In the 1950s and 1960s China went through an episode of mass starvation followed by the chaos of the cultural revolution. Does that mean most Chinese have inherited trauma. Doesn't seem like it.
Thorough takedown of the transgenerational inheritance hype. The germline reprogramming point is critical, those two wipeouts basically reset the slate and any methylation marks from enviromental stress have to survive what amounts to biological reformatting twice. I've seen colleagues cite the Dutch Hunger Winter studies without realizing Tobi's selection bias work undermined the whole caussal chain. The rodent stuff is even sketchier when you dig into effect directions flipping across generations and sexes.
Fantastic breakdown of the germline reprogramming issue. The part about how methylation marks get wiped twice per generation really undercuts alot of the trauma inheritance narratives floatng around. I remember seeing a study on stress in rats being passed down, but honestly that always seemd more like learned behavior from bad parenting than actual molecular memory.
You are completely wrong. Just because you can’t find a mechanism for non genetic heritability doesn’t mean there isn’t one.
I could go on and on with examples that are very specific and hard to disprove using biases or sloppy research. I’m somewhat surprised at this argument at all because the literature is so full of very good studies done with people and with little chance of confounding due to bias.
You seem to confuse what exactly transgenerational epigenetic inheritance actually is and implies. From Razib Khan:
“Intergenerational epigenetic transmission means that the changes affect both the offspring and the parent (and perhaps also the grandchildren, in the case of a female fetus whose eggs are impacted during in utero development). The theory of transgenerational epigenetic transmission extends it a step further, with offspring passing the epigenetic marks down to multiple future generations. This is the form of epigenetic inheritance requisite for hypothesized intergenerational trauma, because it is not a correlation due to the same stress event occurring to the parent and fetus simultaneously, but an event whose impact is transmitted biologically across many generations. A cause that echoes down through the generations.”
…
“A simple illustration of genuine intergenerational transmission that requires no imaginative gymnastics would be famine which induces stress on the pregnant mother, her female fetus and the female fetus’s own eggs, where all exhibit epigenetic responses due to a simultaneous and singular external shock. The longest possible chain of generational impacts of this event would reach to the children of a female fetus in utero at the time of the external stressor (the third generation). And if the fetus were male, the effect could not persist beyond him in the second generation, because males continuously produce new sperm cells throughout their lifetime; no mechanism exists for them to transmit the famine-induced changes. Any posited intergenerational “transmission” cannot then be literal transmission, but at most correlation due to the same shock contemporaneously impacting parent and offspring (and if the fetus is female, egg cells). Multiple generations, yes, but only in the way that multiple generations living through a catastrophic earthquake carry its scars in various forms for the rest of their lives. In contrast, under transgenerational transmission, the stress marks induced by the external shock are thought to be copied generation after generation so that the effect persists much longer.”
So why does this matter? Well, your own first study shows no effect in the F3 generation. Good start.
DES is a pharmacological endocrine disruptor administered at a high, non-physiological dose. Even if we believed the results, it is not epigenetic inheritance caused by germline transmission of epigenetic marks, it is essentially prenatal estrogenic poisoning disrupting ovarian development. But should we take the results at face value? Many reported effects are marginal and some magically reverse or vanish (and none appear in F3). This is just another instance of the “flickering phenotype” from all these studies that dress noise up as inheritance. The fact that these phenotypes are unstable is actually excellent evidence of no way to transmit transgenerationally.
The remaining two malnutrition studies you cite are not evidence. The simple reason is that who gets exposed to nutrition shocks isn’t random. These correlations between exposure and phenotype vanish in sibling comparisons: https://www.cremieux.xyz/p/a-requiem-for-nutrition
I will also add a final note that for the third study, surely even you cannot believe that “epigenetic BMI transmission”, if it was real, would be sex-specific given high polygenicity. Oh and the best part? Multiple subgroup tests (e.g., by age at captivity, season of birth, line of descent) without any explicit corrections for multiple comparisons, and the male-line effects that did exist were at p<.05.
