Slug Life: About That Injectable Memory Study

By Neuroskeptic | May 18, 2018 1:15 pm

A study claiming that a “memory” could be transferred from one animal to another in form of an injection has caused a lot of excitement. The Futurist said that Scientists Transferred Memories From One Snail to Another. Someday, They Could Do The Same in Humans. But I have to say I’m not convinced.

In the paper, published in eNeuro, UCLA researchers Alexis Bédécarrats and collagues report that they extracted RNA from the neurons of sea slugs (Aplysia) after training them to be sensitive to touch. This RNA, when injected into untrained Aplysia, caused them to become sensitized to touch as well, as this key figure shows:

aplysia

The authors hypothesize that the RNA may have induced epigenetic changes in the neurons of the recipient animals which caused the sensitization. This would be a radically different mechanism of memory to the one accepted by most neuroscientists, which is based on the specific pattern of synaptic connections between cells, and which could never be injected.

The discovery that RNA from trained animals can transfer the engram for long-term sensitization in Aplysia offers dramatic support for the idea that memory can be stored nonsynaptically, and indicates the limitations of the synaptic plasticity model of long-term memory storage. In addition, our results suggest that RNA could eventually be used to modify, either enhance or depress, memories.

There’s a couple of reasons why I don’t think this is evidence of “memory transfer”.

Firstly, what was transferred here was hardly a memory in the usual sense of the word. It is simply an increase in the sensitivity of a set of neurons, a single reflex pathway. This ‘memory’ is not specific to any particular stimulus. The training consisted of shocking the animals, which makes them more likely to withdraw in response to touch – not to shock, but any touch. It’s just “turning up the dial” on that reflex. It is hard to see how this relates to the far more complex types of memory in humans.

Secondly, the claimed transfer by RNA injection seems biologically implausible. This isn’t my field, but as far as I know from molecular biology, you can’t just inject RNA into an animal’s bloodstream (or haemocoel in this case) and expect it to enter cells. ‘Naked’ RNA (or DNA) is a large molecule and large molecules don’t cross membranes without help, as I understand it.

Now, Bédécarrats et al. do discuss this point, citing evidence that ‘naked’ RNA can become encapsulated inside packages called exosomes and that this could allow them to enter cells. However, the authors don’t show any evidence that this would be possible with the kind of RNA that they injected, or indeed that their RNA did enter the cells at all. Direct evidence of this would make the whole thing more believable.

Admittedly, I think RNA injections transfering memory is slightly more plausible than the famous 1960’s paper claiming that worms could ingest memories by eating other worms – although that cannibalistic mind-meld was supposedly based on RNA as well.

Overall, like the previous paper from this lab that I covered, I think this is interesting work that deserves further research, but I’m far from being convinced that we need to rethink conventional theories of memory. Not yet anyway.

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  • David Glanzman

    I’m afraid you have a fundamental misconception of what memory is. We claim that our experiments demonstrate transfer of the memory—or essential components of the memory—for sensitization. Now, although sensitization may not comport with the common notion of memory—it’s not like the memory of my Midwestern grandmother’s superb blueberry pies, for example—it nevertheless has unambiguous status as memory. Formally, sensitization is a type of nonassociative learning/memory; by definition, it is not stimulus-specific. Another example of nonassociative learning/memory is habituation, my inability to feel the watch on my wrist unless for some reason I need to attend to it. Nonassociative forms of memory differ from associative forms of learning and memory, such as classical conditioning and operant conditioning; but although there are formal and mechanistic differences between nonassociative and associative memory, that does not mean that nonassociative memories are not real memories. We do not claim in our paper that declarative memories—such as my memory of my grandmother’s blueberry pies—or even simpler forms of associative memories like those induced during classical conditioning—can be transferred by RNA. That remains to be seen.

