Her heart beat in frightened counterpoint
to the rhythm of the mitochondrion.
— Madeleine l’Engle, A Wind in the Door (1973)

As you’ve likely heard, we’re doomed. Earth will soon be overrun by babies with three – three – biological parents each.

More parents per child will mean, of course, more colleagues hawking Girl Scout cookies next year. Facebook friend feeds, along with all organized toddler soccer, will become even less tolerable. If the news pleased anyone, you’d think it might be people who fret about families with too few parents. But it turns out that even they’re upset, now that children might have too many genetically invested adults caring about them.

All this because American and British regulators may endorse women replacing faulty mitochondria in their eggs, with working ones from other women, in order to have healthy kids. As fertilizing eggs still requires sperm, such mitochondrial rescue really does make kids with three genomic parents. And yes, it willfully and heritably modifies human genomes in doing so.

But while those facts make juicy headlines, they’re actually old news. For a start, note that every way to have kids (except cloning) heritably modifies genomes — and does so, in part, to favor specific traits that parents like (in each other). And among those various ways to breed, Parenting v3, in particular, debuted not last month (or in the future) but in 1997.

Early three-parent outcomes were reviewed in 2001, when the FDA slowed things down in the US, to watch how healthy the first such toddlers stayed over time. Answer? Apparently as healthy as any other anecdotally small sample of teenagers. And now, with some of those kids heading to college, regulators are appraising a new version of mitochondrial rescue that cuts one of original method’s already evidently low risks.[1]

Ok, so three-parent baby stories apparently pop up like cicadas, every ~13 or 17 years, for a new chorus of buzz. With them, us, and regulators all brooding anew, keep a few points in mind:

Every human genome unites many parents.

If you worry that kids with three parents are somehow an affront to nature, remember that your own genome melds the DNA of not just three, but four other people. You call them grandparents.

Well, actually, your genome comprises DNA from eight people: your great-grand-parents.

Ok, wait, it’s really sixteen… You get the point. Formally, mitochondrial rescue (and any other trick to make a zygote from more than two people’s cells) just speeds up what villages have long done by serially remixing DNA in batch after batch of kids.

You may scoff at likening earlier generations of forebears to parents. But genealogically, the latter just bundle up the former. And here’s the bottom line: Your average great-great-great-great-great-great-great-great-great-great-grandparent gave you roughly a hundred times more DNA than a mitochondrial donor gives her three-parent child.

By that measure,[2] your own birth should have been tabloid news (‘4096 parents!’). That it wasn’t so says much less about genetic inheritance than, perhaps, about our tangled obsessions with sex and technology.

Yes, mitochondria are heritable. Sometimes.

Future lab methods may let men transmit mitochondria to kids. But for now only women can do so. As such, only about half of kids born today (whether conventionally or by mitochondrial rescue) can pass on mitochondria at all.

So yes, mitochondrial rescue heritably alters genomes, but only for daughters — and specifically, those who grow up healthy enough to securely have kids of their own. Which circularly underscores the point of effective mitochondrial rescue in the first place.[3]

And more pointedly, old-fashioned two-parent breeding heritably alters genomes too (if that means we should ban sex, well, good luck to us…).

Donors and their kids are just like cousins, via time travel.

A key twist to mitochondrial rescue is that mothers hand down their mitochondrial chromosomes whole, without the recombination that, over generations, splits other chromosomes to smithereens. As such, your own ring of mitochondrial DNA is a tiny but sturdy heirloom, inherited — typically fully intact[4] — from a long chain of foremothers, the earliest of whom have given you nothing more of their genomes.

Which makes mitochondrial rescue like sneaking several centuries up into your family tree, with some grafting shears, to set up the last such woman’s father with a different mate. But crucially, and unlike most time travel, this trip brings no (great…) grandfather paradox for you: beyond swapping your mitochondrial type, it would leave no trace in your genome.[5]

In fact, it would leave you only faintly related — exactly like a distant matrilineal cousin — to your mitochondrial parent. Such gossamer kinship doesn’t typify parents and children today, but we know it well in adoptive and extended families. And as reproductive technologies advance, we can handle such new kinds of relationships just fine. If you aren’t horrified by cousins, don’t lose sleep over three-parent kids.

