This method is similar, but uses the parents' genomic data to improve predictions of the embryo's genome (since sequencing only a few cells gives low-quality data).
There really aren't that many reasons to sequence the entire genome in this context. Specific disease causing mutations in the parents can be specifically targeted in the embryo/fetus. Similarly, PRS scores don't require full genome sequencing to generate (but also aren't ready for prime time routine usage). Also, aneuploidy detection doesn't require genome sequencing. This is just a few examples.
Anyone know of any unexpected consequences of using this for IVF? It seems to me that we are falling into brave-new-world territory without really trying. I'm sure parents will do this to help their kids but I wonder what the negative issues will be? Gender selection is one but that's already being done by other means. What will this particular technology bring?
The Gattaca premise sounds pretty logical but not unexpected. Presumably they will optimize for what they might view to be "favorable" genes associated with preferred traits (skin/hair/eye color, beauty/symmetry, strength, height, intelligence, disease resistance, aggression, etc.) while attempting to eliminate the others.
This will (possibly) convey an increased "genetic" advantage upon the wealthy and privileged, while reinforcing societal structures that punish and exploit those who haven't been engineered the same way.
Good point, people don't realize it or admit it but being born with what society defines as beautiful features gives a person big advantages in life. It's like hitting the lottery as far as advantages vs someone that's not. If you're already wealthy you'll be able to buy those advantages for your kids. It will be one of the greatest inheritance parents can give them.
Well the governments job is to create laws to make it easier for humans to live together. Even if Gattaca style gene selection is available, laws can be put into place to prevent discrimination.
I.e. it is 100% illegal to do genetic testing for anyone other then yourself or your under-aged children. Those tests can only be done by a doctor and cannot be transferred or shared with anyone other than another doctor. Any employer or person that attempts to do a genetic test on someone can face jail-time.
Check out Gwern's analysis(https://www.gwern.net/Embryo-selection) of this kind of technology. It suggests a somewhat noticeable effect, but not a particularly large or worthwhile one. That doesn't factor in new technology, but the methodology is all there so it shouldn't be too hard to plug in the new values. I haven't done that yet, but I'd be surprised if there was a big shift.
Impressive study, kudos to the bioinformaticians who did this!
This could be an option for parents with a genetic condition who don’t want to pass it on. In terms of gattaca style super people (which I find quite repugnant) the recombination events are still random at the end of the day, so you’d have to screen quite a few embryos and there would be trade-offs. If you were really serious about it, the process would start with selecting partners based on their genetic fitness, and also using young fathers.
This could be an option for parents with a genetic condition who don’t want to pass it on.
Most of the genetic disorders we know about can already be screened for (those that involve a single gene).
This opens the door for polygenic screening but the underlying patterns to screen for are, in most cases, only weakly understood. We’d need to do a lot more research on adults with these diseases to get to the point where we can select against them in embryos.
On top of that the amount of selection we can do is limited by the number of embryos to choose between. In many cases that’s a very small number.
I’m starting to look into this. We have a single uncommon mutation to deal with, that’s just a fairly large cancer risk. Early advice has been that it’s still pretty hard to do single gene mutation screens. Needing samples from multiple relatives with the mutation to build a reliable screen.
My understanding is that it’s necessary to get genetic samples from both parents and best to get them from all four grandparents, but if you can’t get the grandparents they can still develop a test with slightly reduced accuracy if there are three or more embryos to sample.
There are quite a lot of less severe conditions which aren’t easily testable on an embryo. That was the motivation for the research as I understand it.
The whole polygenic thing isn’t very compelling, I agree.
My understanding is monogenomic testing has gotten very extensive as well as less expensive and faster. It’s gotten to the point where if you can get genetic samples from the parents and all grandparents the only limitation is knowing what to look for.
Expecting a contrarian article in 10 to 15 years that says the IVF genome analysis is imperfect and parents have been making incorrect decisions on flawed data.
Won't matter for highly polygenic traits. For monogenetic disorders like Tay-Sachs, it will provide another line of defence along with conventional pre-implantation screening and pre-natal screening.
Out of curiosity, what other measures might they neglect to take? I feel like I was sort of under the impression that the alternative is going in blind, but in retrospect I guess that's a somewhat silly assumption. Still, how likely is it that better genetic screening would have a net negative effect?
