Twiblings, four-parent babies and other reproductive technology
Two weeks ago I finally published my year-long research project into how to have polygenically screened children. In that post, I explained all the practicalities of embryo screening and how parents can use it right now to make their children smarter, happier, and less prone to disease.
This week I’m going to talk about some of the more off-the-wall methods that have been proposed for increasing genetic gain across a variety of traits, along with their implications for family structure, society, and the human experience.
What are Twiblings?
A twibling is somewhere between a sibling and a twin. If identical twins share 100% of their DNA and siblings share about 50%, twiblings share 75%.
To the best of my knowledge, twiblings don’t exist in nature. EDIT: This process is rare, but we have documented cases of it happening in humans. The proper scientific term is “Sesquizygotic Twins”. See ScottNYX’s comment for more. To get one, you’d need two different genetically identical eggs to be fertilized by different sperm. But why would we create twiblings?
Anyone who has gone through IVF knows that the main limiting factor in all cycles is the number of eggs the female partner can produce. In an average menstrual cycle, a woman will produce exactly one egg. In an average ejaculation, a man produces about 100 million sperm. Using a specialized set of medications, we can increase the number of eggs harvested per menstrual cycle to between 5 and 100 (there’s a lot of variance depending on maternal age and other factors). But even 100 is a lot less than 100 million.
Older women in particular have a very hard time producing eggs. Women over the age of 42 often produce 5 or fewer per retrieval, and many of those have chromosomal issues that prevent them from turning into a baby. So the few eggs without such issues are very precious.
It sure would be nice if there was a way to duplicate the few viable eggs these women can produce…
As it turns out, this is possible! And we’ve already done it in the lab. You can make a haploid stem cell line by tricking an egg into thinking it’s an embryo; you let a sperm fertilize it, then you pull out the sperm’s pronucleus before it fuses with that of the egg.
Success! The egg now thinks it’s an embryo and will start dividing.
So now you have a bunch of haploid embryonic stem cells, each of which is fairly epigenetically similar to an egg.
But there’s still one tricky step left; how do you derive an egg from these haploid embryonic stem cells such that it can be fertilized again?
The most obvious answer is to use nuclear transfer; pull the haploid nucleus out of these embryonic stem cells and stick it in another egg. So you do this for a bunch of the haploid embryonic stem cells using a bunch of other eggs and now you have many eggs from the same mother!
Of course this necessitates HAVING other eggs, which we already established are in short supply. But thankfully, those other eggs don’t need to come from the same woman. You can get donor eggs without too much trouble. And if you don’t care much about the donors’ DNA you can get them for quite a bit less money.
But if you can clear that hurdle you now have a very interesting situation: you’ll have multiple genetically identical eggs, each of which can be fertilized by a different sperm.
If the mother decides to have multiple children, they will be more genetically similar than any siblings, but less similar than identical twins. Twiblings!
Twins of different ages
At the 2, 4 or 8 cell stage, the cells in an embryo can turn into any tissue in the body or placenta. This leads to a natural question: if we split the embryo in half at that stage, will it form two embryos?
It would! Or at least it did in other mammals we’ve studied. For some reason, no one seems to have tried this in humans yet. I don’t fully understand why other than to gesture at the general hand-wringing that happens any time someone proposes doing something new in human reproduction.
However, if the ART establishment ever decides that maybe those parents that desperately want two kids should be able to have them, maybe they will try out embryo splitting and see if it works.
If they do it would lead to quite an interesting possibility; you could have two children that are identical twins, but different ages! Sometimes when I was younger I wished an older wiser version of myself would help me out. With embryo splitting, it could happen!
This could also lead to some very interesting studies on birth order effects and all kinds of other research on temporal effects that would benefit from controlling for genetic influences. Plus it would be neat to have an older or younger version of yourself!
Four-parent babies (or 6-parent babies, or 8-parent babies, or…)
Imagine you’re really into the idea of improving the genetic lot of your future children. Wouldn’t it be great if your kids had all the best traits of you and the best traits of your spouse?
