Astral Codex Ten

cystic fibrosis

16 min read

cystic fibrosis

Article

cystic fibrosis is a recurring concept in the Astral Codex Ten archive, appearing 2 times across 2 issues between June 12, 2024 and July 31, 2025. The archive places it in contexts such as “Do you think cystic fibrosis is a genetic condition which it is bad to have?”; “testing for some of the most severe and easiest-to-detect genetic disorders like … cystic fibrosis”; “single-gene disorders like cystic fibrosis”. It most often appears alongside schizophrenia, US, 23andMe.

Metadata

  • Category: Concepts
  • Mention count: 2
  • Issue count: 2
  • First seen: June 12, 2024
  • Last seen: July 31, 2025

Appears In

Source Context

Recovered passages from the original issue text. When the raw archive preserved outbound links inside the source passage, they are listed directly under the quote.

Nobody Can Make You Feel Genetically Inferior Without Your Consent
June 12, 2024 · Original source
I find it clarifying to set aside schizophrenia for a second and look at cystic fibrosis.
Cystic fibrosis is a simple single-gene disorder. A mutation in this gene makes lung mucus too thick. People born with the disorder spend their lives fighting off various awful lung infections before dying early, usually in their 20s to 40s. There’s a new $300,000/year medication that looks promising, but we’ve yet to see how much it can increase life expectancy. As far as I know, there’s nothing good about cystic fibrosis. It’s just an awful mutation that leads to a lifetime of choking on your own lung mucus.
So: are people with cystic fibrosis genetically inferior, or not?
Suddenly, Trait-Based Embryo Selection
July 31, 2025 · Original source
When a couple uses IVF, they may get as many as ten embryos. If they only want one child, which one do they implant? In the early days, doctors would just eyeball them and choose whichever looked healthiest. Later, they started testing for some of the most severe and easiest-to-detect genetic disorders like Down Syndrome and cystic fibrosis1. The final step was polygenic selection - genotyping each embryo and implanting the one with the best genes overall.
Inline links: 1
Sample Nucleus results. And this week, Herasight4 entered the space with the most impressive disease risk scores yet, an IQ predictor worth 6-95 extra points, and a series of challenges to competitors, whom they call out for insufficient scientific rigor. Their most scathing attack is on Nucleus itself, accusing its predictions of being misleading and unreliable. Let’s start with the science, then move on to the companies and see if we can litigate their dispute. In Theory, All Of This Should Work Polygenic embryo screening is a natural extension of two well-validated technologies: genetic testing of embryos, and polygenic prediction of traits in adults. Genetic testing of embryos has been done for decades, usually to detect chromosomal abnormalities like Down Syndrome or simple single-gene disorders like cystic fibrosis. It’s challenging - you need to take a very small number of cells (often only 5-10) from a tiny proto-placenta that may not have many cells to spare, and extract a readable amount of genetic material from this limited sample - but there are known solutions that mostly work. But most traits are polygenic, requiring information about thousands or tens of thousands of genes to predict. These are too complicated to understand fully at current levels of technology, but some studies have chipped away at the problem and gotten a partial understanding. Often this looks like being able to predict a few percent of the variance in a trait, and determine whether someone’s genetic risk is slightly higher or lower than average. Polygenic prediction of traits in adults is still young and full of hidden pitfalls. Last month, we discussed how some early studies unknowingly conflated direct genetic effects and various confounders6 - for example, they tended to pick up on genes associated with well-off ethnic groups or families who had good health outcomes for social reasons. Pinpointing the direct component requires an additional step where researchers validate their algorithms within families (for example, on pairs of siblings where one has a higher polygenic score than the other) to see how much predictive power remains. This is especially important for embryo selection companies, whose entire value proposition depends on comparing two genomes from the same family. How have they done? It depends on the number of embryos they have to work with; the more embryos, the better you can do by selecting the best. Herasight’s numbers on how breast cancer risk goes down with number of embryos used in selection. A typical round of IVF produces 1-10 embryos (younger women usually = more). Women with