For those who most want it, mitochondrial rescue is much safer than conventional sex.

Methods of mitochondrial rescue carry three main kinds of risk: needle damage to cells; nucleus-cytoplasm incompatibility; and loss of transferred mitochondria. You can read about them in footnotes[6] below, but the evidence suggests that they’re each small.

As such, if you would ban mitochondrial rescue because it might make sick kids, you really should speak up to ban women with some mitochondrial diseases from having kids at all.[7] Because those born conventionally will be sick.

Mitochondrial rescue aims to give a child, whom a woman has freely decided to bear (a right that most societies recognize), a good chance at a healthy life at all. As such, rescue is simply some people’s safest way to have a baby — or to be born.[8]

This is about mate choice.

In discussing reproductive health, we often use ‘choice’ as a euphemism for abortion. But choice is a broader ideal in family policy, as strides in marriage and adoption law in many countries highlight.

Yes, mitochondrial rescue uses fancy tools to remix genomes, splicing our family trees in ways that might surprise the ancestors involved. But it does so for an age-old need that they’d readily understand: to let people find compatible mates. That is, having a healthy child means, for some women, picking two mates: one to provide working mitochondria, and another to provide a male-imprinted copy of each nuclear chromosome.

As ever, such mates don’t have to live together. They are, most simply, adults who agree to mingle DNA — a choice that we protect in everyday sexual freedom, egg and sperm banking, marriage, and other settings. And in mitochondrial rescue the three people who mate do so specifically for a potential child’s well-being; if only the same could be said of every conventional pregnancy.

Methods make real people.

Barring an apocalypse, reproductive technology will likely go far beyond mitochondrial rescue. We may see kids born with no new mating at all (clones) — and kids born to sets of many mates (more than just three). We may find ways for people of only one sex to have kids together, by epigenetically modifying chromosomes. And we may start editing human genomes, letter by DNA letter.

Such breakthroughs, like any technology, can help and hurt people. Many kids will grow up in loving families who otherwise couldn’t have had them. But others will suffer from adults’ hubris (‘Editing that codon didn’t do what we expected…‘), unfair demands (‘My clone will be the violinist I could have been…‘), or even crass neglect (‘Ladies and gentlemen, the 2020 Superbowl Champions’ commemorative child…’).

Having kids has always allowed harmful choices, of course. So new ways to breed, giving us often foolish adults more options, stand to steepen some already slippery slopes. But a bigger question will continue to loom: how we treat each new child, regardless of how (s)he came to be. And on that front, fretting about methods that are medically useful, but socially novel, risks stigmatizing real people born by them (think of prejudices long faced by people born outside conventional bounds of marriage or ethnicity…).

Moreover, such stigma can, in turn, deepen healthcare inequity, by discouraging insurers from covering needed procedures. Our track record there is mixed: IVF has become common, and its beneficiaries may now face little societal prejudice; but in some places it’s hard to find insurance for it. As such, mitochondrial rescue may be a good test case of how we welcome people born by methods that tinker ever more deeply with how we’re made, in order to have healthier kids.

Those three-parent kids are here among us already. They’ve celebrated many birthdays, and perhaps some quinceañeras and bnei mitsva, the latter from Hebrew for ‘children of a good deed’. Extra parents may not, of course, mean extra party gifts; but reaching such milestones, in good health, seems reason to celebrate.

A good deed, indeed.

Line of descent, London. (image by Nathaniel Pearson)

[l] The new methods reduce the chance that any of the original, faulty mitochondria remain in the developing child’s body.

[2] Some age-old phenomena can let one foreparent contribute even more than usual to your genome: there’s inbreeding, of course — but also uniparental disomy, where, by fluke of DNA replication in germline or early embryonic cells, both of a child’s copies of a given chromosome come from the same parent. In extreme such cases, a grandmother can provide more than a third of her grandson’s genome.

