National Geographic

Mice Inherit Specific Memories, Because Epigenetics?

Two weeks ago I wrote about some tantalizing research coming out of the Society for Neuroscience meeting in San Diego. Brian Dias, a postdoctoral fellow in Kerry Ressler’s lab at Emory University, had reported that mice inherit specific smell memories from their fathers — even when the offspring have never experienced that smell before, and even when they’ve never met their father. What’s more, their children are born with the same specific memory.

This was a big, surprising claim, causing many genetics experts to do a double-take, as I discovered from a subsequent flurry of Tweets. “Crazy Lamarkian shit,” quipped Laura Hercher (@laurahercher), referring to Lamarckian inheritance, the largely discredited theory that says an organism can pass down learned behaviors or traits to its offspring. “My instinct is deep skepticism, but will have to wait for paper to come out,” wrote Kevin Mitchell (@WiringTheBrain). “If true, would be revolutionary.”

The paper is out today in Nature Neuroscience, showing what I reported before as well as the beginnings of an epigenetic explanation. (Epigenetics usually refers to chemical changes that affect gene expression without altering the DNA code).

Having the data in hand allowed me to fill in the backstory of the research, as well as gather more informed reactions from experts in neuroscience and in genetics. I’ve gone into a lot of detail below, but here’s the bottom line: The behavioral results are surprising, solid, and will certainly inspire further studies by many other research groups. The epigenetic data seems gauzy by comparison, with some experts saying it’s thin-but-useful and others finding it full of holes.

So what is the surprising part, again? 

If you’ve followed science news over the past decade then you’ve probably heard about epigenetics, a field that’s caught fire in the minds of scientists and the public, and understandably so. Epigenetic studies have shown that changes in an organism’s external environment — its life experiences and even its choices, if you want to get hyperbolic — can influence the expression of its otherwise inflexible DNA code. Epigenetics, in other words, is enticing because it offers a resolution to the tedious, perennial debates of nurture versus nature.

But some scientists dispute the notion that epigenetic changes have much influence on behavior (see this Nature feature for a great overview of the debate). Even more controversial is the idea that epigenetic changes can be passed down from one generation to the next, effectively giving parents a way to prime their children for a specific environment. The key question isn’t whether this so-called ‘transgenerational epigenetic inheritance’ happens — it does — but rather how it happens (and how frequently, and in what contexts and species).

That’s what Dias and Ressler wanted to investigate. Trouble is, environmental influences such as stress are notoriously difficult to measure. So the researchers focused on the mouse olfactory system, the oft-studied and well-mapped brain circuits that process smell. “We thought it would give us a molecular foothold into how transgenerational inheritance might occur,” Dias says.

The researchers made mice afraid of a fruity odor, called acetophenone, by pairing it with a mild shock to the foot. In a study published a few years ago, Ressler had shown that this type of fear learning is specific: Mice trained to fear one particular smell show an increased startle to that odor but not others. What’s more, this fear learning changes the organization of neurons in the animal’s nose, leading to more cells that are sensitive to that particular smell.

Ten days after this fear training, Dias allowed the animals to mate. And that’s where the crazy begins. The offspring (known as the F1 generation) show an increased startle to the fruity smell even when they have never encountered the smell before, and thus have no obvious reason to be sensitive to it. And their reaction is specific: They do not startle to another odor called propanol. Craziest of all, their offspring (the F2 generation) show the same increased sensitivity to acetophenone.

The scientists then looked at the F1 and F2 animals’ brains. When the grandparent generation is trained to fear acetophenone, the F1 and F2 generations’ noses end up with more “M71 neurons,” which contain a receptor that detects acetophenone. Their brains also have larger “M71 glomeruli,” a region of the olfactory bulb that responds to this smell.

“When Brian came in with the first set of data, we both just couldn’t believe it,” Ressler recalls. “I was like, ‘Well, it must just be random, let’s do it again.’ And then it just kept working. We do a lot of behavior [experiments], but being able to see structural change that correlates with behavior is really pretty astounding.”

Still, those experiments couldn’t rule out some kind of social, rather than biological transmission. Perhaps fathers exposed to the fear training treated their children differently. Or maybe mothers, sensing something odd in their mate’s behavior, treated their children differently.

To control for these possibilities, the researchers performed an in vitro fertilization (IVF) experiment in which they trained male animals to fear acetophenone and then 10 days later harvested the animals’ sperm. They sent the sperm to another lab across campus where it was used to artificially inseminate female mice. Then the researchers looked at the brains of the offspring. They had larger M71 glomeruli, just as before. (The researchers couldn’t perform behavioral tests on these animals because of laboratory regulations about animal quarantine.)

“For me it clicked when we did the IVF,” Dias says. “When the brain anatomy persisted, that to me emphasized that it’s not really a social transmission. It’s inherited.”