One way to do that is with regular old embryo selection; you grow a bunch of genetically distinct embryos in a dish using regular IVF, sequence the genome of each, then select the best couple according to which traits you think are important.
But this has problems; most traits are normally distributed. And although there’s a slight correlation across traits, you just can’t produce very large gains by selecting from a normal distribution.
One way around this is to select chromosomes instead of embryos. You and your spouse can produce a bunch of embryos, sequence them using normal PGT techniques, then look at all of their chromosomes. Instead of picking an entire embryo, you pick the best chromosomes among all the embryos. Then you assemble all the best chromosomes together into one cell using some complicated techniques which I won’t get into here and (probably) transfer the resulting nucleus into an egg cell.
But wait! Why stop with two parents? Couldn’t we get chromosomes from the embryos of more than one couple?
And the answer of course is yes. You could get embryos from any number of couples and pick the best chromosomes from all of them, and assemble the best into one single nucleus.
The level of gains you could get through this technique is quite impressive; on a single trait you could expect up to maybe 12 standard deviations of gain. Of course it would be quite insane to select so strongly for a single trait so in reality it would probably be closer to 4 or 5 standard deviations across a broad panel of traits.
Still, 4 or 5 standard deviations is a lot. That’s enough to take an average IQ person to the level of Judit Polgar or Andrew Wiles, or a person of average height to the level of Kevin Durant or Anthony Davis.
The benefits of having children in this manner would be so extreme that if we ever get chromosome selection working I suspect the manner in which we choose our pool of co-parents to become very important.
In a strictly genetic sense, every contributor to the pool has a smaller vested stake in each child because they share less genetic material with the child and many other children raised by different parents will have that same level of genetic similarity. With 8 parents, you’ll share the same amount of genetic material with your child as a great-grandparent.
Would this make parents care less about their kids? Maybe a little? But I suspect not much. Parents that adopt seem about as committed to their kids as those that have kids biologically related to them, although there are likely strong selection effects going on; those that wouldn’t care about their adoptive kids will not adopt.
It also brings up some interesting questions about contact between the “parents” of the children. Would each set of parents raise the kids separately like we do today? Would they all live in one big group house? Would we see couples dating services spring up where couples would try to meet other couples to join their chromosome selection pool?
And how many genetically distinct children would be produced from each pool anyways? Would each group of parents get genetically different kids according to their preferences, or would the cost of assembling genetically distinct genomes be prohibitive enough that only a few different genetic identities be created from each pool?
You could see some very interesting situations where some children differ from others by only a couple of chromosomes, making them almost but not quite twins.
A weird and wonderful future?
I’m probably a little unusual in this respect, but I find something oddly charming and hopeful about the idea of going on double dates with your fellow co-parents down the street who are raising your quarter-son and daughter. You take your prodigious kids over for playdates with their prodigious kids and get a chance to see what the future of the human race is going to look like. They grow up so fast; at 7 years old they are already eclipsing your abilities in mathematics and reading comprehension. But they’re so kind and emotionally mature that you feel alright about being obsolete. You’ve done your part. In another ten years, the world will be in some very good hands.
And who knows; maybe one of them will figure out how to reverse aging and enhance adult intelligence and you’ll be able to catch up to them.
Thank god we paused AI development in the 2020s so these kids would have time to grow up. Can you imagine how bad things would have ended if your generation was the one that had to solve alignment?
Chromosome selection seems like the most consequential idea here if it’s possible
Is it possible now, even in animals? Can you isolate chromosomes without damaging them and assemble them into a viable nucleus?
Edit: also—strong upvoted because I want to see more of this on LW. Not directly AI but massively affects the gameboard
A working protocol hasn’t been demonstrated yet, but it looks like there’s a decent chance it’s doable with the right stitching together of existing technologies and techniques. You can currently do things like isolating a specific chromosome from a cell line, microinjecting a chromosome into the nucleus of a cell, or deleting a specific chromosome from a cell. The big open questions are around avoiding damage and having the correct epigenetics for development.