    Another important point is that many of the same cellular and molecular mechanisms that underlie sensitization—CREB, monoamines, and NMDARs (in the case of so-called “site-specific” sensitization)—have also been shown to be critical to associative memory, particularly classical conditioning. Indeed, CREB activation, whose role in learning-related synaptic plasticity was originally demonstrated by Eric Kandel and colleagues (Dash et al., Nature 345:718-721, 1990) in Aplysia, has now been shown to be essential for many forms of associative memory in mammals. Notice that the type of synaptic plasticity examined in the original CREB study in Aplysia, long-term facilitation, has been implicated in sensitization, the same form of learning and memory that was the subject of our eNeuro paper. It is now indisputable that the basic processes that underlie simple forms of learning and memory in simpler organisms—snails, flies, crayfish—are recapitulated in more complex forms of learning and memory in more complex organisms, including humans, a situation predictable from knowledge of evolution.

    Your knowledge of molecular biology appears quite out-of-date. I urge you to read the papers we cite in the eNeuro paper regarding cell-to-cell communication by noncoding RNAS. You should read also the two studies on Arc, published just this year, that we cite (Pastuzyn et al., Cell 172:275-288 e218, 2018; Ashley et al. Cell 172:262-274.e211, 2018). Those studies show that the protein for Arc, an immediate early gene product whose induction is regulated by CREB and which is prominently involved in various forms of synaptic plasticity and learning, resembles retroviral capsid proteins. Like retroviruses, the Arc protein contains RNA. And just as retroviruses transfer viral RNA to infected cells, Arc capsid proteins transfer RNA between neurons; this transference is mediated by exosomes, or extracellular vesicles. What is the neuronal function of the Arc RNA? One doesn’t know at present, but I’m willing to bet that one of its functions is to regulate learning-related epigenetic changes, exactly the sort of changes that we believe mediate the memory transfer effect we report.

    You are certainly right to be skeptical of our claim of RNA-mediated memory transfer. And I fully appreciate your skepticism, having worked in the field of synaptic plasticity and learning and memory for 38 years. But your skepticism should be better informed.

  • David Glanzman

    I have posted a response to this, but I do not see it under the Comments. Any idea why?

  • TLongmire

    There is obviously a mechanism to transfer memories through DNA in the form of instincts but can we harness it? If humans can’t replace our primitive fears and tribalism that are surely instinctual with higher ideas then A.I. will surely do away with us.

    • Hominid

      Allelic complements provide basic plans that wire up brains in ways that imbue them with certain basic functions – perceptual parameters, reflexes and fixed action patterns, core emotions, and more. This generally consistent, gene-based functionality can be called a type of generational ‘memory,’ just as sensitization can, just as immune responses can, but all are distinct from LEARNED semantic or movement memories. What we have here – as always – is the encumbrance of language ambiguity and a semantic rather than a scientific debate.

  • DavidT

    Some of the methodological problems with this sort of research were described nicely by Collins and Pinch in their classic book “The Golem: What Everyone Should Know about Science,” in the chapter on ‘edible knowledge,” which examines the research on flatworms by McConnell and Unger.

    • David Glanzman

      See my reply to Hominid above. Rather than rely on Collins and Pinch’s book to criticize our methods, I recommend that you actually read our paper and tell me where we went wrong.

      • DavidT

        I read your paper. The description of training sea slugs struck me as comparable to the issue of “training” of flatworms in that earlier research, which was ultimately shown to be faulty. What appear to be neat, clean, measurements or observations often turn out to be much more complicated and subjective. If your measurements and observations were not, congratulations. But I’ve read (and published) enough research in physiology over many years to know that the next lab may have trouble duplicating this experiment, and I like the Collin and Pinch examples as cautionary tales about certainty. BTW, no criticism was offered or implied, only cautions from history. If you are comfortable with your methods, excellent and, again, congratulations on an interesting paper.

        • David Glanzman

          I am quite comfortable with our behavioral and electrophysiological methods. They are the same ones that have been used by me or researchers in my lab to investigate learning and memory in Aplysia for more than 30 years; those methods have contributed to dozens of publications in refereed journals. In other words, this is not a type of experimental work that I am new to.

          Thank you for your congratulations and for your interest in our paper.

          • DavidT

            In that event, I recommend the Collin and Pinch volume only to those who would like to see how research on animal behavior can go wrong, and I am pleased to disconnect that recommendation from your research — we have perhaps become overly quick to suspect flaws in research these days, and I am glad to see that your own work looks very sound. I work in the area of cardiac physiology, so I’ll leave the problems of memory and neurology to others!