Other researchers also seem convinced. “It is high time public health researchers took human transgenerational responses seriously,” says Marcus Pembrey, emeritus professor of paediatric genetics at University College London, who has been championing the idea of epigenetic inheritance for over a decade. “I suspect we will not understand the rise in neuropsychiatric disorders or obesity, diabetes and metabolic disruptions generally without taking a multigenerational approach,” he says.

In an interesting historical aside, Pembrey also notes that the new study echoes an experiment that Ivan Pavlov did* 90 years ago, in which he trained mice to associate food with the sound of a bell. Pavlov “reported that successive generations took fewer and fewer training sessions before they would search for food on hearing a bell even when food was absent,” Pembrey says. Nevertheless, the idea that experience could be biologically inherited fell out of favor in the 20th century. “If alive today, Pavlov would have been delighted by the Dias and Ressler paper, first as a vindication of his own experiment and results, and second by the amazing experimental tools available to the modern scientist.”

Neuroscientists, too, are enthusiastic about what these results might mean for understanding the brain.

“To my knowledge this is the first example, in any animal, of epigenetic transmission of a simple memory for a specific perceptual stimulus,” says Tomás Ryan, a research fellow at MIT who studies how memories form in the brain. “The broader implications for the neuroscience of memory and to evolutionary biology in general could be paradigm shifting and unprecedented.”

There are still some unanswered questions, Ryan notes. For example, the researchers didn’t do a control experiment where the F0 animals are exposed to the fruity odor without the shock. So it’s unclear whether the “memory” they’re transmitting to their offspring is a fear memory, per se, or rather an increased sensitivity to an odor. This is an important distinction, because the brain uses many brain circuits outside of the olfactory bulb to encode fear memories. It’s difficult to imagine how that kind of complicated brain imprint might get passed down to the next generation.

Ressler and Dias agree, and for that reason were careful not to refer to the transmitted information as a fear memory. “I don’t know if it’s a memory,” Dias says. “It’s a sensitivity, for now.”

What’s that got to do with epigenetics?

So let’s call it a sensitivity. How could a smell sensitivity, formed in an adult animal’s olfactory bulb in its brain, possibly be transmitted to its gonads and passed on to future generations?

The researchers are nowhere near being able to answer that question, but they have some data that points to epigenetics.

There are several types of epigenetic modifications. One of the best understood is DNA methylation. There are millions of spots along the mouse genome (and the human genome), called CpG sites, where methyl groups can attach and affect the expression of nearby genes. Typically, methylation dials down gene expression.

Dias and Ressler sent sperm samples of mice that had been fear-conditioned to either acetophenone or propanol to a private company, called Active Motif, which specializes in methylation analyses. The company’s researchers (who were blinded to which samples were which) mapped out the sperm methylation patterns near two olfactory genes: Olfr151, which codes for the M71 receptor that’s sensitive to acetophenone, and Olfr6, which codes for another odor receptor that is not sensitive to either odor.

It turns out that Olfr151, but not the other gene, is significantly less methylated in sperm from animals trained to fear acetophenone than in sperm from those trained to fear propanol. Because less methylation usually means a boost in gene expression, this could plausibly explain why these animals have more M71 receptors in their brains, the researchers say.

What’s more, the same under-methylation shows up in the sperm of F1 animals whose fathers had been trained to fear acetophenone.

“It’s a very precise signal,” Ressler says. “The convergence of this data, we think, shows that this is a really profound and robust phenomenon.”

Others, though, find a number of flaws in this epigenetic explanation.

Timothy Bestor, professor of genetics and development at Columbia University, points out that methylated CpG sites only affect gene expression when they are located in the so-called gene promoter, a region about 500 bases upstream of the gene. But the Olfr151 gene doesn’t have any CpG sites in its promoter.

That means the differences in methylation reported in the paper must have occurred within the body of the gene itself. “And methylation in the gene body is common to all genes whether they’re expressed or not,” Bestor says. “I don’t see any way by which that gene could be directly regulated by methylation.”

But what would explain the methylation differences between the trained animals and controls? They’re pretty subtle, he says, and “could easily be a statistical fluke.”

Bestor was skeptical from the outset, based on the mechanics of the reproductive system alone. “There’s a real problem in how the signal could reach the germ cells,” he says.

For one thing, the seminiferous tubules, where sperm is made inside of the testes, don’t have any nerves. “So there’s no way the central nervous system could affect germ cell development.” What’s more, he says it’s not likely that acetophenone would be able to cross the blood-testis barrier, the sheet of cells that separates the seminiferous tubules from the blood.

By this point in my conversation with Bestor, I was starting to feel a bit defensive on behalf of epigenetics and all of its wonder. “Are you saying you think epigenetic inheritance is a bunch of bologna?” I asked helplessly.