Maybe the test case is to delete one chromosome and insert another a chromosome in a fruit fly. Only 4 pairs of chromosomes, already used for genetic modifications with CRISPR
Goal = complete the insertion and still develop a normal fruit fly. I bet this is a fairly inexpensive experiment, within reach of many people on LessWrong
You probably wouldn’t be able to tell if the fruit fly’s development was “normal” to the same standards that we’d hold a human’s development to (human development is also just way more complicated, so the results may not generalize). That said, this sort of experiment seems worth doing anyways; if someone on LW was able to just go out and do it, that would be great.
That implies the ability to mix and match human chromosomes commercially is really far off
I agree that the issues of avoiding damage and having the correct epigenetics seem like huge open questions, and successfully switching a fruit fly chromosome isn’t sufficient to settle them
Would this sequence be sufficient?
1. Switch a chromosome in a fruit fly
Success = normal fruit fly development
2a. Switch a chromosome in a rat
Success = normal rat development
2b. (in parallel, doesn’t depend on 2a) Combine several chromosomes in a fruit fly to optimize aggressively for a particular trait
Success = fruit fly develops with a lot of the desired trait, but without serious negative consequences
3. Repeat 2b on a rat
4. Repeat 2a and 2b on a primate
Can you think of a faster way? It seems like a very long time to get something commercially viable
It seems fairly straightforward to test whether a chromosome transfer protocol results in physical/genetic damage in small scale experiments (e.g. replace chromosome X in cell A with chromosome Y in cell B, culture cell A, examine cell A’s chromosomes under a microscope + sequence the genome).
The epigenetics seems harder. Having a good gears-level understanding of the epigenetics of development seems necessary, because then you’d know what to measure in an experiment to test whether your protocol was epigenetically sound.
Cochran had a post saying if you take a bunch of different genomes and make a new one by choosing the majority allele at each locus, you might end up creating a person smarter/healthier/etc than anyone who ever lived, because most of the bad alleles would be gone. But to me it seems a bit weird, because if the algorithm is so simple and the benefit is so huge, why hasn’t nature found it?
How is nature supposed to gather statistical data about the population to determine what the majority allele is?
Mildly deleterious mutations take a long time to get selected out, so you end up with an equilibrium where a small fraction of organisms have them. Genetic load is a relevant concept.
Hmm, two individuals of a species mating obviously couldn’t compare their genomes with other representatives of the species and take the modal allele. But many species, especially plants, do carry more than two copies of each chromosome (e.g. black mulberry apparently has 44 copies of each gene). How difficult would it be to evolve a process that compared the alleles on each chromosome that the individual carried and picked the modal one for producing gametes?
Intuitively it feels to me like it’d be hard for biology to do/evolve and that it’d require something more like a computer, but I haven’t studied biology much so I don’t expect my intuition to be very predictive. That Wikipedia article for polyploidy also didn’t mention any research to have found polyploidy to have such a function.
Naively extrapolating, such an allele couldn’t spread, because before it’s very common, it would delete itself!
Yeah, it would have to be at least 3 individuals mating. And there would be some weird dynamics: the individual that feels less fit than the partners would have a weaker incentive to mate, because its genes would be less likely to continue. Then the other partners would have to offer some bribe, maybe take on more parental investment. Then maybe some individuals would pretend to be less fit, to receive the bribe. It’s tricky to think about, maybe it’s already researched somewhere?
Not among mammals, but some insects, including bees and ants, actually have 75% consanguinity (tangent, that’s a more accurate term than “shares 75% of DNA”, since the overlap in DNA is much higher, even among strangers), at least in the case of full siblings (of course it’s not the case with half siblings).
The reason for this is that these insects are “haplodiploid”, meaning that females carry two sets of chromosomes, just like e.g. mammals, but males only have one set. So while the eggs contain recombinatated (and thus varying) DNA, the father always contributes the same DNA to each of its offspring. [1/2 * 1⁄2] + [1/2 * 1] = 3⁄4, so full siblings have 75% consanguinity.