            Cordially, David T, MD, PhD

          • David Glanzman

            Thank you for your comments. I am confident that the data in our study are correct. Of course, it’s possible that our interpretation of the data is mistaken. Again, tiime will tell.

          • C Wilson

            One big test will be whether any of this is reproducible by others working independently. A very large percentage of recent “science” fails this elementary test.

  • Henry Denny

    Hi David, could you explain to me how the RNA finds itself in exosomes after you’ve performed the extraction? Is there a component in the ASW that encapsulates the RNA? Awesome to see you out here discussing your work with us!

    • David Glanzman

      Thank you for your comments. One possibility is that the free extracellular RNA (exRNA) might transfect exosomes of cells in the hemolymph that then intercellularly transfer the now exosome-packaged RNA to neurons; such transfection has been demonstrated in the case of lymphocytes (Bryniarski et al., PLoS ONE 10:e0122991, 2015. However, most of the extracellular microRNA (miRNA), at least, in the body is not encapsulated in vesicles but is nonetheless strongly resistant to nucleases (see the review by Torchinovich et al., Trends Biochem. Sci. 37:460-465, 2012). Some of those miRNAs are associated with Argonaut proteins, but there are other ways for exRNA to be rendered nuclease-resistant. For example, the exRNAs may become associated with high-density lipoproteins (HDLs) in the hemolymph, and the HDL-exRNA may then be delivered to cells (Vickers et al., Nat. Cell. Biol. 13:423-433, 2011). But we don’t actually know how the RNA gets from the hemolymph into the nervous system in our study. We need to find out.

      • Harvey-6-3.5

        There is no reasonable dispute that free nucleic acids can exist in blood, as even fetal DNA can be found in maternal circulation (us patent 6,258,540) and exogenous nucleic acids may enter cells (see the 1940s Avery/McCloud/Mccarty paper). The concern with your very interesting result is in the interpretation. For example, I would expect transferring RNA encoding myogenin might cause muscle growth. I wouldn’t interpret muscle growth after transfer from a bodybuilder to me that included myogenin RNA as being “muscle memory” but rather just the impact of a control molecule on my body. So a transfer of RNA that activates a cellular mechanism associated with touch isn’t memory, but rather just exogenously turning on a cellular pathway. By that logic, gene therapy to treat sickle cell anemia changes blood “memory”.

        • David Glanzman

          Of course, there are many phenomena that can be loosely regarded as memory—the crease in folded paper, for example, can be said to represent the memory of a physical action.

          Notice that our claim for memory transfer rests not only on the observed behavioral changes, but also on the production by the injected RNA of cellular changes identical to those induced in the snail by training with tail shocks. Furthermore, in a study published last year (Pearce et al., eLife 6:e18299, 2017) we showed that the consolidation of the shock-induced long-term memory in the snail can be disrupted by inhibition of DNA methylation; and in our eNeuro study we found that inhibition of DNA methylation also blocked consolidation of the RNA-induced behavioral change. Given these facts, I believe the burden is on our critics to explain why the behavioral change caused by the RNA from trained donors is not memory.

          • Harvey-6-3.5

            If you don’t know the mechanism, inhibiting DNA methylation may simply block the pathway, not “memory”. I think the disagreement is how “memory” is defined. As Inigo says, I don’t think it means what you think it means.

          • David Glanzman

            I agree with your point. And it is certainly possible that our interpretation of our findings is wrong. Time—and additional experiments—will tell.

          • Harvey-6-3.5

            Excellent response! I hope your experiments lead to something very interesting.

          • David Glanzman

            Thank you very much!

  • Hominid

    Over my 30 plus years in science, I have seen at least a half dozen seemingly ‘conclusive’ findings by ‘respected’ scientists that present clear-cut data, appropriate data analyses, and even compelling visual documentation – elimination of Parkinson’s dystonia, chemical enhancers of learning efficiency, restoration of locomotion after spinal cord crush, and others – that failed the test of independent reproducibility. It’s a curious phenomenon in science. I’m reminded of Blondot’s ‘repeatedly confirmed’ discovery of N rays – they turned out not to exist.