“No,” he said, laughing. “It’s just not as dynamic as people think.”

What’s next?

A good next step in resolving these pesky mechanistic questions would be to use chromatography to see whether odorant molecules like acetophenone actually get into the animals’ bloodstream, Dias says. “The technology is surely there, and I think we are going to go down those routes.”

First, though, Dias and Ressler are working on another behavioral experiment. They want to know: If the F0 mice un-learn the fear of acetophenone (which can be done by repeated exposures to the smell without a shock) and then reproduce, will their children still have an increased sensitivity to it?

“We have no idea yet,” says Ressler, a practicing psychiatrist who has long been interested in the effects of post-traumatic stress disorder (PTSD). “But we think this would have tremendous implications for the treatment of adults [with PTSD] before they have children.”

It will take a lot more work before scientists come close to understanding how these data relate to human anxiety disorders. So what, after all of these words, should we take away from this study now?

Hell if I know. Here’s the most rational and conservative appraisal I can muster: Our bodies are constantly adapting to a changing world. We have many ways of helping our children make that unpredictable world slightly more predictable, and some of those ways seem to be hidden in our genome.

Anne Ferguson-Smith, a geneticist at the University of Cambridge, put it more succinctly. The study, she says, “potentially adds to the growing list of compelling models telling us that something is going on that facilitates transmission of environmentally induced traits.”

Scientists, I have to assume, will be furiously working on what that something is for many decades to come. And I’ll be following along, or trying to, with awe.

*Update, 12/1/13, 2:35pm: It seems that that Pavlov experiment may have been retracted in 1927, though I don’t know anything about that beyond what is stated here.

Style note: A few paragraphs of this post were adapted from my earlier post on this research, published November 15.

There are 53 Comments. Add Yours.

  1. Anarcissie
    December 1, 2013

    Having done quite a bit of computer programming, it is not apparent to me why code should not be able to modify itself in response to environmental changes or externally-derived messages, whether that code is in a computer or in a genome. I realize this idea runs athwart orthodox faith in the Wrongness of Lamarck, so it will have a hard time finding acceptance, regardless of how reasonable it may be.

  2. Virginia Hughes
    December 1, 2013

    Thanks for reading, Anarcissie. I’m not sure I totally follow the logic, though. Just because something is true in a computer code means it must be true in the genetic code?

    • Anarcissie
      December 1, 2013

      No, I just mean there is nothing in the idea of code itself to prohibit self-modification. In the case of the genome, there might be some physical limitation I don’t know about, analogous to a machine where all the instructions are stored in read-only memory and can’t be modified. But we do know genetic code sometimes changes randomly (mutation) and there was an article around here (National Geographic) recently about ‘the speckled brain’ which seemed to indicate that some parts of the genome are permitted to mutate whereas others are not. My guess, then, would be that genetic code could have programming that permitted it to change itself in an orderly way as well. However, the actual mechanics of such a hypothetical capacity are well beyond my limited knowledge (or ‘above my pay grade’ as they say).

  3. Tomas Ryan
    December 1, 2013

    It is worth noting that, ‘epigenetics’ classically refers to heritable changes in the contribution of a genotype to a phenotype that are not caused by changes in the DNA sequence, regardless of what the mechanism might be. DNA methylation and histone modification are possible mechanisms of epigenetic transmission, but need not necessarily account for all cases.
    From a classical phenotypic perspective, the behavioral data in this paper are the primary epigenetic data (because genetics is primarily the science of heredity, while molecular genetics is a subset of genetics that tries to explain the mechanisms of heredity at a molecular level).

  4. Mike
    December 1, 2013

    Thanks for the interesting article. The Nature Neuroscience doi link doesn’t seem to work, though…

  5. Cee Wilson
    December 1, 2013

    Maybe this explains the deja vu feelings I had when I visited England, my ancestral homeland. Several times while there, I had the feeling I had been to this specific place before.

  6. Barry Vegter
    December 1, 2013

    I am curious how the researchers were able to measure the size of the M71 Glomeruli in the brain of mice. I would think that it would be very small in either case.

  7. Bradley M Cooke
    December 1, 2013

    This finding reminded me of “Memory transfer by cannibalism in planarian worms”, a paper published in J Neuropsychiatry by James McConnell. I wonder if anyone has attempted to replicate this experiment recently?

    Here’s a bit about it in the entry for McConnell in Wikipedia:
    —-
    Most of McConnell’s academic career was spent in the psychology department at the University of Michigan, where he was a professor from 1963 through his retirement in 1988. He was an unconventional scientist, setting up his own refereed journal, the Journal of Biological Psychology, which was published in tandem with the Worm Runner’s Digest, a planarian-themed humor magazine. His paper Memory transfer through cannibalism in planarians, published in the Journal of Neuropsychiatry, reported that when planarians conditioned to respond to a stimulus were ground up and fed to other planarians, the recipients learned to respond to the stimulus faster than a control group did. McConnell believed that this was evidence of a chemical basis for memory, which he identified as memory RNA. Although well publicized, his findings were not completely reproducible by other scientists and were therefore at the time completely discredited (for review, see Chapouthier, 1973).