There’s a correlation between this haplodiploid condition and eusociality (as exhibited by bees and ants), though it is neither a necessary nor sufficient condition. There are at least two species of eusocial mammals, which are not haplodiploid: Humans and Naked-Molerats (interestingly, both are Euarchontoglirii, which is a fairly specific category of mammal), and many haplodiploid species are not eusocial. But it’s easy to imagine how haplodiploidhood can make the development of eusociality more likely
Humans are not eusocial. That was Edward O. Wilson being dramatic. We don’t have a biological caste distinction between reproducers and non-reproducers.
What you call “twiblings” does happen rarely in nature: it is called polar-body twins or half-identical or semi-identical twins. Only two occurrences are known to have happened in humans (I am sure it has happened other times): Semi-identical twins ‘identified for only the second time’ - BBC News
Here is the paper in NEJM: Molecular Support for Heterogonesis Resulting in Sesquizygotic Twinning | NEJM
Wow, very interesting! Thanks for sharing.
Apparently the scientific name for this is “Sesquizygotic Twinning”.
There’s a great video explanation of this process. I’m still not entirely clear on how the maternal set of chromosomes replicates itself such that it can form diploid cell lines with both sperm. Usually the sperm and egg chromosomes pair up after merging of the pronucleus of each. The authors of the paper you linked propose some strange “triploid spindle apparatus” as an explanation of how this happens. But it’s not clear to me how the chromosomes of each haploid pronucleus replicate before joining with their counterparts. And I’m too lazy to try to figure it out right now.
I’m very, very interested in embryo/chromosomal selection of this kind for my future children… but there is absolutely no chance, no fucking chance at all, that I’d be okay with using the DNA of more than my spouse and I, the idea repulses me on an incredibly deep level. I want my children to look like me, and it’s very important to me that a plurality of their genes be mine. I’m okay with doing CRISPR to change specific genes in addition to the chromosomal selection, so they wouldn’t be 50% my genes, maybe a bit less, but if you can point to some specific third human and say “yeah an equal fraction of genes came from this one other dude”, I’m out.
Yes, I suspect most parents will probably feel like you. Having kids with a big group of people is just going to be too weird for most people.
You can see from Tsvi’s chart that the gains from selection among just two people are already pretty large: probably 1.5-2 standard deviations across a large panel of traits. So if someone manages to get the protocol working you can still benefit from it even if you only want to use it for yourself and your wife.
But it’s worth pointing out that this is not that much different than having grand kids or great-grandkids; you’ll share about these same amount of DNA with them as you would with children you have with 3-7 other people. So if you’re ok with the idea of grand kids this shouldn’t be THAT weird other than the “skipping generations” part.
That comparison misses something crucial, which is the density of genetic material passed on. Each generation represents a dilution of the first parent’s genetic material with non-kin, but also has the potential for increased numbers of descendants at each generation. By the time your family would be producing your great-grandkids, they’d have the potential to have 2 dozen or more of your direct descendants.
With chromosomal selection you’re trading off a massive amount of genetic saturation: essentially getting the percentage genetic inheritance of a great grandchild without the potential for the massive “payoff” of having numerous descendants sharing portions of your genetics.
Putting it like that, it’s no surprise that people are going to feel repulsed by the idea...and that’s before we even get into the part where the chromosomes which don’t get selected are going to be instantly “lost” in a single generation. That’s made more spooky by the fact that we won’t know where demonstrably inheritable traits like “Has his mother’s eyes; has his dad’s smile; has temper/melancholy/mood similarities to one or the other parent” lie on the chromosomes. I wouldn’t be surprised if the idea that you’d be risking losing something important like that is going to be a deal breaker for a lot of people.
That’s only a downside if the other people in the pool don’t plan on having kids.
Also, is your goal really just to maximize the amount of your genetic material in the future? If so just focus on cloning yourself as much as possible.
I personally like some things about myself and dislike other things. The whole point of embryo selection or any other genetic engineering is to have kids that are better than me. I’d like them to have some of the traits I admire about myself, but other than that I’m not very picky.
