is quite misleading. It is true that mitochondrial DNA constitute only 37 genes, but that does not mean they do not have significant phenotypic effects. Mitochondrial DNA has an impact on cognition, aging and cancer, adult-onset diabetes and deafness, and interacts consistently with nuclear DNA. Among other things, mitochondrial DNA provides metabolic energy during embryonic development, which clearly has a large impact on phenotype.
Responding to Turnbull’s claim, New York Medical College Professor of Cell Biology and Anatomy Stuart Newman said:
"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."
Misconception 7: Mitochondria replacement is just another kind of IVF
Numerous media accounts have referred to “3-parent IVF” or called mitochondria replacement an “IVF treatment,” and some have compared the initial uncertainty around the safety of IVF to the current uncertainty about the safety of these techniques.
Fact: There is a critical difference, which Stuart Newman sums up well in The Huffington Post:
"Unlike in vitro fertilization (IVF) which generates embryos from the biological components that evolved to serve this function, the two methods under consideration by the HFEA de- and reconstruct the fertilized egg in radical ways, unprecedented in the history of life."
Misconception 8: The “slippery slope” argument is overstated; no one wants to modify nuclear DNA.
If human trials of mitochondria replacement are approved, it would be the first time that any government has authorized genetic changes that would affect future children and their descendants. Such procedures – known as human germline engineering – have been prohibited by dozens of countries because of concerns that they would open the door to a new form of high-tech eugenics, with profound societal consequences.
Some advocates of mitochondria replacement simply dismiss these concerns, rejecting them as a “slippery slope” argument.
Fact: If mitochondria replacement is allowed, there will almost certainly be increased pressure to permit modifying nuclear DNA in the name of preventing diseases. For example, Robin Lovell-Badge, head of developmental genetics at the MRC National Institute for Medical Research, told Wired that there’s no point in worrying about germline modification, but then went on to state,
I do not argue that germline genetic modification of nuclear genes should never be considered, for example, parents might accept modifications that would protect their child against diseases such as AIDS. However, we do not yet have the technology or knowledge to guarantee that any such genetic alteration would be safe.
Well, we don’t have the technology or knowledge to guarantee that PNT would be safe either. (In fact, Newcastle University did not submit any published material to the HFEA’s safety review.)
The reason there has been an international consensus against human germline modification is that it is incredibly hard to draw a line anywhere else. Lovell-Badge proves that point above. If this line is crossed for the prevention of certain kinds of diseases, there will be increased pressure to research and fund other kinds of genetic prevention – in spite of safer alternatives in very nearly every case, as there are with mitochondrial disease.
And if interest and money begin flowing into development of germline genetic modification, it is naïve to imagine that there would not be fertility clinics willing to offer couples the ability to choose “designer” traits of their liking, and some who would argue this is simply a matter of reproductive choice.
But when the facts are presented without misrepresentation, the case for mitochondria replacement – as for other kinds of inheritable genetic modification – is flimsy at best.