    • Barry Vegter
      December 2, 2013

      Reply to Bradley Cooke’s reply: I think that part of McConnell’s problem was that he wrote a humor magazine and a science magazine. If you write a science paper about cannibalism in worms, the community of science readers were predisposed (nature? nurture? epigenetics?) to treat the paper as a humor article. Hopefully, scientists can have a sense of humor and respect the science findings of an unconventional scientist.

  8. Brian C
    December 2, 2013

    Strange. If this paper is so groundbreaking why was it not published in Nature? Presumably the peer reviewers for Nature smelt a rat? I’d love to have open reviews at Nature.

    I can’t read pass the paywall but I agree with Bestor, how can methylation be transferred from adult to sperm cells?

  9. HI
    December 2, 2013

    It is intriguing. But, while I don’t want to sound close-minded, I remain somewhat skeptical until the results are reproduced and the mechanism is explained. This could be like the case of the faster-than-light neutrino. They could be overlooking something subtle. And/or some of the effects could be experimental variations, even if the effects they found could be considered statistically significant.

    I remember attending a seminar by Oliver Rando from University of Massachusetts Medical School, who also studies epigenetic inheritance. (Although what he studied was the effect of diet, so it is not as complicated or controversial as inheritance of specific memories; It is not hard to imagine that the gonads can feel the influence of nutrition.)

    His group also tried IVF and looked at DNA methylation. And I don’t remember any of the details, but I think he mentioned that there was something very tricky about doing these things and his group had to do a lot of troubleshooting. I am interested to know what Rando think about this new report.

  10. ron
    December 2, 2013

    Many thanks for a fascinating article and the very understandable way you manage to explain epigenetics basics for people like me.. ;)
    With the reference to knowing not much about epigenetics in mind, apologies if the questions/comments are out of place..

    There seem to be a link between research that shows epigenetic inheritance and dramatic – even traumatic – events.. I have seen a bbc show about epigenetics that illustrated inheritance using events such as the Jewish holocaust and periods of famine in Sweden..
    I can understand that environmental hardships may trigger certain hormones that in turn turn on/off particular genes, and that – or linked – memories might be inheritable.
    However, might it not be a case of something else? Of some inheritable characteristics for dramatic/traumatic/life-threatening situations?
    I just wonder whether there is a comparable research somewhere that checks more mundane things.. Like a general preference to smell A rather than B, or for certain tastes, without a dramatic link to trigger these preferences, but some sort of intergenerational cultivation – if indeed that is possible..
    Does the question make sense?
    Many thanks for any illuminations!
    Cheers!!

  11. JW
    December 2, 2013

    Reminds me of Sheldrake’s morphogenetic fields. They are serendipitous (meaning without causation) and therefore explanatory without specifying a mechanism, no different than string theory, IMO.

  12. Rebel Brown
    December 2, 2013

    Great article but no surprise.

    Has everyone read The Biology Of Belief by Bruce Lipton,MD? He has much more research than this paper alone and has proven the power of our environment in cells and our body…

    Check it out for even more depth and detail on these discoveries!

    If only we humans can learn to upgrade our mindware programs about how we humans tick – neuroscience is giving us such amazing insights into how we really think and behave. These programs have been created by traditional scientific dogma for generations, but its time to let them go to see and think differently! we are so much more than we’ve been led to believe!

    Great article and thanks for sharing the latest!

  13. Ken Saville
    December 2, 2013

    I haven’t read the article yet, but this is an excellent and balanced description of the issues involved. I agree that the evidence for ‘something’ happening in a trans-generational way seems to be accumulating. The comment about the planarian experiment is interesting. Also – my gut feeling for a possible mechanism of transmitting the information from brain the germ line is the involvement of microRNAs

  14. BL
    December 2, 2013

    @Anarcissie: the physical limitation is that the changes in the central nervous system have to be edited into not just the DNA in the central nervous system, but way over on the other side of the mouse, in the germ line. There’s no known mechanism for this (and any such mechanism would be rather complicated); that’s why “orthodoxy” has quite reasonably frowned on Lamarckism for so long.

  15. Kenneth Litwak
    December 2, 2013

    If we are trying to determine if an experience of your ancestors can affect you today, exposing mice to an aroma accompanied by an electric shock is not going to give us the answer or even lead us in the right direction. The authors of the Nature article are making assumptions about the mouse based upon very subjective observations of the muzzle twitching. Should our scientific knowledge be directed by interpretive mouse twitching or by reasoned and thoughtful responses from people? The answers may be take longer to obtain and be more difficult to get from people, but they will lead our science in the right direction.