Here's where I'm at for the possible outcomes of a test for something like muscular dystrophy:
True Positive: non-viable, next embryo/round of IVF
False Positive: non-viable, next embryo/round of IVF
True Negative: Cool, parents move ahead with a healthy (in this regard) child.
False Negative: Parents move ahead with a false confidence.
Going in blind for muscular dystrophy, parents may hedge their bets by ensuring they live close to a school that can deliver against their childs needs, housing that is accessable (no stairs, easily accessable etc.), setting aside money for healthcare.
Of course the testing is only worse off in the case of a False Negative. I have no idea what the odds on that are, but I can imagine it'd be quite the shock for some people. In all I'm very bullish on the good IVF testing has the potential to do.
Not necessarily, if the confidence of the prediction doesn't match the real odds of outcome.
Parents may make special accommodations for the needs of children with genetic difficulties that they otherwise wouldn't based on their confidence in genetic screening.
For IVF embryos, it's the small amount of genetic material which makes accurate sequencing difficult. For standard human whole genome sequencing (WGS), the fastest times are down to five hours[1] (although that is exceptional), for which the imaging was massively parallelized and it seems that the choke point was computational for that particular case (sequencing like this basically multiples the DNA, shreds all the copies, images each shred in a reasonably-parallel manner, and then uses longest-common-subsequence to put all the shreds back together digitally).
Average WGS times for something a person can buy for a couple hundred dollars take a few weeks, and will usually be bottlenecked by logistics (mailing things, getting it to the lab, etc.) and then the imaging (a flow cell runs the fragments over an imaging device; parallelization is accomplished by running multiple flow cells at once).
I might be slightly off on my terminology here but the idea is broadly correct, I think: Differing grades of sequencing are determined by the average depth of fragments for each base-pair -- e.g. 1x sequencing implies an average coverage of one fragment per base-pair, which could lead to mis-aligned or improperly joined samples. 30x-50x sequencing is pretty common for consumer grade WGS these days, which gives a higher number of fragments that allows you to weed out bad reads or incorrect joins of the sequence, though errors can still occur. This is usually sufficient for diploid (having two values for each base pair, one maternal and one paternal) humans, since it's important to determine if the basepair is heterozygous (different bases from each parent) or homozygous (same base from each parent). However, if you're doing cancer sequencing, a tumor may contain many many more different genes, so a massively deeper sequencing depth is required to ensure you have reasonable statistical certainty on what variations occur within the different genomes. Higher depth == more material == longer time to sequence since you have more material to image.
Note that services like 23andMe are NOT doing whole genome sequencing; they are using specialized flow cells that only examine certain specific sites on the genome called single nucleotide polymorphisms[2], which are traits or indicators that are turned on or off by a single nucleotide, hence it being much cheaper and faster to run.
Average WGS times for something a person can buy for a couple hundred dollars take a few weeks,
I hadn't realize that we'd actually gotten the $1,000 genome. It was a big point of discussion 20 years ago, but seems to have arrived without the fanfare I would have expected. According to Wikipedia, it's been around for a few years, and claims the X-prize for it was canceled before that since it no longer looked like much of a challenge.
So we sailed right through it and are now pushing an order of magnitude below that. Thanks; I had missed it.
As someone who was interested in projecting that back in like 2013 and watched the $1k arrive, I got the impression that it never became headlines in part because there was never a crystal-clear moment for the "$1k genome".
Someone spends $1k and gets back a DVD of data ~2017. Well, is that $1k just the cost of the reagents? What about storage/assembly/analysis? How many samples did you run in that batch? Are you including the amortized cost of the sequencer (what utilization, discount rate, and upfront cost)? Are these long reads or short reads? To what depth? (There being energetic advocates for low depth / few passes + imputation.) Is this list price or institutional bulk price? Did Illumina give you a special deal (everyone knows they have hefty margins)? Are you even allowed to talk about the cost by Illumina? And so on. If the genome were $100k, or $10k, these could be rounded off, but as the cost drops, these nuisance factors become ever more of the price.