polycystic ovarian syndrome (prevalence: 10%) may get as many as 20. For more, you will probably need to do multiple IVF rounds. Here is a table of different companies’ reported risk reductions, slightly adjusted7 for different reporting conventions but otherwise taking all claims at face value (we’ll talk about how wise that is later). Relative risk reduction for five conditions (gray = no data / disputed data). Here baseline is for embryos neither of whose parents have the condition. GP and Orchid both say their technology has improved since reporting these numbers and they will report better numbers soon. GP numbers are not within-family validated and might be lower if they were. Absolute risk after selection for five conditions (gray = no data / disputed data), ibid. Some people might genuinely want to select on a single condition. For example, people with a strong family history of schizophrenia might want to minimize the chance of their children getting the disease; for these people, reducing schizophrenia risk by 58% (while keeping everything else constant) sounds pretty good. Everyone else probably wants a generically healthy embryo with low risk of all conditions. Exactly how this works depends on the customer’s own values - would they prefer an embryo with lower cancer risk to one who will have fewer heart attacks? - and the exact benefits will depend on how parents make that decision. Genomic Prediction and Herasight try to help by providing semi-objective measures of which embryo is overall healthiest according to different conditions’ effects on longevity and patient-rated quality of life. For Genomic Prediction, that’s the “embryo health score” If you selected the single highest-health-score embryo from a set of five, here’s how they’d do: For Herasight, it’s a “polygenic longevity index”. They don’t give exact risk reduction numbers for each disease, saying that it depends too much on a couple’s specific family history, but say that most people gain 1-4 years of healthy life (when I test it on a set of twenty embryos, the the healthiest gets an extra 1.66 years). How much would you pay to give your children an extra 1-4 years of healthy life? This is no longer a hypothetical question. Here are the costs of the companies in this space: Is it worth it? If: You’re already doing IVF
Inline links: Herasight, 4, 5, 6, https://substackcdn.com/image/fetch/$s_!VOdq!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2Fb1ba32f3-72fa-4be1-846c-6b0b04a5a213_774x279.png, 7, https://substackcdn.com/image/fetch/$s_!0oUh!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2Fe8419603-9239-43bb-8c79-77b078ff0789_548x136.png, https://substackcdn.com/image/fetch/$s_!rpEJ!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2Fc539a717-a130-460d-90c9-4ab64619f26d_548x133.png, https://substackcdn.com/image/fetch/$s_!3Kc6!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2Fbda325bb-13fb-4c27-b8c3-24facce5c71a_676x153.png, https://substackcdn.com/image/fetch/$s_!t1Am!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2F831ab3c6-4053-4ff9-bc2f-879aee4349cf_673x740.png, https://substackcdn.com/image/fetch/$s_!Q2vE!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2Fadcf2bb4-8dd1-4a88-9728-6953a820971b_422x575.png
…which included a section on how Orchid is a polygenic selection company, and polygenic selection companies are inherently “sketchy” and “honestly should be illegal”. But Nucleus is also a polygenic selection company! This is like Marlboro attacking Camel on the grounds that cigarettes are addictive and should be banned! Obviously something went wrong here - my guess is AI - and it’s a really bad look, especially when these scientific issues are so hard to litigate, and so many of us will have to go off gestalt impressions of corporate culture. Nucleus states that they validate their models internally and intend to make their results public soon. A Foothill Of The Future It’s hard not to love this technology. Lots of people (and the aforementioned professional organizations) manage anyway, but it’s hard. If this were a single-use medical treatment, delivered by a doctor after someone got the relevant condition, it would be one of the biggest advances of the decade - imagine a drug that cures 10 - 40%17 of breast cancers with no side effects! But in fact, it works for breast cancer, and schizophrenia, and heart attacks, and approximately everything else. The only things comparable are antibiotics and GLP-1RAs. And then there’s the IQ effects. Even after studying the literature, people have wildly different opinions about the importance of IQ. One of the most important debates is to what degree IQ differences are a cause of poverty, a consequence of poverty, or both. I lean towards both - a country with limited access to schools and medical care