  16. David Bennett
    December 2, 2013

    My first thought is that it ties in with the extrinsic evidence that Rupert Sheldrake has been chasing for years

    http://www.sheldrake.org/homepage.html

  17. J Kulli
    December 2, 2013

    The report includes a discussion of possible mechanisms for DNA modification, and of the neuroanatomy of the olfactory pathways, but nothing on the most basic issue: are the behavioral results reliable? Just for starters, there is no mention of how the shock and the odor were administered, how the “startle” response was measured, or whether the observer of the behavior was blinded. These details have long been known to be critical. As Carl Sagan said, “extraordinary claims require extraordinary evidence.” The behavioral evidence in this paper is not impressive.

  18. Preston Garrison
    December 2, 2013

    I think I have seen a paper where they found intercellular transfer of microRNA in vesicles (exosomes.) This is a conceivable mechanism, although transfer of these things through the brain-blood barrier and blood-seminal barrier would presumably require specific transport mechanisms. I’d say a lot of skepticism is appropriate at this point.

  19. Matt Valley
    December 3, 2013

    @J Kulli
    You are right that they don’t give a detailed description of some of their methods in this paper, but they reference previous papers that do. It takes a bit of digging, but after following two and three cross-citations through their publication record gives Jones et al (Behavioral Neuroscience, 2005) and Paschall & Davis (Behavioral Neuroscience, 2002) that describe in detail their olfactometer. Their fear measurements are made by a commercially bought system: http://www.sandiegoinstruments.com/startle-response-system/
    They state in their methods that all measurements are double blind, and they acknowledge the students who blindly did the analysis. Everything here seems above board.

    Given their ability to publish detailed supplementary methods in Nat Neuro, it is annoying at the least that I have to dig through four different publications to get a full description of their methods.

    *disclosure, I am not affiliated with the authors in any way, but I have made these sorts of measurements before and am sensitive to the difficulty of reproducing olfactory fear-conditioning data.

  20. Bodo Brückner
    December 3, 2013

    This is a great piece of science reporting on one of my favorite topics, epigenetics. I especially like that not only the pros but also the cons like epigenetics hero Tim Bestor have been interviewed. It clearly shows that science is a dynamic process whose authority does not rest on dogma but also on its never ending quest for valid data and insight.

  21. Celine Cammarata
    December 3, 2013

    Hi there, and thanks for a great post! I read this while doing background research on the differing opinions this paper has raised and actually ended up linking back to you in my piece for Scizzle (http://www.myscizzle.com/blog/family-fear/) – I loved how you captured the different views of the science community.

  22. Sarah Cavanaugh
    December 3, 2013

    “It will take a lot more work before scientists come close to understanding how these data relate to human anxiety disorders. So what, after all of these words, should we take away from this study now?”

    Not much. Exploring the inheritance of fears, anxieties, and addictions in humans would be a complicated endeavor. Rather than attempt to unravel these complexities, the researchers involved in this study have settled for what they perceived to be the simpler road. In the long term, however, any data gleaned from this research will ultimately need to be replicated, in some capacity, in human beings. Biomedical research has demonstrated time and again the obstacle of translating data from animal models to humans, but there’s no way to know if this is the case without actually performing the “difficult” human studies. Ultimately, Dias and Ressler have done nothing but subject a lot of animals to unnecessary pain, when experiments could have been designed to address the issue in humans in the first place.

  23. HI
    December 3, 2013

    @Matt Valley

    You sound like you are familiar with this kind of research. What do you think about their data? I have no experience in this field, but their data don’t look very clear-cut to me. The response of the animals have wide distributions even among the cohorts. This, to some extent, could be expected because measuring animals behavior is never going to be precise. But are these convincing enough? They report statistical significance, but the p-values are not that great. I understand that these are difficult experiments. But wouldn’t you want to make sure before drawing such a bold conclusion, especially because data were bound to be noisy in these experiments?

    Recently, there have been a lot of discussions on the lack of reproducibility in science. Potential problems include complexity of using animal models and lack of rigors by some of the researchers (“Their idea of randomization is, you stick your hand in the cage and whichever one comes up to you, you grab. That is not a random way to select an animal.” Some animals might be fearful, or biters, or they might just be curled up in the corner, asleep. None will be chosen. And there, bias begins. – Lisa Bero in an article by Jennifer Couzin-Frankel), small sample size and low statistical power, and lack of understanding of statistics by the researchers.

    Dias and Ressler could turn out to be right. But I’m not convinced at this point.

