A Third Parent contributes her Mighty Mites (Mitochondria)

Two biological parents are enough for any baby, aren’t they? Maybe not: sometimes it’s better to have two mamas.

The media have hyped a story that broke in September about a boy who was conceived by “mitochondrial replacement therapy.” His parents had lost two previous children to Leigh syndrome, a rare but severe condition affecting the brain, nerves and muscles caused by mutations in mitochondria, the mites that energize every cell inherited from our mothers’ egg (never from our fathers’ sperm). Less than 2% of the boy’s mitochondria were damaged, which was well below the 18% threshold for disease. An anonymous egg donor has given him the prospect of a full and healthy life.

Mitochondrial transfer
Thousands of tiny mitochondria fluorescing brightly in a human egg and its moon-like polar body

John Zhang, whom I knew when I worked in NYC, led the clinical team and is director of a fertility service that is popular there among Asian Americans. But he carried out the procedure in Mexico where, according to reports of his words, there are “no rules (for assisted reproduction).” That statement was as responsible for the media furor as the procedure itself, and he may regret playing into the polemics of conservatives at a time when Mexico is considering legislation for assisted reproduction. Ahem!

His “breakthough” probably put noses out of joint in a Newcastle team in my mother country because they have done the painstaking research work. The UK has often been at the forefront of reproductive technology (clinical IVF, Dolly the cloned sheep, etc.), and has a well-respected system for ethical review (HFEA) which, admittedly, delays the launch of new treatments such as this projected to help 10-20 British families annually. The Geordies should have been first, but were scooped.

Two methods exist for switching mitochondria when a prospective mother carries a harmful load of mutations in her mitochondria. Zhang chose the spindle method in which maternal DNA is transferred to replace the nuclear DNA removed from a healthy donor egg before it is fertilized with her husband’s sperm. Only one of the five embryos thrived in vitro, but after placing in the uterus it conceived a healthy pregnancy.

In the 1990s, a New Jersey clinic transferred small fractions of cytoplasm from donor eggs to improve the quality of eggs for patients who repeatedly failed with IVF treatment. None of the women were carrying mitochondrial mutations, but the clinical team had a hunch that eggs often fail to develop if they are under-energized, but can be boosted with an infusion of fresh mitochondria. After treatment resulting in 17 viable pregnancies with two of the girls missing an X chromosome (Turner’s syndrome), the FDA set a bar too high for the program to continue.

There are now reports from other countries of imminent births after mitochondrial transfer, and these too are said to aim at improving embryo quality instead of correcting a genetic fault. And in Boston a company is offering an expensive treatment (‘Augment’) for improving fertility by transferring mitochondria from a type of ovarian stem cell that some of us doubt exists (my recent critique is available on request).

These therapies have been called ‘eugenic,’ which is a word that makes us shiver, but if they are safe and effective and purely aim to restore a healthy population of mitochondria, need we worry? Some commentators have called the boy in Mexico a GMO baby, but that’s strictly inaccurate, because the mitochondrial genome containing a mere 37 genes and 0.0005% of the nuclear DNA was switched, not chemically altered. Moreover, there is no basis for concern about transmitting his new mixture of mitochondria to future children, although a girl treated likewise could and that possibility requires deeper study. We can’t be sure how her mitochondria would segregate in the bottleneck when eggs inherit tiny numbers of them, possibly creating a very different mix compared to her grandmother and donor, even the remote possibility of bringing back the former disease to her descendants.

Robert Hughes coined the expression Shock of the New for a TV documentary about modern art, but it is an apt expression for public responses to the ongoing revolution in fertility treatment. I imagine hands lifted in horror after every new development is announced, but it would be a hard person who condemns joyful parents by saying their healthy children “should never have been born!” The arrival of healthy babies quenched most opposition to IVF in the 1980s, and I predict the same for the next generation of therapies provided they meet the same standard of ethics and safety.

Human fertility has been said to be the prerogative of God or the gods. The Ancient Greeks had a hoard of myths, and woe betide gods or mortals who broke the reproductive code! Hera was the patron of marriage and childbirth, yet she covered the shame of being raped by Zeus by marrying him. She ate lettuce to improve her fertility, probably because its white sap resembles semen, which is something to think about next time you are served a salad.

One of her sons was Hephaestus. The virgin goddess Athena fled when he lusted after her (he was ugly), but spilled his seed on the ground, which caused Gaia, the Mother of the Earth, to conceive Erichthonius (“Eric” for shorthand). Athena made no biological contribution to Eric, but she was the object of desire and necessary for his conception, and afterwards she helped to bring him up. She was the third parent, and no less for that.

Eric looked so monstrous that he alarmed people and they tried to conceal him (depicted by Peter Paul Rubens). The Greeks were pondering extraordinary conceptions long before we added a third parent by  surrogate pregnancies with IVF or mitochondrial transfer. They posed the question whether a parent is defined by nature or nurture, but the answer is, of course, nature and nurture, and three parents can be better than two.

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