It has taken me a while, but I think I'm gradually coming around to Eric's side of the debate about all things genes and genetic. I think his is the less commonly accepted position because it's the most sophisticated and nuanced. And as we all know, anything sophisticated and nuanced is rarely popular. Also, his arguments about heritability and its derivatives seem to me to display certain virtues that are critical to keeping science and scientific enterprises grounded: virtues like caution and humility seem rather lacking on the side that is asserting an inevitable El Dorado for applied genetics.
I understand the allure of this promise because I've also been infected by it. However, this cautionary warning by Eric strikes me as potentially prescient: "I don’t think people would want to live in a world where scientists could predict their behavioral outcomes from either their genes or their environment." This is a highly important warning but one most likely to be dismissed by the vast majority of people desperate for utopia or freedom from a miserable life, becoming easy target for Mephistopheles-style covenant.
One last point: I felt immensely gratified to read a confirmation of one of my correct logical intuitions (the vast majority of others are probably incorrect) about heritability: that it has to be a primarily statistical process when one observes the highly variable (less than predictable except in MZ pairs) phenotypic outcomes. This fact is so fundamental to our understanding of heritability because even in the most heritable conditions (eg Huntington, some cancers, even height), the outcomes are still statistical rather than given. Thus, the only difference between the heritability of say religiousity, intelligence, and height is in their statistical probability. In the former (religiousity) the within-family variance will be very high (similar to what is found in the general population), while it'll be very low in the latter (height). Thus we could summarize that for attributes/traits with high heritability, within-family differences is low, and for those with low heritability, within-family differences is high. We can use this principle to study heritability in reverse, that is, to determine the degree of heritability by aggregating and analyzing traits based on whether they possess high, mid, to low within-family variance across many families.
PS: My knowledge of genetics and heritability is very very basic (only perhaps slightly better than a layman's) and I can't boast of being familiar with the literature at all. Hence, it's possible that my suggestion in the last paragraph is (1) off the mark (2) already stale.
I'm still 'slightly' more inclined to the hereditarian side of things. (As a mostly clueless layman btw. My knowledge being very surface) but the more I read Eric the more his position makes sense. He is definitely NOT a heritability denier or environmentalist. But you have to really get down to the nitty gritty to understand the nuance and complexities of his position.
Fascinating discussion. My only quibble is with ‘the most important breakthrough in psychiatry in my lifetime has been cognitive behavior therapy’.
I can think of various psychiatric treatments from 70s onward which seem more transformational than CBT - clozapine for treatment resistant schizophrenia and lithium for bipolar disorder spring to mind.
If anything, recent research seems to challenge the superiority of CBT over other modalities of psychotherapy!
On a quick look, Clozapine was first developed in 1958 (I was 4) and Lithium long before i was born. On a fair reading of lifetime to mean, "my professional career" we are talking about developments since the 80s.
Ha! I had a quibble with that too, and Eric and I had a little discussion off the books about it. I think the development of second-generation antipsychotics and antidepressants and elaboration of the associated molecular pharmacology shaped psychiatric practice as much as CBT shaped clinical psychology. The limitations of both are also painfully evident now.
Other than clozapine and lithium, I agree with you!
Maybe you could make an argument for CBT having the potential to help more people with common mental disorders (mild-moderate depression / anxiety), but I don’t think it has greatly influenced the treatment of major mental illnesses (bipolar disorder, schizophrenia)
There is nothing “gloomy” about the prospect of leveling a century and a half of genetic determinism, which has led to so much harm and misery. It’s a chance to have real discussions about the human mind without the usual suspects pigeon-holing it. Good riddance to the fantasy that is behavioral genetics.
Wait surely there are DNA interaction effects. Isn't every promoter technically a DNA, DNA interaction? What about cases where there are multiple copies of a gene and some disease occurs only when they are all broken? What about the DNA coding for the proteins that do transcription/translation? Change how those work and you can break every other gene.
So at least technically it seems like there is something like DNA/DNA interactions. Did you have something else in mind? If you meant ones detected by statistical means that's asking alot from limited data.
