This is not what I expected. I thought this article would be about molecular methods of directly altering the genome—CRISPR, artificial chromosomes, etc.
But instead I only see one method mentioned, and it consists of a quasi-darwinian cycle in which lots of eggs are fertilized, allowed to divide a few times, genetically screened for desired traits, and then cells from these early-stage embryos are used to make a new generation of sperm and eggs so as to repeat the cycle.
Darwinian evolution consists of variation followed by selection, and here the engine of variation is the all-natural process of chromosomal recombination that occurs during sexual reproduction. In nature, the fertilized egg then grows into an organism, and the selective filter is how well it survives and reproduces out in the world. But in the described process of accelerated artificial selection, the fertilized eggs don’t grow into organisms. Instead, they are sequenced in order to discover the individual genotypes produced, and evaluated on the basis of a guess as to how they would fare, if they did grow into an organism.
To put it another way, natural selection is a cycle of genotypes that grow into phenotypes that mate and create new genotypes, but this accelerated artificial selection uses virtual phenotypes obtained by combining sequence information with GWAS-based interpretation.
I’ll admit that’s ingenious. And it would be interesting to know if an analogous method has ever been used successfully, on any kind of organism.
I see two opportunities for doubt: the selection criteria, and the safety of repeated artificial fertilization/gametogenesis. Regarding the first, one may doubt GWAS on the grounds of reliability (false positives) and power (not enough variance accounted for). Regarding the second, one would like to know that this process isn’t creating e.g. some cumulative epigenetic artefact.
A few further comments:
This article is headlined as a “review of current and near-future methods”, but it really seems to be about promoting this one particular method (iterated embryo selection). There’s discussion in the comments here about the history of this idea—it was mentioned in a bioethics journal in 2012, under the name “in vitro eugenics”; it was discussed by Carl Shulman at MIRI in 2009; and Gwern found a precursor dating from 1998.
I think a genuine review would have to say more about direct genetic modification. The one instance of human genetic engineering that we know about, performed in China in 2018, of course used CRISPR. I believe this is now illegal in China (see draft item 39 here), as of last month. And CRISPR ends up modifying more than just the targeted gene. Nonetheless, genome editing will surely be part of future human genetic engineering.
Meanwhile, iterated gametogenesis will just as surely have its own safety issues. They say there were 276 failed attempts before the successful cloning of a sheep (Dolly). Cumulative epigenetic modifications, of a kind not occurring in nature, seems an extremely likely risk.
Speaking of epigenetics, I’ve just discovered the existence of another class of methods, epigenome editing… And then there’s the topic of nonheritable (and possibly temporary) genetic modifications made to mature organisms. If what you care about is biological intelligence increase, somatic gene-hacking seems likely to get there before germline gene-hacking, because you don’t have to wait for your first generation to grow up.
Speaking of epigenetics, I’ve just discovered the existence of another class of methods, epigenome editing… And then there’s the topic of nonheritable (and possibly temporary) genetic modifications made to mature organisms. If what you care about is biological intelligence increase, somatic gene-hacking seems likely to get there before germline gene-hacking, because you don’t have to wait for your first generation to grow up.
I read something relevant to this idea tonight that I think makes it less likely we will be able to significantly impact intelligence with epigenetic editing. A paper in PNAS from last year looked at which functional regions of the genome saw enrichment of educational-attainment associated SNP hits:
The EA3 study on educational attainment, a highly polygenic trait, is another notable recent example of this type of analysis (39). A very large number of category enrichment analyses was performed on 1,271 independent genome-wide significant signals detected in a GWAS of 1.1 million individuals with educational attainment data. The authors highlight two broad findings. First, the most significantly prioritized genes that were implicated as causal show trajectories of expression in the brain that are increased before the late prenatal stage of development and decline thereafter. Weaker, newly discovered, associations showed no such trajectory. This suggests a modestly disproportionate influence of brain development relative to active brain functioning in determining differences between individual abilities underlying educational attainment, which is perhaps not surprising.
This suggest that even if we were somehow able to inject some epigenome modifying vector into brains capable of modifying a significant fraction of neurons and even if the inevitable cell mosaicism induced by such changes had no negative impact on cognitive function, we would STILL be severely limited in the proportion of genetically influenced intelligence we could impact.
Not to mention it seems very likely that the cost of modifying 86 billion cells in the brain would far exceed the cost of sequencing embryo DNA.
Thank you for writing such a thoughtful comment. I have to confess, I probably gave this post the wrong title. For the longest time I simply titled it “Genetic Engineering Part 3” as I wasn’t sure what to call it when I first started. I then accidentally left that title in when I first published it and hastily changed it to its current title even though that doesn’t quite fit either.
You’re correct, of course, that I did not comprehensively review all possible techniques for genetic engineering. Most notably among these is whole-genome synthesis, with which we could theoretically create an entire genome with any base pairs we wanted. In my research I estimated that synthesizing a whole human genome from scratch would cost about $200 million. So we still have a few orders of magnitude to go before whole genome sequencing becomes a viable method for creating superhumans.
I also have some serious concerns about other much more dangerous uses of whole-genome synthesis. If the technology becomes cheap enough and widely enough available it could become an incredibly dangerous weapon for engineering biological weapons. This is such a big worry that I think pursuing human genetic modification via genome synthesis might actually end up INCREASING the risk of human extinction rather than decreasing it.