>I could go on and on with examples that are very specific and hard to disprove using biases or sloppy research
That one is another popular one and has not been independently replicated.
When that study was originally published, some have already pointed out the results were “too successful”. Even *if* the effect was actually real, the probability of getting uniformly positive results like they did, including the neuroanatomical ones, is 0.4% (and if the effect isn’t real… take a wild guess) As one of them speculated:
“How could the findings of Dias and Ressler (2014) have been so positive with such low odds of success? Perhaps there were unreported experiments that did not agree with the theoretical claims; perhaps the experiments were run in a way that improperly inflated the success and type I error rates, which would render the statistical inferences invalid.”
Now, the authors of this original paper did issue a reply to this criticism, but suffice to say, I am not impressed with their response. It essentially boils down to “well we did include *some* negative results” but it doesn’t deal with the main criticism. And, the same skeptic noted in a follow-up:
“1) Dias & Ressler claim that they did include some negative results. Interpreting this claim requires understanding what counts as a “negative result”, which is always relative to the proposed theory. The non-significant effects reported by Dias & Ressler were not characterised by them as being “unsuccessful” but were either integrated into their theoretical ideas or were deemed irrelevant (some were controls that helped them make other arguments). Of course scientists have to change theories to match data, but if the data are noisy then this practice means the theory chases noise (and the findings show excess success relative to the theory).
2) I think Dias & Ressler misunderstand the nature of my critique. They say that they stand by their results as being robust and reproducible, but that seems difficult to accept given that their own data suggests that, with experiments similar to those they reported, multiple successful outcomes should be quite rare. Moreover, their opening paragraph reports that they have replicated the findings multiple times within their laboratory. In general, this makes their situation even worse because such replication efforts should have produced some unsuccessful outcomes. The success probability of their original experiments, low as it was, must be larger than the success probability for the original experiments and additional successful replications.”
The fact that the original study also wasn’t preregistered doesn’t provide much confidence either (not to say that preregistration solves everything obviously).
Additionally, another commentary of this study, while praising it, also raises some critical questions:
“First, the authors did not find a DNA methylation mark in the particular olfactory receptor genes in olfactory response neurons, where one would anticipate that the epigenetic memory would express itself. Second, epigenetic marks are inherently tissue specific. There is a long series of differentiation steps between sperm and olfactory receptor neurons, which must involve many stages at which cell type–specific DNA methylation patterns are sculpted. How is the DNA methylation mark in the sperm maintained through these steps to guide the expression of the phenotype in the appropriate neurons and not in other cells? This is even more perplexing in that it seems that this DNA methylation mark is absent in the olfactory receptor neurons themselves. Third, not just the memory for the odor, but also the association of the odor with a fearful experience, is transmitted across generations. This should involve a more complex neuronal circuitry than just the olfactory receptor. What are the epigenetic marks in the sperm that are transmitted to the particular neurons involved in this linking of fearful response to an ancestral odor exposure? Fourth, how does the germ cell recognize and integrate both the olfactory signal and fearful experience? Is there a channel of communication between the CNS and specific loci in the gametes?”
And lastly, if the effects truly are real, then, as Kevin Mitchell has asked, “in those ten years since this initial "discovery", did this lead to cumulative, progressive research of the kind that supports the validity of the initial discovery and extends it in ways we'd expect for a real thing?” I think anyone honest will admit that we are no less in the dark about this supposedly real discovery now as we were then, despite the rate of advancement science makes nowadays.
I think the author believes these studies wouldn’t reproduce, they are too confounded with errors and bias. I happpen to. not agree, but that’s what he says here, I believe.
In the 1950s and 1960s China went through an episode of mass starvation followed by the chaos of the cultural revolution. Does that mean most Chinese have inherited trauma. Doesn't seem like it.
Thorough takedown of the transgenerational inheritance hype. The germline reprogramming point is critical, those two wipeouts basically reset the slate and any methylation marks from enviromental stress have to survive what amounts to biological reformatting twice. I've seen colleagues cite the Dutch Hunger Winter studies without realizing Tobi's selection bias work undermined the whole caussal chain. The rodent stuff is even sketchier when you dig into effect directions flipping across generations and sexes.