The discussion is interesting, but the monogenic rare variant data is already very clear. There is also work already pulling together rare and common variants with the same directional effects (aka the liability threshold models). And the rare gene findings are already positively influencing drug development (there was an approval in this vein for SCZ this past year and evidence that genetics informed development increases R&D efficiency). There is also the obvious example in everyone's faces where we have drugs that influence a largely behavioral outcome (GLP-1 agonists and obesity).
It's right to say that neither a Lockian/Rousseauan view of human nature nor a Galtonian view of human nature is correct based on the evidence we have today. This is likely to remain true since experiences matter. However, it's always quite clear that behavior is under the powerful genetic influences. If we think that human behavior was shaped to any extent by natural selection, this is the inevitable conclusion anyway.
It is also true a great deal of the imprecision concerns the way we measure and classify behavior. Given the frequent quasi-redundancies and partial interdependencies in biological systems, there is almost certainly many biological paths to otherwise similar developmental pathways and pathophysiologies that increase the likelihood of certain similar looking behavioral outcomes that happen to be banned under the same clinical entity.
The drug target has been connected to SCZ biology by genetics research. And the actual pathophys being targeted has been consistently showing up in rare gene work. It strains credulity to say this wasn't a part of the early decision making in development.
I did not think this had anything to do with genetics but with the fact that clozapine's mechanisms of action included muscarinic receptors, which created more interest in targeting those receptors since the 90s. I'd love to see any literature that ties rare variant genetics to mechanism, but I haven't come across that so far. I suspect rare variant results didn't influence this work in the 90s anyway. And noteworthy is that while cobenfy worked, Abbvie's emraclidine did not.
I believe the known hits in CHRM were polymorphism. Rare situation were candidate gene research worked out. The rare variants/structural variants affect the dopamine physiology.
Additionally, my point made elsewhere is that the drug works and there is a mechanism there that was unearther by population, family, and molecular genetic research. This is evidence that psychiatric diseaee is not some major departure from the typical assumptions of medical science (i.e. physicalism that can be understood via reductionism).
Thanks I thought you must mean that but I wasn't sure what the link with rare gene research was - do you mean that contributed to its initial development for Alzheimer's?
Genetic research in SCZ implicated the target of the drug (CHRM4) in disease biology awhile ago. Additionally, the broader dopaminergic circuitry is the ultimate target which has been regularly implicated by rare gene family studies.
I think it strains credulity to say this knowledge didn't influence decision making and I'm sure if we are to dig deeply into the documentation we could substantiate this. Additionally, even if it had no influence on the developer, the fact there is genetic evidence that provides a rationale for the effectiveness of a pharmaceutical is central to the point I was making.
Great article and interview! However, this made me laugh: "The old eugenicists may have had ideas about eliminating the mentally ill from the population, and psychiatric genetics did have some roots in Nazi Germany, but none of that is especially active today."
Let me introduce you to a little field called BIOETHICS! Lots of philosopher active today argue that we should try to wipe out mental illnesses, not by actively killing people, but through some sort of genetic manipulation or embryo choice or the like. Julian Savelescu, who's a huge name in the field, argues that in the future, all reproduction should be IVF, and then we always pick the genetically best embryos. There should be no schizos in the future! Sure, there are hundreds of schizo genes, but let's pick embryos with as few schizo genes as possible (and just the best genes in general, but he's been specifically pressed on schizo in an interview I watched).
Obvs this is still unrealistic, even if we set ethics aside and assume that these eugenic goals are laudable. Just for starters, Kyaga et al did this huge quantiative study where they found (in extreme brief) that people with schizo or bipolar, although more often unemployed than the population at large, are somewhat over-represented in some creative professions, and their SIBLINGS have a BIG over-representation in arts and science. Presumably, insofar as there are schizo-bipolar genes, these are simultaneously art-and-science genes.
But yeah, eugenic ideals are VERY alive and well in philosophy, and just generally among the tech bro population.
Which sounds exactly like what he said -- instead of killing people or stopping them from breeding they are trying to cure diseases.