Maximizing the amount of your genetic material in the (near) future is my null hypothesis. I don’t think it’s totally accurate, but in the absence of a good understanding of which parts of our genetic material produce the non-quantifiable traits we care about: things like the shape of one’s smile, personality, taste in food, overall “mood”, then I expect people to be reluctant to trade off genetic density at rates greater than ~25-60%
The alternative extreme hypothesis would be a “parent” who wants to maximize their “children’s” traits to the point where they’d prefer 0% genetic inheritance if the resultant child would be superior in some respect.
I’ve thought about this more and I don’t think the downside you’re pointing at exists unless the members of the pool have significantly fewer children than you do.
Suppose there are N members in the pool and you contribute 1/N to the children in each pool. Then the next generation will still have the same amount of your DNA as they would if you conceived normally unless you have more children than other people in the pool.
Genetic density doesn’t really matter if your goal is maximizing the amount of your DNA out there.
Also, if you DO care about maximizing the amount of your DNA out there, have you considered donating to a sperm bank?
Who says you contribute to the pool at the same rate you’d contribute to your own children? Surely other people in the pool would have different priorities than you, wouldn’t they? What if there are N people in the pool and you contribute 1/5N to the children in each pool?
Add that to the fact, that maybe you only have one standout chromosome, and you could easily see a situation where genetic analysis of the population in your family + your pool shows a sudden disappearance of 90% of your genes with a proliferation of 5% of your genes. Is that equivalent to having children? Some people might say it’s not.
Also, yes, obviously if you were trying to maximize your genetic genetic density you’d do all of the above: contribute to pools, clone yourself a couple times, have children normally (or with chromosomal selection), and contribute to a sperm banks. That’d be the route to take if you view maximizing genetic density as a terminal goal.
I think the reality is that people have some instinctual need to see more of themselves and their loved ones in the world, and that a learned person would use genetic inheritance as a proxy for this emotional non-quantifiable goal. I also suspect it’s a threshold goal, and not a maximization goal, which is why people want some number N of children and not “as many children as I can afford to have”.
Well it depends on how large the pool is, but unless other members of the pool have a significantly higher set of polygenic scores than you it’s pretty likely you’ll have roughly equal contributions. I suppose I’d have to do the math to see exactly how big of an influence that would have.
Interesting hypothesis. This matches fairly well with my own observations, though that might just be because there is no way for parents to have a quarter of their DNA be in any of their children.
One interesting test might be to see if grandparents favor grandchildren with more of their DNA than ones with less, since there can be variance among grandchildren and not among children.
That’s really weird. Why do you identify so strongly with a sequence of nucleotides? Isn’t it more important that a child inherits your memes?
I could ask just the same why you’d identify so strongly with a mere pattern of neural activation that make up the memes in the child’s mind. This preference of mine is getting close to the bedrock of my preference ordering, I want my child to share my genes because that’s just kind of what I want, I don’t know how to explain that in terms of any more fundamental desire of mine.
But like I said, I’d be fine with CRISPR to change a small fraction of the genes which have an out-sized impact on success, what I don’t want is to change (or worse, take from someone else) the large number of genes which don’t particularly influence success or intelligence, but which make me who I am.
So twiblings using donor eggs would still have mitochondrial DNA from the donor, right?
Yes. In fact, we already do this kind of treatment for people with mitochondrial disease. The offspring this produces is often casually referred to as a “three-parent baby”, even though the “third parent” (the egg donor) only contributes about 14 genes to the child.
https://www.hfea.gov.uk/treatments/embryo-testing-and-treatments-for-disease/mitochondrial-donation-treatment/
I get unnerved reading speculation about a Gattaca-like future. The biggest issue is that this technology will likely be much more accessible to the wealthier strata among us, allowing the gap between richer and poorer families to magnify significantly.
The problem with technology like this that tends towards eugenic aims is that there’s no certainty that those who choose tactically advantageous traits (height, intelligence, attractiveness) for their children will also choose eusocial traits (humility, honesty, kindness). There could be an arms race among amoral billionaires who could father leagues of superhuman, psychopathic children.