Regarding the first, one may doubt GWAS on the grounds of reliability (false positives) and power (not enough variance accounted for)
If there were false positives in a GWAS then the model would have poor performance on the test set. Of course there ARE issues with GWAS predictive power when you try to generalize to other populations with a high ancestral distance from your training set. For example I remember reading about a GWAS for general cognitive ability that predicted about 10% of variance in Europeans, but only 2.5% for people of African descent. However that isn’t an issue of false positives. It’s an issue of different genes having different frequencies in each population. We could create a good predictor for people of African descent if we had data sets that included more people from those populations.
Regarding the second, one would like to know that this process isn’t creating e.g. some cumulative epigenetic artefact.
This is something I didn’t even think about when writing the paper, so thanks for bringing it up. I would think that the epigenome would be preserved throughout this process, but that assumption might be wrong.
This is not what I expected. I thought this article would be about molecular methods of directly altering the genome—CRISPR, artificial chromosomes, etc.
But instead I only see one method mentioned, and it consists of a quasi-darwinian cycle in which lots of eggs are fertilized, allowed to divide a few times, genetically screened for desired traits, and then cells from these early-stage embryos are used to make a new generation of sperm and eggs so as to repeat the cycle.
Darwinian evolution consists of variation followed by selection, and here the engine of variation is the all-natural process of chromosomal recombination that occurs during sexual reproduction. In nature, the fertilized egg then grows into an organism, and the selective filter is how well it survives and reproduces out in the world. But in the described process of accelerated artificial selection, the fertilized eggs don’t grow into organisms. Instead, they are sequenced in order to discover the individual genotypes produced, and evaluated on the basis of a guess as to how they would fare, if they did grow into an organism.
To put it another way, natural selection is a cycle of genotypes that grow into phenotypes that mate and create new genotypes, but this accelerated artificial selection uses virtual phenotypes obtained by combining sequence information with GWAS-based interpretation.
I’ll admit that’s ingenious. And it would be interesting to know if an analogous method has ever been used successfully, on any kind of organism.
I see two opportunities for doubt: the selection criteria, and the safety of repeated artificial fertilization/gametogenesis. Regarding the first, one may doubt GWAS on the grounds of reliability (false positives) and power (not enough variance accounted for). Regarding the second, one would like to know that this process isn’t creating e.g. some cumulative epigenetic artefact.
A few further comments:
This article is headlined as a “review of current and near-future methods”, but it really seems to be about promoting this one particular method (iterated embryo selection). There’s discussion in the comments here about the history of this idea—it was mentioned in a bioethics journal in 2012, under the name “in vitro eugenics”; it was discussed by Carl Shulman at MIRI in 2009; and Gwern found a precursor dating from 1998.
I think a genuine review would have to say more about direct genetic modification. The one instance of human genetic engineering that we know about, performed in China in 2018, of course used CRISPR. I believe this is now illegal in China (see draft item 39 here), as of last month. And CRISPR ends up modifying more than just the targeted gene. Nonetheless, genome editing will surely be part of future human genetic engineering.
Meanwhile, iterated gametogenesis will just as surely have its own safety issues. They say there were 276 failed attempts before the successful cloning of a sheep (Dolly). Cumulative epigenetic modifications, of a kind not occurring in nature, seems an extremely likely risk.
Speaking of epigenetics, I’ve just discovered the existence of another class of methods, epigenome editing… And then there’s the topic of nonheritable (and possibly temporary) genetic modifications made to mature organisms. If what you care about is biological intelligence increase, somatic gene-hacking seems likely to get there before germline gene-hacking, because you don’t have to wait for your first generation to grow up.
I read something relevant to this idea tonight that I think makes it less likely we will be able to significantly impact intelligence with epigenetic editing. A paper in PNAS from last year looked at which functional regions of the genome saw enrichment of educational-attainment associated SNP hits:
This suggest that even if we were somehow able to inject some epigenome modifying vector into brains capable of modifying a significant fraction of neurons and even if the inevitable cell mosaicism induced by such changes had no negative impact on cognitive function, we would STILL be severely limited in the proportion of genetically influenced intelligence we could impact.
Not to mention it seems very likely that the cost of modifying 86 billion cells in the brain would far exceed the cost of sequencing embryo DNA.
Thank you for writing such a thoughtful comment. I have to confess, I probably gave this post the wrong title. For the longest time I simply titled it “Genetic Engineering Part 3” as I wasn’t sure what to call it when I first started. I then accidentally left that title in when I first published it and hastily changed it to its current title even though that doesn’t quite fit either.
You’re correct, of course, that I did not comprehensively review all possible techniques for genetic engineering. Most notably among these is whole-genome synthesis, with which we could theoretically create an entire genome with any base pairs we wanted. In my research I estimated that synthesizing a whole human genome from scratch would cost about $200 million. So we still have a few orders of magnitude to go before whole genome sequencing becomes a viable method for creating superhumans.
I also have some serious concerns about other much more dangerous uses of whole-genome synthesis. If the technology becomes cheap enough and widely enough available it could become an incredibly dangerous weapon for engineering biological weapons. This is such a big worry that I think pursuing human genetic modification via genome synthesis might actually end up INCREASING the risk of human extinction rather than decreasing it.
If there were false positives in a GWAS then the model would have poor performance on the test set. Of course there ARE issues with GWAS predictive power when you try to generalize to other populations with a high ancestral distance from your training set. For example I remember reading about a GWAS for general cognitive ability that predicted about 10% of variance in Europeans, but only 2.5% for people of African descent. However that isn’t an issue of false positives. It’s an issue of different genes having different frequencies in each population. We could create a good predictor for people of African descent if we had data sets that included more people from those populations.
This is something I didn’t even think about when writing the paper, so thanks for bringing it up. I would think that the epigenome would be preserved throughout this process, but that assumption might be wrong.