There just was never a specific moment where you could write a headline "$1k Genome Arrives At Long Last!", and by the time you get Dante Labs doing consumer sales for $500 or whatever (as long as you don't mind waiting half a year for the results), it's a bit late to write any articles as it is no longer 'news', now is it? So, people just stopped talking about the $1k genome because it had arrived quietly in the night, and switched to the $0.1k genome. And then you get similar issues, like that '$100 genome' BGI announced the other year - yes, there's a '$100' number there, kinda sorta, but there are so many caveats and questions that it discourages anyone from saying 'the $100 whole genome is here at long last!'
Different grades of sequencing are basically down to the technology and depth.
The short read sequencing you're describing makes reads that are like motes of dust in comparison to the genome.
More modern long read methods can read off sequences with high accuracy and/or length. These tend to be much higher in cost and substantially higher in the completeness and quality of the resulting bioinformatically inferred genome.
Starting material is a huge problem. You need at least 50ng of DNA for an Illumina sequencing run, usually more if you want to sequence ultra deep, which you will need for whole genome sequencing. For PCR you need at least 0.1ng (usually higher) of DNA. But a single cell has about 80 pg of DNA. So you need to amplify the DNA several orders of magnitude before you can apply standard PCR. Several approaches can solve this problem, DOP-PCR, MDA, MALBAC. But each results in biased amplification, with differing biases with each method.
The most interesting idea from the article, that was new to me, was using larger samples available from each parent, to augment and guide the analysis of the small amount of material available from the embryo. Obvious idea after you hear it, but very clever nonetheless.
if you're asking whether we could sequence 7 billion people, yes, it would be absolutely possible. Obtaining samples would be harder than the sequencing. If you really took this seriously there would be only 3 sequencing sites in the world and they would be located close to the largest datacenters. Each sequence is about 100G data (the raw data file that's shipped around) so if you really wanted to keep all of that it's 700 exabytes, but since you're sequencing everybody, you can instead create a tree structure of deltas from references with additional nodes representing major haplotypes and other structure. This would be more like ~1M-1G/person, so 7 petabytes to 7 exabytes, well within the storage limits of a modern datacenter cluster. To go along with that storage, you'd also need ~1M fast CPUs and ~250K fast GPUs, plenty of RAM, and a really good privacy and security story.
All of that could be formatted for large-scale analytics and the problem treated much like machine learning/data science problems in ads and other similar areas.
If you're really serious, this is just a bulk buy for one of the data center providers and they would be happy to make a fixed profit margin contract to do this for you. I helped set up all the infrastructure to enable google to do this ~10 years ago (I got a patent on compressing DNA for storage) and now they're at the point of hosting this sort of service (terra bio). I could do everything I described above for $25B but there is absolutely no medical reason to do anything of this scale.
It's very doable, but we only know what a small amount of the genome is actually doing. Whole Exome testing hits the majority of the points people are interested in and is way less computationally expensive, since it's a fraction of the genome.
Coincidentally, I have a friend who is in the second cycle of this IVF procedure to select an embryo that does not carry the genes associated with polycystic kidney disease (PKD). When I heard it last week for the first time, I thought it is already an established procedure. Here, I'm learning that it is a relatively cutting-edge approach and I am now looking forward to asking my friend more about this next time we meet.
Commercial products in the space have been around for several years but can only screen for a small number of genetic diseases at a time. For example, Natera's Spectrum screens for chromosomal abnormalities (eg Down Syndrome) plus one custom genetic problem for a single condition of greatest concern. https://www.natera.com/womens-health/spectrum-preimplantatio...
Some polygenic screening services that look at a much larger number of conditions are just reaching market now (eg Orchid Health), though our ability to map genes correlated with polygenic traits to phenotype results is still in its early stages. https://www.orchidhealth.com/
Thinking about the social and political implications of this in the long run. Any society or segment of any society that isn't producing average 120 IQ babies with superior sensory perception, physical strength, dexterity, and so forth, is going to turn itself into a permanent human underclass. Eugenics is here to stay this time.
We don't have a very good understanding of the genetics of many of these traits. Intelligence is especially thorny, involves numerous genes, and is probably only about half hereditable which is actually reasonably high.
We're likely to get a bunch of tall people, until everyone remembers they die younger due to cardiovascular strain. We'll probably wipe out most single gene hereditable diseases, which will be great. We're also somewhat likely to see fads around eye color in "designer" babies. We may also get people selecting for a single gene that make for great endurance athletes.