  24. Matt Valley
    December 3, 2013

    @HI
    Behavioral data of this sort is always very noisy, and the data in this paper seems similarly variable to what I’ve seen published elsewhere. Its true some of their effects just barely pass significance, but they made several measurements of the same effect and so some will naturally be expected to be weaker than others (see: repeated measurements bias), and so a few weak effects don’t worry me. That being said, I doubt anyone will take this too seriously until another lab independently replicates this effect behaviorally, and until a mechanism is identified explaining how neural activity can influence DNA methylation in sperm.

    @Sarah Cavanaugh
    Almost every basic biological mechanism that describes how the human body works was first characterized in a model system animal. Mice are great models for some things, and lousy for others, something that we as scientists are well aware of (despite frequent articles in the press claiming otherwise). The paper we are discussing here is valuable because this experiment gives an observable ‘hook’ that can be used to untangle the sequence of events by which a behavioral experience epigenetically imprints DNA leading to changed gene expression. This sort of mechanistic exploration can only be done in model systems.

    • Sarah Cavanaugh
      December 3, 2013

      @Matt Valley

      As a fellow scientist and former animal researcher, I’m afraid I have to disagree. As former NIH director Elias Zerhouni said, “We have moved away from studying human disease in humans. We all drank the Kool-Aid on that one, me included…The problem is that it hasn’t worked, and it’s time we stopped dancing around the problem…We need to refocus and adapt new methodologies for use in humans to understand disease biology in humans.”

      Scientists are facing a serious issue in our inability to reproduce data and to translate that data from animal models to the human patients we allege we seek to understand and treat. Ultimately, what we need is more investment in developing methods that will allow us to study the human patient, rather than taking the easy way out by looking to the animal models that so frequently fail.

      • Matt Valley
        December 3, 2013

        Yeah, I actually agree with your point. But I also think it is totally misplaced here. Zerhouni’s point referred to animal models of human disease. I don’t think we were discussing human disease until you raised this point. Dias et al, has no more relevance to humans than to any other species. Instead, this work makes a new claim about a basic biological mechanism in mice, and if this mechanism exists, like many others related to gene regulation, it is likely conserved between mammals. So, it should be confirmed in mice before anyone does the difficult, expensive, and ethically challenging task of replicating it in humans. There is no other plausible route to discover basic biological principles in humans than to first go through lab animals. Please save your anger against animal experimentation for a target that is more deserving.

  25. Alejandro Burga
    December 3, 2013

    This is a very interesting article

    There was an extremely similar study and finding in the nematode C. elegans published 3 years ago (I was not part of this study). The advantage of using C. elegans as a genetic tool is that it’s going be much more easier to find the genetic/epigenetic basis of these interesting phenomena.

    “Stable inheritance of an acquired behavior in Caenorhabditis elegans”
    Remy (2010) Current Biology

    http://www.cell.com/current-biology/fulltext/S0960-9822(10)01003-1

  26. Alison
    December 3, 2013

    This is an interesting article. However, I think it may be important to remember that these genetic occurrences have been going on for thousands of years, way back to when man was being chased by saber-toothed bit cats. It does not make sense to see this in a context of recent history, for instance, among ethnic groups, etc. We are who we are today in a basically human sense from these many genetic reactions over time. Just a thought.

  27. Jill Escher
    December 3, 2013

    Of course various exposures can affect germ cell epigenetics, and this has zippo to do with Lamarck.

    All you need is (1) a window of susceptibility such as germline reprogramming during early fetal development; and (2) an exogenous exposure (such as an endocrine disruptor) that can interfere with normal methylation or other epigenetic mechanism.

    And voila! A disrupted F1 germline, with F2 pathologies aplenty!

    Oh gosh, did you know that millions of us were heavily prenatally exposed to endocrine disrupting pharmaceuticals? That these drugs (synthetic hormones, antinausea drugs, sedatives, etc) were widely administered to preg women in the 50s, 60s and 70s?

    What happened to all those poor fetal germ cells? Well, my kids, to cite an example of such exposed germ cells, are mysteriously autistic. These exposures can cause subtle germline derangements that ravage F2 neurodevelopment. Oh, and I’ve met 25 autism families with similar exposure histories.

    It’s time to connect the dots. Enough referencing and complaining about Lamarckianism. Wake up, please, to the horror of direct germline exposure.

    http://youtu.be/8_0iMnxsKSo. Presentation on germline disruption.

  28. E
    December 4, 2013

    Was this study limited to whether fathers pass down the memory? There’s no mention of mothers.

  29. Sarah Cavanaugh
    December 4, 2013

    @Matt Valley

    To be fair, studies funded by the NIH (and this one is) are supposed to have some relevance to human health. If the authors aren’t interested in making a connection to human disease, perhaps their funding should be found elsewhere.

    It’s not that I’m angry about animal experimentation. I just feel taxpayer dollars funneled through NIH should be used to study potential advances in the treatment and prevention of disease. And, in many cases, this means finally shifting our focus from lab animals to the actual human patient.