will have low average IQ, but as a consequence it probably won’t become the next big semiconductor hub. This technology could close half the IQ gap between poor and middle-income countries, or between middle-income and rich. Or it could give rich countries average IQs that have never been seen before, and let us see what kind of O-ring technologies (and new forms of social cooperation) lie just beyond the frontier. (this is the nice quantifiable argument in favor of IQ enhancement, but I find myself more convinced by fuzzier things - how much is it worth to be able to enjoy great art and literature? To fully comprehend what we know of nature, and be able to fully appreciate the mystery of the rest? To have a sense of why society works the way it does, instead of feeling like you’re being blown back and forth by institutions you don’t really understand? Amateur psychoanalysts like to say that the only people who care about IQ are those looking for an excuse to boast about how high their own is, but my experience is the opposite: I care about IQ because I bang up against the limits of my own a thousand times a day, and I hate it. I fantasize about ways to make my children smarter than I am for the same reason a dog confined in a tiny crate might fantasize about getting her puppies adopted out to a nice house with a big grassy yard.) My biggest qualm is that it might not matter. This is such a tiny foothill, flanking such a vast and foreboding range of mountains, that it might be a mistake to care about it at all. Selecting the best of five or ten embryos is not a very effective way to get the genes you want. There are things in the pipeline that will make this look like Hippocrates draining black bile. By the time the first polygenically selected children are adults, they’ll be old news. And then there’s AI. The average age at diagnosis for Type II diabetes is 45 years. Will there still be people growing gradually older and getting Type II diabetes and taking insulin injections in 2070? If not, what are we even doing here? Many people in the transhumanist community are still bullish on this technology. They think - well, there’s still an outside chance that something comes up and AGI takes another few decades. If we can enhance humans to be smarter, healthier, and more determined by the time it arrives, maybe we’ll have a better chance. Or maybe, if there’s a positive optimistic vision of a human-based high-tech future, people will be more willing to delay AI in the first place. I like this argument, but I also think it’s worth stepping back. What’s the point of anything? Why have kids at all in a world that’s changing this fast? Why save for the future? At some point your answer has to be romantic and aesthetic - it’s never been clear whether anything you do matters in any ultimate sense, but you’ve got to act as if it does and hope for the best. From that perspective, this is the most romantic technology of all. You’re not just giving a better life to your kids. Genes travel from generation to generation; you’re giving a better life your grandkids, your great-grandkids and so on to the point 1.77*log₂(population) generations from now when you are the ancestor of everybody and nobody. Somebody in Macaronesia in 3525 AD will avoid getting breast cancer because of you (if there is still cancer; if there are still breasts). Some combination of reasonable cost-benefit analysis and romantic/aesthetic commitments makes me want to have children despite the uncertainty, and the same combination made me sign up to use this technology despite the same. More later on how that’s going. 1I’m slightly mixing up two different things here - Down Syndrome can be detected with an aneuploidy test, but cystic fibrosis takes a more involved PGT-M test. 2There are two separate questions here. First, how much would diabetes risk decline if you selected the embryo with the lowest risk for diabetes - something you have no reason to do, since you have no reason to privilege diabetes risk over risk of any other disease? Second, how much would diabetes risk go down if you selected the embryo with the lowest health risk overall? Genomic Prediction’s their risk calculator calculator shows, seemingly paradoxically, that you get -38% relative risk by selecting against diabetes alone, but -41% relative risk by selecting against everything at once. Over email, they stand by this surprising result, saying that “for a couple of diseases (type II diabetes and CAD), the EHS actually accomplishes a larger risk reduction than the individual predictors. The explanation is that the EHS takes into account multiple PRS of diseases with high comorbidity”. See eg Figure 3 here: …and the section of the post called “Antagonistic Pleiotropy” for more. However, this paradoxical benefit is only true for a few conditions like diabetes - for everything else, selecting on health index does better than you would naively think, but still does not decrease the risk of a given condition as much as selecting against that condition directly. 