Anything much beyond that is science fiction in the near future. The knock on effects of tinkering with more than a handful of well understood genes is going to be really dangerous.
Quick Edit* There are around 1000 genes that have some bearing on intelligence. The 22 most impactful together account for 5% of variation.
By the way, I spent about 20 years of my life pursuing this goal, and I've concluded that most cultures aren't that keen on superintelligent babies right now.
> Any society or segment of any society that isn't producing average 120 IQ babies with superior sensory perception, physical strength, dexterity, and so forth
Where all the women are strong, all the men are good-looking, and all the children are above average.
IQ is overrated. If IQ mattered as much as people think, then all the jeopardy champions would be millionaires. Some of the dumbest people are willing to go up to strangers and ask them to buy something they don't need. Intelligence can get in the way more than people think. Just gotta be above the disability level. Your emotional, energetic, environmental, and cultural traits will do the rest.
If anything, it is liberating that this can (potentially) be achieved using editing instead of partner selection and stimulating child birth among "desirable" couples. Using editing, such things should be within reach for everyone. What's not to love?
A 120 average IQ population would run circles around a 100 average IQ population, even starting from a much lower position. Of course, there's still the question of whether society is organized such that people of exceptional talent rise to power, and whether they have the incentive to do great things.
My main concern isn't the tech being inaccessible to poorer people or countries. International intellectual property protection has always been precarious, and I guarantee that e.g. India won't just accept having a dumber population because "oh well, an American company owns the patents and we can't afford mass licensing."
Rather, Western societies have strong anti-eugenic impulses because of 1) the Christian legacy, 2) the popular fixation on WW2 atrocities, and 3) a political taboo against acknowledging population-level differences in mental (and to a lesser extent, even physical) attributes. I could see China being much more willing to embrace eugenic technology on a shorter timescale than the United States. And that could be the death blow to the US.
Is this a joke? Yes, by definition an IQ test is normalized to 100 for the population it's targeted for. But that doesn't mean that you can't compare intelligence across different populations, by not doing that normalization.
Average IQ will always be 100, but 100 today is not the same as 100 50 years ago. Renormalization is about 3 points per decade, so you have to take that into account when you compare IQ results across longer time spans.
So a person that would have scored '100' on an IQ test 50 years ago would be expected to score about 85 on a test administered today. Note that I'm not a fan of collapsing everything about human intelligence to a single number, but if you are going to use that number then you at least should be aware of how it is defined and how it develops over time.
That particular underclass problem seems unlikely, relative to how much any 120 IQ human pales in comparison to any synthetic AGI or even domain-expert AI.
The real underclass would be humans vs. machines, which would 10x, 100x or 1000x IQ, perception, strength, dexterity... pretty much any measure.
By the time we can make 120 IQ humans consistently, we'll be able to make 120 IQ machines consistently. And a couple years or perhaps hours after that the 120 IQ machines will be able to make 240 IQ machines and so on.
I see a lot of comments underscoring the possible eugenics implication of this, but I am curious as to why everyone always paints it as a negative? Even in our very diversity-conscious institutions we can generally agree that some things are plain bad. You don't want a blind or deaf child. You don't want one with down syndrome or deformities that would just make their life difficult.
I wonder if the high level of opposition to this does not come from us being naturally scared of becoming irrelevant. A society capable of producing disease-less 120 IQ adults would progress faster.
Yes there are a ton of ethical concerns about building a society where hierarchical boundaries find their justification in science, but I see these arguments as myopic. Inequalities have always existed, the only difference is that now nobody would have genetic diseases.
Because we have no idea how any of this works, selecting against one gene may have negative externalities that we don't even know how to measure. For example: a genetic cure for schizophrenia also dulling the creative traits it's correlated with. We cant even really understand how an emergent property like language works (see: every conlang), and you think we can engineer a civilization to be better by radically altering the balance of potential equality that we have been genetically optimized for?
A society of 120 IQ adults would probably be an insufferable hell beyond comprehension, considering the track record of intellectual movements and the proclivity of smart individuals, probably like yourself, to vastly overestimate the merits of rationality and concepts that can be limited to the mind of one human.
