Newsletter #002: Genetic Enhancement
The most important works on embryo selection for IQ (Shulman, Bostrom, Branwen); the utility of polygenic screening from Karavani et al.; genetic architecture of intelligence from Hsu
Embryo Selection for Cognitive Enhancement: Curiosity or Game-changer? (2014) by Carl Shulman and Nick Bostrom: Carl Shulman and Nick Bostrom of the Future of Humanity Institute published this seminal work on embryo selection for cognitive ability. Since IQ is influenced by genes and we are now able to sequence the genomes of embryos, we can select embryos to implant that are more intelligent than the average of the batch. Shulman and Bostrom look at the theoretical returns to cognitive ability selection, and an especially promising process called iterated embryo selection:
1. Genotype and select a number of embryos that are higher in desired genetic characteristics;
2. Extract stem cells from those embryos and convert them to sperm and ova, maturing within 6 months or less (Sparrow, 2013);
3. Cross the new sperm and ova to produce embryos;
4. Repeat until large genetic changes have been accumulated.
Currently, we cannot turn stem cells into sperm and ova in humans, a process called in vitro gametogenesis, but we may be able to soon. Metaculus expects it sometime in the next twenty years. After this becomes possible, the upper limit is so high that it may be difficult to imagine the level of intelligence attainable.
Embryo Selection for Intelligence (2020) by Gwern Branwen: Polymath and pseudonymous internet writer Gwern Branwen has the best collection of resources on embryo selection for intelligence on the internet. Branwen covers several methods and their costs and benefits at length.
With genetic predictors of a phenotypic trait, it is possible to select embryos during an in vitro fertilization process to increase or decrease that trait. Extending the work of Shulman & Bostrom2014/Hsu2014, I consider the case of human intelligence using SNP-based genetic prediction, finding:
a meta-analysis of GCTA results indicates that SNPs can explain >33% of variance in current intelligence scores, and >44% with better-quality phenotype testing
this sets an upper bound on the effectiveness of SNP-based selection: a gain of 9 IQ points when selecting the top embryo out of 10
the best 2016 polygenic score could achieve a gain of ~3 IQ points when selecting out of 10
the marginal cost of embryo selection (assuming IVF is already being done) is modest, at $1500 + $200 per embryo, with the sequencing cost projected to drop rapidly
a model of the IVF process, incorporating number of extracted eggs, losses to abnormalities & vitrification & failed implantation & miscarriages from 2 real IVF patient populations, estimates feasible gains of 0.39 & 0.68 IQ points
embryo selection is currently unprofitable (mean: -$358) in the USA under the lowest estimate of the value of an IQ point, but profitable under the highest (mean: $6230). The main constraints on selection profitability is the polygenic score; under the highest value, the NPV EVPI of a perfect SNP predictor is $24b and the EVSI per education/SNP sample is $71k
under the worst-case estimate, selection can be made profitable with a better polygenic score, which would require n > 237,300 using education phenotype data (and much less using fluid intelligence measures)
selection can be made more effective by selecting on multiple phenotype traits: considering an example using 7 traits (IQ/height/BMI/diabetes/ADHD/bipolar/schizophrenia), there is a factor gain over IQ alone; the outperformance of multiple selection remains after adjusting for genetic correlations & polygenic scores and using a broader set of 16 traits.
Screening Human Embryos for Polygenic Traits Has Limited Utility by Karavani et al. (2019): A more skeptical look at embryo selection for intelligence and height. I prefer Shulman and Bostrom (2014) and Branwen (2020). One issue with the utility analysis is the comparison is between best and average, whereas one might care a lot about avoiding a horrible outcome like an extremely low IQ. See Steve Hsu’s blog post on the paper for more on that.
The increasing proportion of variance in human complex traits explained by polygenic scores, along with progress in preimplantation genetic diagnosis, suggests the possibility of screening embryos for traits such as height or cognitive ability. However, the expected outcomes of embryo screening are unclear, which undermines discussion of associated ethical concerns. Here, we use theory, simulations, and real data to evaluate the potential gain of embryo screening, defined as the difference in trait value between the top-scoring embryo and the average embryo. The gain increases very slowly with the number of embryos but more rapidly with the variance explained by the score. Given current technology, the average gain due to screening would be ≈2.5 cm for height and ≈2.5 IQ points for cognitive ability. These mean values are accompanied by wide prediction intervals, and indeed, in large nuclear families, the majority of children top-scoring for height are not the tallest.
On the genetic architecture of intelligence and other quantitative traits (2014) by Steve Hsu: Hsu discusses psychometric intelligence, genetics, and some of the mathematics behind discovering causal gene variants. A large number of genes are associated with intelligence, so there is a lot of room to work with using genetic enhancement.
Abstract: How do genes affect cognitive ability or other human quantitative traits such as height or disease risk? Progress on this challenging question is likely to be significant in the near future. I begin with a brief review of psychometric measurements of intelligence, introducing the idea of a "general factor" or g score. The main results concern the stability, validity (predictive power), and heritability of adult g. The largest component of genetic vari- ance for both height and intelligence is additive (linear), leading to important simplifications in predictive modeling and statistical estimation. Due mainly to the rapidly decreasing cost of genotyping, it is possible that within the coming decade researchers will identify loci which account for a significant fraction of total g variation. In the case of height analogous efforts are well under way. I describe some unpublished results concerning the genetic architecture of height and cognitive ability, which suggest that roughly 10k moderately rare causal variants of mostly negative effect are responsible for normal population variation. Using results from Compressed Sensing (L1-penalized regression), I estimate the statistical power required to characterize both linear and nonlinear models for quantitative traits. The main unknown parameter s (sparsity) is the number of loci which account for the bulk of the genetic variation. The required sample size is of order 100 s, or roughly a million in the case of cognitive ability.
For a less technical discussion of the same topics from Hsu, you can see “Super-Intelligent Humans Are Coming.” Steve Hsu writes over at Information Processing.
These newsletters contain links, articles, and papers that remain relevant. If you enjoyed this, consider taking a look at previous newsletters:
Newsletter #001: Cognitive Ability — Independent intelligences as a degenerating research program; against IQ threshold effects; the IQ halo effect; and IQ fadeout
How far are we from the technology described by Heinlein in _Beyond This Horizon_, an early novel? The idea was to select separately on sperm and ovum. The trick to examining them nondestructively was to take advantage of the fact that the process of creating either throws off additional bodies with the genes not included which can be analyzed destructively to determine the genetic content of the gamete.
Obviously the gametes have to be produced in vitro for this to work. If it could be done it would be a much more powerful technology than selecting on embryos.
This is completely mind-blowing to me. Why are there not more governments funding this? I can't think of many things that would have a better return on investment for a country than increasing the average IQ of its citizens.