Fantastic breakdown of the germline reprogramming issue. The part about how methylation marks get wiped twice per generation really undercuts alot of the trauma inheritance narratives floatng around. I remember seeing a study on stress in rats being passed down, but honestly that always seemd more like learned behavior from bad parenting than actual molecular memory.
Great essay. Very readable.
Does Alden have any STEM credentials?
You are completely wrong. Just because you can’t find a mechanism for non genetic heritability doesn’t mean there isn’t one.
I could go on and on with examples that are very specific and hard to disprove using biases or sloppy research. I’m somewhat surprised at this argument at all because the literature is so full of very good studies done with people and with little chance of confounding due to bias.
For instance, DES and female offspring:
https://www.nature.com/articles/s41598-024-81093-8
Prenatal exposure to diethylstilbestrol has multigenerational effects on folliculogenesis
https://pubmed.ncbi.nlm.nih.gov/35449569/
Association of Parental Famine Exposure With Offspring Depression and Cognition Function
https://www.nber.org/system/files/working_papers/w30599/w30599.pdf
Overweight Grandsons and Grandfathers' Starvation Exposure
You seem to confuse what exactly transgenerational epigenetic inheritance actually is and implies. From Razib Khan:
“Intergenerational epigenetic transmission means that the changes affect both the offspring and the parent (and perhaps also the grandchildren, in the case of a female fetus whose eggs are impacted during in utero development). The theory of transgenerational epigenetic transmission extends it a step further, with offspring passing the epigenetic marks down to multiple future generations. This is the form of epigenetic inheritance requisite for hypothesized intergenerational trauma, because it is not a correlation due to the same stress event occurring to the parent and fetus simultaneously, but an event whose impact is transmitted biologically across many generations. A cause that echoes down through the generations.”
…
“A simple illustration of genuine intergenerational transmission that requires no imaginative gymnastics would be famine which induces stress on the pregnant mother, her female fetus and the female fetus’s own eggs, where all exhibit epigenetic responses due to a simultaneous and singular external shock. The longest possible chain of generational impacts of this event would reach to the children of a female fetus in utero at the time of the external stressor (the third generation). And if the fetus were male, the effect could not persist beyond him in the second generation, because males continuously produce new sperm cells throughout their lifetime; no mechanism exists for them to transmit the famine-induced changes. Any posited intergenerational “transmission” cannot then be literal transmission, but at most correlation due to the same shock contemporaneously impacting parent and offspring (and if the fetus is female, egg cells). Multiple generations, yes, but only in the way that multiple generations living through a catastrophic earthquake carry its scars in various forms for the rest of their lives. In contrast, under transgenerational transmission, the stress marks induced by the external shock are thought to be copied generation after generation so that the effect persists much longer.”
So why does this matter? Well, your own first study shows no effect in the F3 generation. Good start.
DES is a pharmacological endocrine disruptor administered at a high, non-physiological dose. Even if we believed the results, it is not epigenetic inheritance caused by germline transmission of epigenetic marks, it is essentially prenatal estrogenic poisoning disrupting ovarian development. But should we take the results at face value? Many reported effects are marginal and some magically reverse or vanish (and none appear in F3). This is just another instance of the “flickering phenotype” from all these studies that dress noise up as inheritance. The fact that these phenotypes are unstable is actually excellent evidence of no way to transmit transgenerationally.
The remaining two malnutrition studies you cite are not evidence. The simple reason is that who gets exposed to nutrition shocks isn’t random. These correlations between exposure and phenotype vanish in sibling comparisons: https://www.cremieux.xyz/p/a-requiem-for-nutrition
I will also add a final note that for the third study, surely even you cannot believe that “epigenetic BMI transmission”, if it was real, would be sex-specific given high polygenicity. Oh and the best part? Multiple subgroup tests (e.g., by age at captivity, season of birth, line of descent) without any explicit corrections for multiple comparisons, and the male-line effects that did exist were at p<.05.