>A society of 120 IQ adults would probably be an insufferable hell beyond comprehension, considering the track record of intellectual movements and the proclivity of smart individuals, probably like yourself, to vastly overestimate the merits of rationality and concepts that can be limited to the mind of one human.
The world is full of societies of 120 IQ individuals. That would be, like... a typical office full of programmers. That's 1 in 10 people. Even 145 is 1 in 1,000. This gene stuff could only begin to surpass what you'd be able to do by holding a conference in an academic field at... 170? 180? For the foreseeable future the kinds of selection that operate on full-grown adults will greatly surpass this other kind which is limited to four or five embryos.
In so many words, more than four or five former embryos are selected between in a typical round of SWE interviews.
>A society of 120 IQ adults would probably be an insufferable hell beyond comprehension
> That would be, like... a typical office full of programmers.
Is this an argument in support of the OP?
Anyway, much like with global warming, the issue isn't so much the averages, but the impact on the extremes. Now the world suddenly has 10x as many 140 people or 100x as many 160s, etc.
This cuts both ways too. A smart person isn't necessarily a nice person. A 20 point IQ increase could make the difference between someone who is a successful telephone scammer, and someone who brings down entire economies.
All of our culture deals with interactions between average people. People with significantly greater or less intelligence than average do not have a bank of ancient answers to ancient questions to draw on. One simple example of that would be norms against debt and lending - if you are very clever they don't apply to you, but that doesn't mean you don't need any norms. In fact someone who borrows and lends needs more guidelines and more complex guidelines if they're going to navigate business risks successfully.
Oddly enough since I'm both a programmer and a jazz musician, I've noticed some interesting parallels. In both cases the practitioners come from all walks of life, and many of them either bailed out of the mainstream education system, or had a negative experience with it. For this reason you have people with music degrees sharing the bandstand with those who learned by doing. I'm halfway between those camps, having taken classical music lessons through high school but learning jazz on my own.
> A society of 120 IQ adults would probably be an insufferable hell beyond comprehension, considering the track record of intellectual movements and the proclivity of smart individuals, probably like yourself, to vastly overestimate the merits of rationality and concepts that can be limited to the mind of one human.
Disregarding the personal attack (I am well aware of downsides, but it's called having a discussion), higher median IQ is not really the point, it's about giving the same chances to everyone.
We could use this to eradicate a wealth of issues that we do understand, there's no good reason to have babies born with Cystic Fibrosis, we know what genes are causing it.
>there's no good reason to have babies born with Cystic Fibrosis, we know what genes are causing it.
IVF is expensive and difficult and all easily identified genetic diseases are rare, so until one of those conditions changes (cost reduction and better techniques, or so many diseases being discovered that the odds that you will be saving your kid from one become significant), it will not be used for this purpose but rather as something extra to do when IVF is required for other reasons.
We agree on that part, I am not advocating for editing every foetus' genome in the next 10 years. I just think it's short-sighted to put a ban on that kind of research based on fear of inequalities.
You’re not curing cystic fibrosis, or any other genetic disease, are you? You’re just stopping disabled people from being born because you’ve decided their lives have no intrinsic value.
This can be said to a wide swath of people. Down syndrome people, bipolar people, blue people, people with physical deformities.
Why do you get to choose? Have you ever asked one of these people if they find their lives to be meaningless? How about their parents?
I can think of few hells more dull than a world of smart ass public radio listeners providing unrequested comments lathered in snark and cynicism.
That's like saying "You’re just stopping people from breaking their legs because you’ve decided lives of people with broken legs have no intrinsic value."
I would consider cystic fibrosis to be cured when there are no longer any carriers on the planet who could procreate and make another person who will suffer from that terrible affliction.
> Why do you get to choose? Have you ever asked one of these people if they find their lives to be meaningless? How about their parents?
My hope with this technology is that we can give prospective parents the kind of tools that allow them to make reproductive choices that best reflect their desires and hopes and dreams for their children. The question of course is what are they going to do with these tools? Will they eagerly use them or throw them away in disgust?
And then what do we do as a society in response to that?
Is it legal to feed your new born child alcohol?
Is it legal for pregnant women to drink alcohol?