I mean yes, technically I guess curing mental illness universally does eliminate the mentally ill from the population just like curing smallpox eliminated smallpox suffers but that's clearly what he is gesturing at.
And showing an overrepresentation in some professions doesn't show the illness offers any advantage (people without legs are overrepresented in jobs which don't require walking too) and same goes for siblings. I mean there are always correlations but if the siblings had been overrepresented in welding or carpentry or the non-art/science jobs would that have been a reason to object? And any correlation can easily reflect a compensatory factor (the ppl w/ only the mental illness risk gene were selected against).
And even if one thought there were benefits one has to weigh that against the costs.
--
Sorry, as someone who suffers from certain mental health issues it really upsets me the way people seem to treat curing them as less important or more optional. I mean no one ever tries to suggest we shouldn't cure heart disease because sufferers are more likely to have X other property -- and some such correlation could certainly be found.
Mental illness is usually far far worse for quality of life than physical illness so it's particularly horrible we aren't as eager to eliminate it.
Look, I've had lots of really terrible psychotic experiences myself. I don't want to downplay the suffering. But the idea that we should alter the gene pool of the whole population, making it that much more homogenous and the entire population more streamlined and normal, is VERY different from inventing a vaccine, or from just coming up with better psychiatric treatments.
Required reading for anyone interested in behavioural genetics, heritability of behavioural/"psychological" patterns, and also the general old nature/nurture conundrum.
While the "is it more like Huntington's or more like divorce" might seem simplistic a question, it expands into a nuanced, informative take.
It has taken me a while, but I think I'm gradually coming around to Eric's side of the debate about all things genes and genetic. I think his is the less commonly accepted position because it's the most sophisticated and nuanced. And as we all know, anything sophisticated and nuanced is rarely popular. Also, his arguments about heritability and its derivatives seem to me to display certain virtues that are critical to keeping science and scientific enterprises grounded: virtues like caution and humility seem rather lacking on the side that is asserting an inevitable El Dorado for applied genetics.
I understand the allure of this promise because I've also been infected by it. However, this cautionary warning by Eric strikes me as potentially prescient: "I don’t think people would want to live in a world where scientists could predict their behavioral outcomes from either their genes or their environment." This is a highly important warning but one most likely to be dismissed by the vast majority of people desperate for utopia or freedom from a miserable life, becoming easy target for Mephistopheles-style covenant.
One last point: I felt immensely gratified to read a confirmation of one of my correct logical intuitions (the vast majority of others are probably incorrect) about heritability: that it has to be a primarily statistical process when one observes the highly variable (less than predictable except in MZ pairs) phenotypic outcomes. This fact is so fundamental to our understanding of heritability because even in the most heritable conditions (eg Huntington, some cancers, even height), the outcomes are still statistical rather than given. Thus, the only difference between the heritability of say religiousity, intelligence, and height is in their statistical probability. In the former (religiousity) the within-family variance will be very high (similar to what is found in the general population), while it'll be very low in the latter (height). Thus we could summarize that for attributes/traits with high heritability, within-family differences is low, and for those with low heritability, within-family differences is high. We can use this principle to study heritability in reverse, that is, to determine the degree of heritability by aggregating and analyzing traits based on whether they possess high, mid, to low within-family variance across many families.
PS: My knowledge of genetics and heritability is very very basic (only perhaps slightly better than a layman's) and I can't boast of being familiar with the literature at all. Hence, it's possible that my suggestion in the last paragraph is (1) off the mark (2) already stale.
I'm still 'slightly' more inclined to the hereditarian side of things. (As a mostly clueless layman btw. My knowledge being very surface) but the more I read Eric the more his position makes sense. He is definitely NOT a heritability denier or environmentalist. But you have to really get down to the nitty gritty to understand the nuance and complexities of his position.
Fascinating discussion. My only quibble is with ‘the most important breakthrough in psychiatry in my lifetime has been cognitive behavior therapy’.
I can think of various psychiatric treatments from 70s onward which seem more transformational than CBT - clozapine for treatment resistant schizophrenia and lithium for bipolar disorder spring to mind.