And that leaves aside other ways in which we’re already walking mixtures of cells from various parents, via maternal-fetal microchimerism, organ donation, and so forth…

[3] Some women born by rescue may even choose to swap their own kids’ mitochondria — perhaps even back to an earlier family haplotype, if particular mitochondrial diseases are otherwise readily curable a generation from now.

[4] New mutation, of course, can alter the heirloom as it’s handed down — sometimes causing the grave mitochondrial disease that makes mitochondrial rescue sensible.

[5] As such, a genome made by mitochondrial rescue looks much like any other: scanning just your own DNA, we couldn’t confidently say whether or not you were born by mitochondrial rescue.

By contrast, if we instead replaced one of your long autosomes — say, a copy of chromosome 1 — you might look obviously triparental, if your parents’ ancestries varied so much that conventional two-parent breeding couldn’t plausibly have given you exactly one whole long autosome, but nothing else, from a particular ancestral population

[6] Foreseeable risks in mitochondrial rescue include

Needle damage

Tinkering with a cell can, of course, harm membranes, chromosomes, or otherwise components. While it’s a mechanistic stretch, such damage could in principle affect tissues descended from the originally altered cell, leaving a child sick in ways tracing not to mitochondria themselves, but just to the nano-surgery needed to transplant them.

As in macro-scale surgery, we weigh such procedural risk against likely benefit. And by that measure, mitochondrial rescue works well: so far, kids born by it show no problems attributable to needle damage, and overall tend to be as healthy as typical kids — which is also, of course, far healthier than they would have otherwise been.

Incompatibility

All methods of mitochondrial rescue entail separating an egg’s long chromosomes from some or all of its cytoplasm (the rest of its cellular guts, including mitochondria with their tiny chromosomes). The idea is to then pool healthy cytoplasm with the long chromosomes of a second, already fertilized egg. In a very loose everyday analogy, picture separating a chicken egg’s yolk and whites, in order to put whites together with a new yolk.

But even after an egg’s chromosomes are removed, its cytoplasm reverberates with chemical crosstalk from all of them, including commands to make so-much of specific proteins and other important molecules. When that chatter bathes new chromosomes, of the child-to-be, some of those commands may help the cell thrive (which is the point of mitochondrial transfer). But other commands may, in principle, go awry if they’re out of sync with other messages in the newly formed cell, or when they’re parsed through DNA spellings in the new nucleus that differ from those of the chromosomes that sent them.

While we can’t yet track (let alone understand or modify) all the messages in question, known examples of such problematic messaging are scarce; and their effects would likely be much milder than those of the original mitochondrial disease that rescue served to prevent.

In future, we may start to make zygotes by transferring nuclear chromosomes from cells other than other fertilized eggs (or sperm themselves). In such methods, we’ll need to carefully steward chemical flags, called epigenetic marks, that govern when particular genome segments are read. Patterns of such flags vary importantly from cell to cell; and while those of eggs complement those of sperm (perhaps in a well matched tug of war), other cells’ marks may need to be overwritten to make a healthy zygote.

Loss of rescuing mitochondria

Early methods of mitochondrial rescue mixed cytoplasm from one egg into the cytoplasm of another, to add genetically hardier mitochondria to the zygote’s existing stock. As cells grow and divide, so do their mitochondria, some of which go into each descendant cell. So a given cell line that starts with both healthy and unhealthy mitochondria might slowly lose the healthy ones — whether by chance, or by mechanisms that purge newly arrived mitochondria (e.g., those from sperm) that are replicating out-of-sync with others already there. And such loss of the healthy mitochondria could risk resurgence of the disease that mitochondrial rescue aimed to avoid.

The new methods that may win American and British approval, however, don’t mix cytoplasm, but instead move nuclei (bags of long chromosomes) into cytoplasm containing only healthy mitochondria, so original unhealthy aren’t there to resurge in the developing child. As such, the risk of losing the new, healthy mitochondria is minimized.

[7] This would, of course, be a kind of state-enforced eugenics.

[8] Legal arguments about the health of kids who might not otherwise have be born are apparently nuanced, however.