>I could go on and on with examples that are very specific and hard to disprove using biases or sloppy research
Well… looks like that didn’t age very well.
You seem to omit the most famous study:
Mice can inherit learned sensitivity to a smell
Dec. 2, 2013
https://news.emory.edu/stories/2013/12/smell_epigenetics_ressler/index.html
Do you have any info on how that went or if it fell down in the replication crisis?
That one is another popular one and has not been independently replicated.
When that study was originally published, some have already pointed out the results were “too successful”. Even *if* the effect was actually real, the probability of getting uniformly positive results like they did, including the neuroanatomical ones, is 0.4% (and if the effect isn’t real… take a wild guess) As one of them speculated:
“How could the findings of Dias and Ressler (2014) have been so positive with such low odds of success? Perhaps there were unreported experiments that did not agree with the theoretical claims; perhaps the experiments were run in a way that improperly inflated the success and type I error rates, which would render the statistical inferences invalid.”
https://academic.oup.com/genetics/article/198/2/449/5935942
Now, the authors of this original paper did issue a reply to this criticism, but suffice to say, I am not impressed with their response. It essentially boils down to “well we did include *some* negative results” but it doesn’t deal with the main criticism. And, the same skeptic noted in a follow-up:
“1) Dias & Ressler claim that they did include some negative results. Interpreting this claim requires understanding what counts as a “negative result”, which is always relative to the proposed theory. The non-significant effects reported by Dias & Ressler were not characterised by them as being “unsuccessful” but were either integrated into their theoretical ideas or were deemed irrelevant (some were controls that helped them make other arguments). Of course scientists have to change theories to match data, but if the data are noisy then this practice means the theory chases noise (and the findings show excess success relative to the theory).
2) I think Dias & Ressler misunderstand the nature of my critique. They say that they stand by their results as being robust and reproducible, but that seems difficult to accept given that their own data suggests that, with experiments similar to those they reported, multiple successful outcomes should be quite rare. Moreover, their opening paragraph reports that they have replicated the findings multiple times within their laboratory. In general, this makes their situation even worse because such replication efforts should have produced some unsuccessful outcomes. The success probability of their original experiments, low as it was, must be larger than the success probability for the original experiments and additional successful replications.”
The fact that the original study also wasn’t preregistered doesn’t provide much confidence either (not to say that preregistration solves everything obviously).
Additionally, another commentary of this study, while praising it, also raises some critical questions:
“First, the authors did not find a DNA methylation mark in the particular olfactory receptor genes in olfactory response neurons, where one would anticipate that the epigenetic memory would express itself. Second, epigenetic marks are inherently tissue specific. There is a long series of differentiation steps between sperm and olfactory receptor neurons, which must involve many stages at which cell type–specific DNA methylation patterns are sculpted. How is the DNA methylation mark in the sperm maintained through these steps to guide the expression of the phenotype in the appropriate neurons and not in other cells? This is even more perplexing in that it seems that this DNA methylation mark is absent in the olfactory receptor neurons themselves. Third, not just the memory for the odor, but also the association of the odor with a fearful experience, is transmitted across generations. This should involve a more complex neuronal circuitry than just the olfactory receptor. What are the epigenetic marks in the sperm that are transmitted to the particular neurons involved in this linking of fearful response to an ancestral odor exposure? Fourth, how does the germ cell recognize and integrate both the olfactory signal and fearful experience? Is there a channel of communication between the CNS and specific loci in the gametes?”
https://www.nature.com/articles/nn.3603
And lastly, if the effects truly are real, then, as Kevin Mitchell has asked, “in those ten years since this initial "discovery", did this lead to cumulative, progressive research of the kind that supports the validity of the initial discovery and extends it in ways we'd expect for a real thing?” I think anyone honest will admit that we are no less in the dark about this supposedly real discovery now as we were then, despite the rate of advancement science makes nowadays.
https://x.com/wiringthebrain/status/1803147228904571389?s=46
I think the author believes these studies wouldn’t reproduce, they are too confounded with errors and bias. I happpen to. not agree, but that’s what he says here, I believe.