If anything, recent research seems to challenge the superiority of CBT over other modalities of psychotherapy!
On a quick look, Clozapine was first developed in 1958 (I was 4) and Lithium long before i was born. On a fair reading of lifetime to mean, "my professional career" we are talking about developments since the 80s.
Apologies for inadvertently discussing your age!
Ha! I had a quibble with that too, and Eric and I had a little discussion off the books about it. I think the development of second-generation antipsychotics and antidepressants and elaboration of the associated molecular pharmacology shaped psychiatric practice as much as CBT shaped clinical psychology. The limitations of both are also painfully evident now.
What would be on your list?
Other than clozapine and lithium, I agree with you!
Maybe you could make an argument for CBT having the potential to help more people with common mental disorders (mild-moderate depression / anxiety), but I don’t think it has greatly influenced the treatment of major mental illnesses (bipolar disorder, schizophrenia)
There is nothing “gloomy” about the prospect of leveling a century and a half of genetic determinism, which has led to so much harm and misery. It’s a chance to have real discussions about the human mind without the usual suspects pigeon-holing it. Good riddance to the fantasy that is behavioral genetics.
Wait surely there are DNA interaction effects. Isn't every promoter technically a DNA, DNA interaction? What about cases where there are multiple copies of a gene and some disease occurs only when they are all broken? What about the DNA coding for the proteins that do transcription/translation? Change how those work and you can break every other gene.
So at least technically it seems like there is something like DNA/DNA interactions. Did you have something else in mind? If you meant ones detected by statistical means that's asking alot from limited data.
Hi Peter! Are you referring to any particular portion of the interview?
Yes, this quote
"Any talk of additive effects or interactions in actual DNA is speculation. "
He is talking about how genomic studies work and I understood it to be a defense of the largely additive linear statistical models.
After your interview with Sasha I was asking for more genetics so thank you both! Really enlightening and this book will be going on my list.
The discussion is interesting, but the monogenic rare variant data is already very clear. There is also work already pulling together rare and common variants with the same directional effects (aka the liability threshold models). And the rare gene findings are already positively influencing drug development (there was an approval in this vein for SCZ this past year and evidence that genetics informed development increases R&D efficiency). There is also the obvious example in everyone's faces where we have drugs that influence a largely behavioral outcome (GLP-1 agonists and obesity).
It's right to say that neither a Lockian/Rousseauan view of human nature nor a Galtonian view of human nature is correct based on the evidence we have today. This is likely to remain true since experiences matter. However, it's always quite clear that behavior is under the powerful genetic influences. If we think that human behavior was shaped to any extent by natural selection, this is the inevitable conclusion anyway.
It is also true a great deal of the imprecision concerns the way we measure and classify behavior. Given the frequent quasi-redundancies and partial interdependencies in biological systems, there is almost certainly many biological paths to otherwise similar developmental pathways and pathophysiologies that increase the likelihood of certain similar looking behavioral outcomes that happen to be banned under the same clinical entity.
He is not rejecting genetic influences on behavior, though.
What do you understand his claim to be?
Which drug development approval are you referring to?
Cobenfy
Correct me if I’m wrong but I don’t think genetics had anything to do with Cobenfy’s drug development
The drug target has been connected to SCZ biology by genetics research. And the actual pathophys being targeted has been consistently showing up in rare gene work. It strains credulity to say this wasn't a part of the early decision making in development.
I did not think this had anything to do with genetics but with the fact that clozapine's mechanisms of action included muscarinic receptors, which created more interest in targeting those receptors since the 90s. I'd love to see any literature that ties rare variant genetics to mechanism, but I haven't come across that so far. I suspect rare variant results didn't influence this work in the 90s anyway. And noteworthy is that while cobenfy worked, Abbvie's emraclidine did not.
https://substack.com/@manjarinarayan/note/c-76298279?utm_source=notes-share-action&r=50pac
I believe the known hits in CHRM were polymorphism. Rare situation were candidate gene research worked out. The rare variants/structural variants affect the dopamine physiology.
