By Stuart Newman

from GeneWatch 27-3 | Sept-Nov 2014

Techniques now exist for generating infants which, if implemented, would constitute the first cases of large-scale human genetic engineering. These techniques are widely referred to - by their scientist-creators and other proponents, by journalists, by bioethicists, by members of regulatory panels, by legislators, and even by some critics of the procedure - as "mitochondrial transfer" or "mitochondrial replacement." These descriptions are not only scientifically inaccurate, they are also easing the way to public acceptance of these manipulations.

What exactly are these techniques? An isolated nucleus from the egg of one woman is inserted into an enucleated (nucleus-lacking) egg of another woman. Done before fertilization, it is called "maternal spindle transfer" (MST). Done after, it is called "pronuclear transfer" (PNT). In fact, no transfer of mitochondria (the organelles that extract energy from fuel molecules and make it available for the cell's functions) is involved in these "three-parent" procedures. So why are they referred to as mitochondrial "transfer" or "replacement"?

The techniques are being promoted as a way of circumventing mitochondrial mutations, which can lead to severe disease. It is understandable that an affected woman who intends to become pregnant would seek to avoid passing down this genetic predisposition to her offspring. Methods such as MST and PNT represent radical interventions in the reproductive process that, if accurately portrayed, would stir fears in prospective parents and rightly attract the attention of legislators and regulators. The laboratory scientists and doctors for whom these women are clients (not patients - their own conditions are not being treated), thus have an interest in minimizing the perceived scale of what they are proposing to do.

Since it is true that nuclear genes of an affected woman or couple will eventually find themselves in the presence of mitochondria from a second woman, from the viewpoint of the first woman the mitochondria of her egg are "replaced." But this is only mitochondrial replacement in the sense that someone who moves into a new home may experience "refrigerator replacement," i.e., only by employing a highly idiosyncratic (and misleading) use of the term.

Focusing only on mitochondria ignores the other significant features of the second woman's egg such as its cytoplasmic and membrane composition and structure. Shifting attention in this fashion must raise questions about disingenuousness of the methods' proponents. In fact, the manipulation of the second woman's egg (i.e., the egg that will actually be implanted) constitutes a "genome transfer" or "genome replacement." Choosing a conceptual frame based solely on who is soliciting or paying for the procedure (i.e., the woman seeking to avoid passing on a genetic predisposition for mitochondrial disease) is not motivated by scientific or medical concerns.

In biological terms, both MST and PNT are very much like cloning by nuclear transfer, the methodology that produced Dolly the sheep. Like cloning, the techniques involve replacement of an egg's nucleus by a nucleus from another cell. When cloning, the transferred nucleus is from a differentiated cell of a fully developed animal (or potentially, a person), making the resulting organism a genetic "copy" of the nucleus donor. When undertaking MST and PNT, the transferred nucleus is from an egg or a fertilized egg, so that the resulting organism will have a novel genome. Otherwise, however, the hazards of cloning also pertain to MST and PNT, since the manipulations are the same. Clones tend to die prematurely, as happened with Dolly, or exhibit enlarged organs and metabolic abnormalities. Some human embryos constructed by MST unexpectedly had unbalanced chromosomal duplications (aneuploidy). This is the case because unlike the sorts of cellular aberrations repeatedly encountered over the course of evolution - breaks in DNA, the unfolding of protein molecules - the experimental combination of fragments of two broken cells generated by cloning or the two proposed techniques have no inbuilt mechanisms to correct the range of functional and developmental defects inevitably associated with their construction.

It is unfortunate that few science journalists have the training or inclination to assume a critical stance toward the assertions of the scientists they interview. It is therefore common to see these procedures described in the popular and scientific press as the mere replacement of the 37 mitochondrial genes (compared to the 20-25,000 of the nucleus). The scientists who promulgate the transfer/replacement imagery and those bioethicists who do the same know better. Indeed, bioethicists should be scrutinizing the scientists' practice and language as opposed to promoting their fantasies and business models. Their collusion in these deceptions is inexcusable.

Moreover, anyone familiar with the relevant science would have been aware, over the period during which the techniques were being evaluated by the British Human Fertilisation & Embryology Authority (HFEA) and the U.S. Food and Drug Administration (FDA), of evidence that mitochondria are not (as the impact-minimizing refrain has it) mere energy-providing organelles. The very existence of mitochondrial DNA mutations affecting hearing, vision, pancreatic function and neuromuscular activity (the justifications of the entire enterprise), would be enough to tell us this. Indeed, in the past two years the evidence for the non-passivity of the mitochondria has become inescapable. Since mitochondria are active participants in cell function and organismal development, integration among coevolved nuclear and mitochondrial systems would contraindicate arbitrary mixing and matching. (The engines of a Jaguar and a Rolls-Royce do essentially the same thing, but they are not interchangeable.) This adds an array of hazards to MST and PNT that go well beyond those they share with cloning.

A prospective child made by MST or PNT would be the result of an evolutionarily unprecedented experiment with known, or easily anticipated, hazards. Juxtapose this against the fact that the biological identity and long-term health of the three biological parents undertaking MST or PNT are not directly at risk in the procedures. It is, therefore, entirely unwarranted to make their perspective (or more specifically that of the nuclear gene donor) the one from which the procedure is judged, thereby allowing the techniques to be characterized as being of minimal impact. Rather, the perspective of the individual brought into being by the procedures should be paramount. Combining fragments of two damaged eggs to produce a human embryo is, despite the rhetoric of mitochondrial "transfer" or "replacement," large-scale manipulation of nuclear genes. Its backdoor admittance to the repertoire of assisted reproduction techniques in the guise of being a trivial tweak bodes ill for future attempts to regulate gene transfer methods for any other purpose.

A kind of omertà among scientists and bioethicists has prevented a significant number of them from representing to the HFEA and FDA, and the press, the gravity of these alterations. But the health implications and the eugenic outcomes these procedures would enable are too great to ignore.


Stuart A. Newman, Ph.D., is Professor of Cell Biology and Anatomy at New York Medical College.


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