  30. Me
    December 4, 2013

    It’s Pavlov’s dogs. They eventually salivated just at the sound of the bell. Never heard of Pavlov’s mice.

  31. Coenraad Meyer
    December 5, 2013

    The possible implications are mind blowing. Thank you for a well-written article.

  32. D E
    December 6, 2013

    “There’s a real problem in how the signal could reach the germ cells,” he says.

    Sounds like biology’s “spooky action at a distance” problem. Therefore, quantum biology!

    • Anarcissie
      December 6, 2013

      Again, I don’t see the problem. There are routes for transmission of signals through the body, principally through the nerves and various special substances, like hormones. The genome is executing code and can probably modify itself (in limited ways). It can contain code which, in targeted cells, receives signals on a molecular level and modifies itself accordingly. While the method may seem Rube-Goldbergian, the ability to respond genetically to external conditions could have very high survival value.

  33. D E
    December 6, 2013

    @Anarcissie (sorry, don’t know how to respond to you in-line)

    Oh, I don’t see a problem either (even if we may not fully understand it). I was just being a bit cutesy and churlish as that quote reminded me of Einstein’s famous proclamation of disbelief because there was no clear mechanism to account for the “spooky action at a distance” (according to current models of understanding). Quantum biology is in fact a field gaining steam, and, for all we know, there could be some of that “spooky action” at play here!

  34. caw
    December 19, 2013

    Might such inheritance be better classified as an “adaptive behavioral instinct” – rather than “memory” related? The question then becomes whether the adaption happens through understood natural selection processes OR some previously unknown experience feedback mechanism (genetic?) within a generation.

  35. Anarcissie
    December 19, 2013

    Some of the convo here made me wonder if there are any apparent cases of humans exhibiting evidence of inherited memory. Humans have a way of putting large numbers of their kind through the mills of extreme experiences — usually bad ones, like wars — and the offspring of populations that went through those experiences (and survived) might show some common behaviors not shared with others.

  36. caw
    December 19, 2013

    Inheritance of a specific “memory” is implausible: The meaning / information associated with a specific memory is dependent upon its context within previous memories/experiences. Therefore, a memory cannot stand alone (have meaning/interpretation) without its basis. To inherit a meaningful memory, one would have to also inherit its background/foundation. Inheritance of a behavior instinct, however, could be a simpler, more appropriate mechanism here.

  37. kipp
    December 20, 2013

    Ms. Hughes,

    Why do you start the article using the particular term “memory/memories” that the author specifically rejects later in the article; instead favoring the more accurate (and un-loaded) term “sensitivity”? This creates, from the very start of your article, the wrong impression about the nature of the research you describe.

    • Anarcissie
      December 20, 2013

      I don’t think we know the subjective experiences of the mice in question. Maybe it is memory-like.

      While I think caw is probably right, it does seem possible that long-term memories might be stored in some way that was transferable.

  38. Tofi M. Rahal
    December 22, 2013

    As an educator, I am very interested in knowing how epigenetics can help the process of learning. It is well established that prior knowledge and experiences affect the way we learn new information. We also know that our structure of prior knowledge and how well it subsumes new knowledge depends on earlier academic experiences, cultural background and social interactions. With this new research one might raise the following key questions:
    – To what extent our prior knowledge is also a function of epigenetics?
    – Can learning be enhanced by specialized cognitive training and manipulation?
    – Can rewards have similar effect in producing desired learning (behavior) as trauma?
    – Can transferred acquired behaviors that hinder learning be unlearned?

  39. David Percival
    December 27, 2013

    It has long been known that newly hatched goslings demonstrate a fear of the silhouette of predator birds. There must therefore be some mechanism such as this which enables this to happen.

  40. María Fernández
    January 9, 2014

    From a specific smell memory to the whole landscape of homeostasis: Can this reframing make Dias & Ressler’s claim less absurd?
    *************
    Behavior directed towards absent goals does not need to be based on the evocation of such absent objects. Innate ‘teaching mechanisms’ sustain the search for and recognition of appropriate stimuli that had never previously been experienced by the subjects.
    ((A pigeon that has never seen a nest has absolutely no image of a nest. Proof of this is that a pigeon will perform the ‘settling into the nest’ innate motor pattern on a typewriter or a biscuit box. However, once it has behaved in this manner, the pigeon becomes aware that these objects are not correct: it never returns to them and keeps on searching. When confronted with a nest, the pigeon tests it as it has done with all the previous objects. But now the pigeon’s ‘teaching mechanism’ (as Lorenz, 1966 expresses it) apparently emits an OK signal. The pigeon settles into the nest and does not look any further. So, animals’ innate baggage cannot be an evoked image: if this were the case, they would not look for their goal in inadequate and outlandish stimuli. But neither can it simply consist of pure ignorance: if this were the case, they would be unable to opt for the right stimulus. What is required is an empty but well-defined profile))
    The question is: do we have the same situation when the appropriate stimulus has been previously experienced by the subject? I would say: empty profiles are very likely as efficient as evoked full contents, but less costly than these contents. So, the expectation of previously experienced objects, instead of involving evoked images, could define a point in the merely subjective landscape–or gradient–that the animal’s learning would have been shaping around a particular consummatory pattern. That whole landscape could be understood in the frame of much extended homeostasis.
    From a specific smell memory to the whole landscape of homeostasis: Can this reframing make Dias & Ressler’s claim less absurd?
    Are philogenesis and ontogenesis completely different things? No bridge between evolution and individual learning?