Additionally, my point made elsewhere is that the drug works and there is a mechanism there that was unearther by population, family, and molecular genetic research. This is evidence that psychiatric diseaee is not some major departure from the typical assumptions of medical science (i.e. physicalism that can be understood via reductionism).
Thanks I thought you must mean that but I wasn't sure what the link with rare gene research was - do you mean that contributed to its initial development for Alzheimer's?
Genetic research in SCZ implicated the target of the drug (CHRM4) in disease biology awhile ago. Additionally, the broader dopaminergic circuitry is the ultimate target which has been regularly implicated by rare gene family studies.
Ok thanks - I think we might have slightly different perspectives on what constitutes an influence on drug development!
I think it strains credulity to say this knowledge didn't influence decision making and I'm sure if we are to dig deeply into the documentation we could substantiate this. Additionally, even if it had no influence on the developer, the fact there is genetic evidence that provides a rationale for the effectiveness of a pharmaceutical is central to the point I was making.
Great article and interview! However, this made me laugh: "The old eugenicists may have had ideas about eliminating the mentally ill from the population, and psychiatric genetics did have some roots in Nazi Germany, but none of that is especially active today."
Let me introduce you to a little field called BIOETHICS! Lots of philosopher active today argue that we should try to wipe out mental illnesses, not by actively killing people, but through some sort of genetic manipulation or embryo choice or the like. Julian Savelescu, who's a huge name in the field, argues that in the future, all reproduction should be IVF, and then we always pick the genetically best embryos. There should be no schizos in the future! Sure, there are hundreds of schizo genes, but let's pick embryos with as few schizo genes as possible (and just the best genes in general, but he's been specifically pressed on schizo in an interview I watched).
Obvs this is still unrealistic, even if we set ethics aside and assume that these eugenic goals are laudable. Just for starters, Kyaga et al did this huge quantiative study where they found (in extreme brief) that people with schizo or bipolar, although more often unemployed than the population at large, are somewhat over-represented in some creative professions, and their SIBLINGS have a BIG over-representation in arts and science. Presumably, insofar as there are schizo-bipolar genes, these are simultaneously art-and-science genes.
But yeah, eugenic ideals are VERY alive and well in philosophy, and just generally among the tech bro population.
Which sounds exactly like what he said -- instead of killing people or stopping them from breeding they are trying to cure diseases.
I mean yes, technically I guess curing mental illness universally does eliminate the mentally ill from the population just like curing smallpox eliminated smallpox suffers but that's clearly what he is gesturing at.
And showing an overrepresentation in some professions doesn't show the illness offers any advantage (people without legs are overrepresented in jobs which don't require walking too) and same goes for siblings. I mean there are always correlations but if the siblings had been overrepresented in welding or carpentry or the non-art/science jobs would that have been a reason to object? And any correlation can easily reflect a compensatory factor (the ppl w/ only the mental illness risk gene were selected against).
And even if one thought there were benefits one has to weigh that against the costs.
--
Sorry, as someone who suffers from certain mental health issues it really upsets me the way people seem to treat curing them as less important or more optional. I mean no one ever tries to suggest we shouldn't cure heart disease because sufferers are more likely to have X other property -- and some such correlation could certainly be found.
Mental illness is usually far far worse for quality of life than physical illness so it's particularly horrible we aren't as eager to eliminate it.
Look, I've had lots of really terrible psychotic experiences myself. I don't want to downplay the suffering. But the idea that we should alter the gene pool of the whole population, making it that much more homogenous and the entire population more streamlined and normal, is VERY different from inventing a vaccine, or from just coming up with better psychiatric treatments.
Required reading for anyone interested in behavioural genetics, heritability of behavioural/"psychological" patterns, and also the general old nature/nurture conundrum.
While the "is it more like Huntington's or more like divorce" might seem simplistic a question, it expands into a nuanced, informative take.
IN ANY CASE WE’LL NEVER KNOW CAUSE CERTAIN PEOPLE IN SCIENCE HAVE DISRUPTED THE COLLECTIVE 🤬
what does that mean please?
I think you know !