    • David Glanzman

      Thanks for your supercilious—and anonymous—remarks on our study. I’ve been in science 35 plus years and have published in most of the best journals in the field. I suspect I know as much, or more, about what’s involved in scientifically establishing a phenomenon as you do. Our methods are fully described in our paper. I fully expect attempts to replicate our findings and welcome them.

      • Hominid

        Too vague to be meaningful.

        • David Glanzman

          This merits an ad Hominid response, but I’ll restrain myself.

  • http://blogs.discovermagazine.com/neuroskeptic/ Neuroskeptic

    Thanks for the detailed reply!

    On the first point, I do accept that nonassociative memories are memories. However, I don’t think they are typical examples of what people mean when they talk about “memories”. They are a special case, and perhaps a unique one.

    In particular – and I’m echoing here what I said in my comments on the Chen-Cai et al. paper – I think that nonassociative memories are fundamentally more amenable to non-synaptic explanation than are associative ones. Because while it is possible to imagine how RNA or another factor could increase the excitability of genetically-determined cell types (e.g. sensory neurons), I do not see any way that they could encode a ‘vector’ of information such that they could selectively encode connectivity between particular neurons. And if they can’t do that then it’s hard to see how they could encode associative memories. So when we talk about “memory” I think we are mostly talking about something that would be hard to encode in this way. I agree that you didn’t claim that complex memories would work the same as Aplysia sensitization but, at the least, a lot of the media coverage implied it.

    On the RNA entry, I know that there has been much fascinating work showing that intercellular transfer of RNAs could be possible. What I was trying to say in the post is that this is interesting but it remains unknown whether this is what happened in this case.

    • David Glanzman

      Your objections to regarding sensitization as a “typical” example of memory seem to me like arguing that what the Wright Brothers achieved on December 3, 1903, did not actually represent powered flight because their airplane was only in the air for 20 seconds and reached an altitude of only about ten feet. Frankly, it doesn’t matter, scientifically, what most people mean when they talk about “memory”. What truly matters is whether the basic cellular and molecular mechanisms that mediate sensitization memory also mediate, in part, more complex forms of memory. The scientific evidence strongly argues that they do.

      It may well be that more complex forms of memory, particularly associative memories, cannot be transferred from one animal to another using methods like those in our study. That would not change our conclusion that, at least for this paradigmatic form of long-term memory (refer here to any introductory neuroscience textbook), the storage mechanism cannot be synaptic.

      As to your objection that you cannot see any way that an RNA-induced epigenetic mechanism can encode associative memories, I refer you to the writings of Randy Gallistel (for example, Gallistel, Trends Cog. Sci. 21:498-508, 2017), who has cogently argued for years that a synaptic mechanism cannot possibly encode associative memory.

      Also, I’m afraid I’m not responsible for the more extravagant claims about our findings by the media. Clearly, our study has powerfully tapped into the cultural zeitgeist. For the record, however, I would like to state unequivocally, here and now, that we are not on the threshold of transferring human memory. The real Westworld will have to wait.

      • Jacob Reimer

        “Also, I’m afraid I’m not responsible for the more extravagant claims about our findings by the media. Clearly, our study has powerfully tapped into the cultural zeitgeist.”

        Classic. Anyone who is interested can read the press release here and decide for themselves: http://newsroom.ucla.edu/releases/ucla-biologists-transfer-a-memory

        • David Glanzman

          Yes, they certainly can.

    • smut clyde

      Kandel set the precedent that reflexes in Aplysia are “memories”, and now we’re stuck with it.

  • Dana Zeid

    Great post, and very relevant paper considering the growing interest in the role of noncoding RNAs in cell-to-cell communication. I agree with your point that this phenomenon is perhaps only relevant to information related to shifts in magnitude of a reflex, etc. However, I’m not sure it’s fair to imply that we should be skeptical of the results because the mechanism of RNA uptake wasn’t tested. Assuming their results are sound and replicable, I think the paper works without this information, as their only manipulation was injection of pure RNA, which has to have induced the reflex enhancement somehow. Of course, inclusion of a specific test of potential mechanisms of transmission would strengthen the paper, but I expect that will require an additional panel of followup studies that might best be presented in their own paper.