Even further, in all likelihood the prospect of chromosomal selection will be obsolete compared to direct modification of the embryo’s DNA, maximizing all possible traits with minimal relatedness to the parent. If your goal is perfect children, why care if they’re statistically your spawn by virtue of genetic relatedness? Or if you care so much, you could preserve similarity in superficial traits like certain neutral facial features but maximize every other aspect.
The whole “intelligent psychopaths” idea is an interesting one. I’ve spent time thinking about such a possibility.
I think there is a legitimate risk that if you had a high-trust, kind society with a lot of selfless people, such an environment would be ripe for exploitation by a smart psychopath.
But I’d be surprised if intelligent psychopaths have an advantage over intelligent non-psychopaths in today’s world. Reciprocal cooperative tendencies evolved in humans because groups of humans are extremely powerful, and cooperation is required to make such groups function.
I don’t think you can push traits more than 4-5 standard deviations in any direction without serious risks. I don’t have a good way to estimate the exact safe levels, but my guess is if you push more than 2 or 3 standard deviations out from the most extreme humans you’re going to find negative pleiotropy between the traits you’re selecting for and some other trait that are important but weren’t included in your index.
You can see examples of this in animal husbandry and agriculture. When Normal Borlaug made the first strain of hyper-productive dwarf wheat, the heads were so heavy with grains that the stalks bent and broke in the wind, causing large crop failures. He had to breed the wheat to reinforce the stalks before the crop became a viable alternative to existing varieties.
Likewise, I think if you literally just flipped every IQ-affecting allele into the position expected to maximize IQ, there would almost certainly be some unanticipated negative side-effects.
So even though the theoretical gains from genome synthesis or iterated CRISPR editing are larger, I don’t expect them to provide that much of a practical advantage due to the limitations with how far we can push traits.
Edward O. Wilson, in his book “The Meaning of Human Existence”, posits that there exists a natural tendency for humans to act selflessly when the in-group is endangered by an out-group, but selfishly when there is no danger, as a selfish action that negatively impact’s the group’s fitness would not harm his or her survival.
This implies that human societies have nursed a dual-cooperation strategy, which selects for traits that create fertile, productive, high trust societies to guard against threats, but creates in those societies fertile ground for exploitation by selfish behaviors, the genes coding for which are passed on more and thus become more common in successive generations.
Cooperation is powerful, but even the smartest, most cooperatively adept groups are susceptible to exploitation. There are things that non-psychopathic people just couldn’t stomach doing that psychopaths could easily do. The magnitude for material, reproductive and social success is too high for a highly productive, amoral agent to ignore the benefits. The only way for a cooperative society to guard against it is to be, by default, zero-trust.
Your point about negative pleiotropy makes sense and will likely be a huge hurdle for genetic modification that seeks specific metrics. However there are just too many low-risk low-hanging fruit in the human gene pool to make it necessary for genetic modification to venture into the more extreme territories to get the benefits it needs. There already exist natural born humans 5 standard deviations above any given average trait: the success of serendipitously fit humans by pure natural chance is enough of a basis for artificial traits to be easily pushed to a reasonably higher level. Winning the genetic lottery isn’t about hitting one giant bullseye, it’s about avoiding 1,000,000 micro bullets.
Also, regarding this common chain, my comment got a very strong immediate negative reaction, but I’m unsure what people’s main dismissal of it stems from. The belief that I’m veering towards false alarmism?
I think that a relative weakness of psychopaths is that they have to be rare in the population, because (a) an interaction between two psychopaths is likely detrimental for one or both of them, and (b) the psychopaths lose the element of surprise as people become more familiar with them.
So if we genetically engineer superintelligent children, some of them psychopathic, some of them not, I suppose the interactions between them will lead to some stable ratio.
People have adaptations against exploitation, such as trusting people you know for a long time or someone you trust knows them for a long time, or getting drunk together (it is difficult to fake non-existing emotions when drunk, and the next day people will remember weird behavior). In a high-trust society we often stop relying on them, but as the trust reduces, they can become more popular again.