Is it legal for two cystic fibrosis gene carriers to knowingly produce a child who will suffer from cystic fibrosis?
Is it legal for someone to modify their embryo so that it turn into a child that will be a cystic fibrosis carrier?
Is it legal for someone to modify their embryo so that it turn into a child that will suffer from cystic fibrosis?
Which of these things should be legal and which shouldn't? How do we enforce them?
Presumably this "you" is the parent. They get to decide when (or if) they have kids and they can now decide what kind of kids they have. Just like folks can (and should) already screen for certain heritable disabilities.
> Have you ever asked one of these people if they find their lives to be meaningless?
They'll either be depressed or they won't feel this way. By definition, the ones that are well-functioning parts of society won't feel this way. I don't see why it should matter.
> I can think of few hells more dull than a world of smart ass public radio listeners providing unrequested comments lathered in snark and cynicism.
For someone who finds that dull, there is a lot of snark and cynicism in this comment. It's really not necessary, we're all here to engage with each others' view points.
That's a good argument for not engineering all children all at once - we don't understand the consequences. It seems like a good argument for starting to engineer a few children so we can start to learn what the consequences are. As engineering becomes more palatable to the general population we will better able to deliver good results.
Engineering children would likely introduce horrible diseases because as you say, nobody understands the consequences. What's being proposed is selection, the selection of embryos which have already proven themselves to be viable and passed several steps of Nature's disease filtration.
There was quite a bit of outrage around that case from hearing people, but it seems no different than two parents with genetic deafness choosing each other and then not trying to use genetic testing/embryo selection to have a hearing baby.
I do think when this type of genetic manipulation becomes possible/mainstream there will be many traits chosen by parents that aren't considered universally desirable.
I don't think there's anything wrong with having a blind or deaf kid. I take issue with the idea that given the technology we would refuse to fix their disability before they are born.
Try explaining to your son or daughter that they could've been able to see and hear, but you refused to avoid hurting the feelings of existing blind and deaf people...
> Try explaining to your son or daughter that they could've been able to see and hear, but you refused to avoid hurting the feelings of existing blind and deaf people...
more like try explaining to your son or daughter that they wouldn't have been born at all
> I am curious as to why everyone always paints it as a negative
Fear of the unknown and distrust of everyone else. This might give someone an advantage, so it must be bad for me. I view it kind of like metaphorical crabs trying to climb out of a bucket.
Nobody with parents who can afford IVF would have genetic diseases. Nobody would rise from an ignoble birth to greatness ever again... or at least not in countries without universal healthcare.
Equality is great, but the situation would be no different than someone having access to healthcare/higher education/equal opportunities. After a few decades that technology would become commoditized just like everything else. It's not as if it was impossible to enforce regulations around that sort of thing.
The real world is a mixture of zero-sum and positive-sum games, and people do not like the idea that they and their descendants will be destined to lose (in a compounding way) every competition. After a few generations of selection you will have a large population of people who wouldn't be good starting points even if they could afford it, because their genomes would be far behind by that point. Unless you want that you happen, you'd better make sure that everybody gets it if anybody does.
Those kids would still potentially breed the normal way. If a rich kid knocks up a bunch of poor ones, those children will have similar genetic advantages.
And rich people fall from grace all the time. It's difficult for families to hold onto their wealth over successive generations. One of the keys to maintaining wealth is to keep it from being diluted, which means that some kids are going to get cut off.
Directly testing people's IQ through say contrived interview questions (ever wondered why people care about leetcode[0]?) will always be more accurate than predicting it from their DNA. It is difficult to say how much of IQ is genetic, but estimates range from 50% to 80%, placing an upper bound on the effectiveness of the exact technique they used in GATTACA. (But, I want to emphasize, the more accurate way of doing it is already being done.)
[0] One objection to calling leetcode an IQ test would be that some people "grind leetcode," as in, practice at it to get better, but did you know that Raven's progressive matrices has a large practice effect? In fact, I might raise your score just by telling you that a lot of the questions are based around XORing the presence of symbols in the pictures. If companies were giving culture-free IQ tests rather than leetcode ones we'd see the exact same pre-interview behaviors, including practicing tasks that don't resemble the job being interviewed for.
https://astralcodexten.substack.com/p/welcome-polygenically-...