"Three-Person IVF" Update Reveals How Little We Know

Three-person IVF is a critical departure from the traditional kind. This new and biologically extreme technique, which has generated scientific and bioethical controversy on both sides of the Atlantic, would combine genetic material from one man and two women in a single embryo. It is currently prohibited in the United Kingdom, but has been heavily promoted by its developers, and the law could be changed as soon as this year to allow it to move into fertility clinics.

The technique under consideration is being proposed for women with a rare form of mitochondrial disease who wish to have an unaffected and mostly genetically related child. It requires the extraction of the nucleus from her egg or embryo followed by its reinsertion into another woman's egg or embryo. Any resulting child would inherit nuclear DNA from the intended mother and mitochondrial DNA from an anonymous egg provider.

The UK's fertility regulator, the Human Fertilisation and Embryology Authority (HFEA) has just released an update on the safety and efficacy of this "three-person IVF." The HFEA report will help inform the upcoming Parliamentary vote on whether to make an exception to the UK law that currently prohibits inheritable genetic modification of humans.

The HFEA panel's strongest statement of endorsement is that "the evidence it has seen does not suggest that these techniques are unsafe." The HFEA has been saying this for three years now, and it should not be interpreted to mean that the techniques are safe.

In fact, the report acknowledges that "there are still experiments that need to be completed before clinical treatment should be offered."

One set of experiments that is considered "essential" is the study of cells of early embryos created via these techniques to determine the levels of heteroplasmic mosaicism, which could include an amplified proportion of carryover mutated mitochondria. If this is found, it could severely compromise the health of a future child and lead to him or her developing mitochondrial disease down the road.

Other embryonic experiments that are recommended prior to use in humans include an analysis of the number and appearance of chromosomes found in cells, a detailed analysis of epigenetic modifications and gene expression, and the use of induced pluripotent stem cells derived from patients carrying different mitochondrial mutations. This final study would be of particular value since, barring one study in mice in 2005, there have been no experiments done on eggs or embryos that actually have mutated mitochondria.

In addition to these important proof-of-concept studies that have not been completed, the report also mentions that there have been some worrying outcomes in past studies. For example, in 2011, the HFEA considered proven success of pronuclear transfer (PNT) in a non-human primate model to be "critical." Then in 2012 the agency found that "[f]rom unpublished data it appears that Macaque zygotes do not survive the PNT process well." Instead of heeding this huge red flag, the HFEA simply rescinded the requirement of any primate model at all. This reversal was explained as a concession to the argument that continuing experiments on macaques would be "unethical." Does that imply that the decision makers are exercising less caution with humans?

Here is the HFEA's response to the inherently high degree of uncertainty and risk that this technique would pose:

"The panel strongly recommends that permission is sought from the parents of the children born from MST or PNT to be followed up for an extensive period... 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 her child, and if female, subsequent generations at risk of mitochondrial disease."

Elsewhere in the report, the panel makes a small concession to the huge ethical, social and political implications of these procedures:

"Furthermore, although not within the scope of this review, it is important to note that issues other than purely scientific need also to be considered."

These issues include the increased need for young women's eggs, the ethical dilemma of turning children into medical and social experiments, and the global policy implications of a decision that would cross the crucial line of manipulating the genes of future children and generations.

As the Center for Genetics and Society states in its press statement, it would be a shame "to let enthusiasm for novel technologies trump the need for clear evidence and for serious consideration about the policy implications of a decision on these controversial techniques."