3That is, new mutations in that particular baby, as opposed to older mutations already present in the parents. 4Conflicts of interest: I have used Orchid’s and Herasight’s products on my own embryos (not the ones used to conceive my existing kids, but for a potential third child), employees of Genomic Prediction and Herasight have been extremely helpful in contributing expertise to ACX posts on genetics, and I might invest in this field at some point (though haven’t done so yet). This post started as Herasight asking me to write about their white paper, then spiraled out of control. There were some unexpected time pressures and the result is that I didn’t get a chance to run everything in Herasight’s white paper by their competitors as thoroughly as I would like. Although I talked to representatives of all four companies profiled here, I feel like this probably reflects Herasight’s perspective better than other companies’, and that this is a major flaw. If other companies have responses, I’ll publish them. Thanks to all companies involved for their assistance on this article. Finally, I am favorably disposed toward Herasight because of how I learned about them: a professor named Jonathan Anomaly got cancelled from Penn for being too gung-ho about genetic enhancement, and used his newfound freedom to join a very-early-stage Herasight, raise their ambitions, and sell everyone (including me) on the idea. I grew up on a diet of books and movies about mad scientists, and I’m a sucker for a story about a guy named Doctor Anomaly pursuing revenge against the small-minded fools who destroyed his career by creating a race of superbabies. 5The version of the tool I looked at said 5.9 points for five embryos, up to 9 points for twenty embryos. The version of the tool on their current said says 5.3 - 9, so they might have recalculated after I finalized this article. 6Used in quotation marks because these scores were fine for the predictive tasks they were applied for - they just weren’t finding genes that directly caused the outcome of interest. 7Conflict of interest notice: this table was originally unadjusted. A representative of Herasight claimed that this was unfair, because each company used slightly different reporting conventions, and offered to correct for this in a neutral way. I retraced their reasoning, confirmed that the correction did not especially benefit Herasight at the expense of other companies, and accepted the correction. The original unadjusted table is below: Herasight was insufficiently comfortable with Nucleus’ methodology to even be willing to posit a corrected value, so I left their self-reported value in gray. 8Zagorsky (2007) says an extra IQ point means $234-$616/year in higher salary. The midpoint of $425 equals $670 in today’s dollars; assuming a forty-year career, Nucleus’ +1 point estimate is worth $26,800 (vs. $9,249 Nucleus cost) and Herasight’s +6 point estimate is worth $160,800 (vs. $53,250 Herasight cost). 9As part of researching this article, I asked all four major companies about their within-family validation strategies. Here are some details: Genomic Prediction discusses their strategy in this paper. The results are complicated to interpret - the within-family numbers often have such wide error bars that they overlap with both the across-family numbers and with zero - but looking qualitatively it seems like most scores on average lose about 25% of their risk reduction ability (though averages might not be the right way to do this, and some might be much more affected than others). Their website reports unadjusted, not within-family validated numbers; GP says they say this clearly on their site (which is true), Herasight counters that they still present their numbers as applicable to embryo selection (which is also true). To get the most applicable-to-embryo-selection numbers, you might want to adjust GP’s stated numbers down somewhat; it’s hard to say exactly how much, but maybe 20 - 25%?
Inline links: 17, GLP-1RAs, O-ring technologies, things in the pipeline, everybody, nobody, 1, 2, their risk calculator, everything, here, https://substackcdn.com/image/fetch/$s_!jtkY!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2Fd645c392-fed1-4f02-9a2e-878b8c7ef7f2_909x878.png, 3, 4, 5, 6, 7, https://substackcdn.com/image/fetch/$s_!Vimq!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2Fca0f1f15-268d-465a-a70f-b7f1173c6111_566x166.png, https://substackcdn.com/image/fetch/$s_!3B0A!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2Faccc7a65-b142-4bf6-927d-53eb607d71ef_552x155.png, 8, 9