  41. SAK
    January 17, 2014

    I’m not sure I would agree with those earlier comparing this lab finding to Sheldrake’s morphogenesis theory. According to his theory, mice everywhere should start indicating an aversion to the particular smell…as the ubiquitious morph fields, once in place, start to replicate everywhere…meaning all rats will eventually dislike the smell. I don’t believe this…but the Epigenetic article is landmark…kind of like Hammeroff/Penrose’s recent proofing on quantum microtubules in the noggin…

    Have a good day…SAK

  42. Homer
    January 27, 2014

    Once scientists invent magic, science will be much simpler to figure out.

  43. Max_B
    February 1, 2014

    Certainly very interesting stuff, the most intriguing aspect to me is that the First-Generation-IVF offspring exhibit consistently smaller neuroanatomical changes, than even Second-Generation-natural-conception offspring.

    Dias and Ressler didn’t carry out any behavioral studies with the IVF offspring, unlike Eric Nestler’s paper, but on the surface the reduced neuroanatomical changes in IVF offspring they report seem similar to results from Nestler et. al. (2011).

    Nestler’s only potential explanation for his results is that the IVF process itself, inadvertently selected immature sperm, leading to reduced inheritance effects, and that seems a reasonable idea to me. Dias & Ressler’s paper doesn’t even mention that they found consistently reduced neuroanatomical changes in IVF offspring?

    In both papers the IVF fathers were killed to extract sperm, so these fathers were dead, long before the IVF offspring were even conceived, this is not mentioned in either paper as the authors don’t see the relevance. This certainly leaves the door open, as to what is responsible for the reduced inheritance effect seen only in IVF offspring. It could be the IVF process as Nestler suggestions, or it could be the dead IVF fathers.

    I accept the latter is a ‘way out’ theory, but in my view, it needs ruling out.

  44. Dennis Clayton
    April 19, 2014

    Um, did they check only for the fruity smell gene and then neglect to check to see if ALL sweet smells or ALL fruity smells or some major category of smells may have been triggered to methylate less by a hormone in the blood, and that reached the cells that reproduce? If there is an evolutionary basis for such a development, it should be taken seriously, but it is a far cry from passing down very specific smells. There were no controls, apparently, for one smell triggering a whole category of similar smells for the future generations. That would be far easier to explain and believe and it’s odd they didn’t anticipate that with some appropriate controls, or checking other genes for similar methylation changes.

  45. Holly Mohmed
    May 30, 2014

    This topic fascinates me. When I was a child, I often wondered if genetic memory exists. Genetic mutations do occur in order for people to adapt to new foods or ingredients…so why is it preposterous to think that genetics record other information that can be passed down to future generations?

    How many people here have had some dreams not of their current time and at an age where you did not receive information of that time period making you ponder where such information had been obtained? This could be a possible explanation.

    Genes mutate and evolve. It is not a ridiculous notion to research with the thought that perhaps DNA and RNA are also recording events, memories, fears, misdeeds, injustices of the past, happiness, sorrow alongside the obvious components.

    The increase is autism most likely is over a gene mutation which is evolution in progress (not to say autism itself is evolution) but the evolution of a gene in transition phase. Look up information on gene mutation of MTHFR and autism.

    Many people have misunderstood Charles Darwin’s “Survival of the Fittest” and warped it into eugenics. What he really was talking about was the survival of genes and adaption of change with evolution. Those who have genes that will adapt to the new changes will survive. This has nothing to do with war of superior traits. Just evolution on a deeper level that will be researched further.

    Now the bad news is there are always people who decide to twist intentions to suit their narcissistic mindsets in order to accomplish their own agendas instead of using such information to actually help people. Patterns repeat because we ALLOW them to repeat.

    Sometimes going up against the grain and the in-grained is necessary.

  46. Ramji Bhandari
    July 1, 2014

    Does this study also suggest similar mechanisms could be associated with upstream and downstream migration of salmon? Parental experience of homing migration establishing memory in offspring that follow the same path. Interesting!!

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