    • David Glanzman

      I very much appreciate your remarks. And I certainly agree that it is incumbent upon us (or another lab) to demonstrate just how the RNA can induce behavioral change in the snail. Obviously, this will be one of the major objectives of our followup studies.

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  • Smartacus

    Layperson here. Could the act of injecting them sensitize them to touch as well?

    • David Glanzman

      A control group of recipients received injections of RNA from untrained animals. Twenty-four hours later, there was no significant reflex enhancement in this group. See the graph in figure D in Neuroskeptic’s original post.

  • Smartacus

    Also, asking again as a layperson, is it customary for a researcher to defend his or her research (in this instance, rather vitriolically) in blog posts?

    • David Glanzman

      Possibly not. But I believe the discussion is helpful.

      • http://blogs.discovermagazine.com/neuroskeptic/ Neuroskeptic

        It’s extremely helpful! Thanks so much.

        • David Glanzman

          My pleasure! And thank you very much for this forum.

    • smut clyde

      It should be!
      OK, that’s going too far.
      PubPeer is one common forum where people raise questions about published research, and (sometimes) the researchers answer those questions, and (sometimes) there is vitriol. Perhaps Neuroskeptic’s blog will come to fill a similar role, in this specialised niche,

  • C Wilson

    Sounds like you didn’t transfer a “memory,” but a “reflex.”

    • http://blogs.discovermagazine.com/neuroskeptic/ Neuroskeptic

      Well, it’s kind of a reflex’s memory

      • C Wilson

        I am a very big fan of basic research. Lots of trees grow from these seeds. But the research should be a) reproducible, and b) portrayed in an accurate way. This research was accompanied by a press release to the general public, and I think it vastly overstated what was actually shown.

        Too many people think that “science” belongs to a priesthood of a kind. In fact, “science” is really nothing more than a way of thinking, i.e., the scientific method, and it extends to endeavors of all kinds.

        Implanting a reflex might qualify as implanting a “memory” when a term of art is used, but in the common language (hey, someone issued a press release, so that’s the standard to some extent) a “memory” refers to something learned or experienced. A “reflex” is different in the common understanding.

        I suggest to Mr. Glanzman that he a) find a way for his research to pass the reproducibilty test, and b) to ask his university’s p.r. department to be a good deal more careful and humble about how it’s potrayed to the general public.

        • David Glanzman

          Mr./Ms. Wilson, I fundamentally disagree with your remarks about both science and memory. Regarding science, you recommend that I “find a way for [my] research to pass the reproducibility test”. Anyone familiar with the scientific enterprise knows that establishing whether or not our research passes this test is not my responsibility, but, rather, that of my scientific peers. My responsibility as a practicing scientist is to perform the research rigorously and report the results to the public via a peer-reviewed scientific publication, one that includes a thorough description of all materials used by us and our experimental methods. That is precisely what I and my co-authors did. My colleagues in the field of learning and memory research can then use the information provided in our paper to attempt to replicate our findings. I have no doubt that other researchers are even now readying such attempts.

          I also take issue with your assertion that scientists are obliged to limit their use of language to accord with common understanding. Scientific language began to separate from everyday language with the Scientific Revolution. The atom as understood by a modern physicist is quite different from the atom as understood by the ancient Greeks. More pertinently, the investigator who pioneered research into learning and memory by Aplysia—the marine snail used in our study—Eric Kandel, was awarded a Nobel Prize in Physiology or Medicine in 2000; and the Nobel citation for his award reads as follows:

          “Eric Kandel studied how memories are stored by these nerve cells. His breakthrough came in 1970 while he was at New York University studying a marine snail with a simple nervous system. Eric Kandel found that as the snail learned, chemical signals changed the structure of the connections between cells, known as synapses, where the signals are sent and received. He went on to show that short-term and long-term memories are formed by different signals. This is true in all animals that learn, from molluscs to man.”

          Notice that the citation makes unblushing use of the term “memory” to describe the behavioral phenomena that Kandel studied in the snail. Would you claim that the Nobel Foundation is guilty of careless and misleading use of language?

          I approved the press release issued by UCLA. The press release accurately describes the results in our paper, as well as the limitations of our findings. It also attempts to convey to a lay audience the potential excitement of those findings. You may not agree that the findings are exciting, and that’s your right. Others, many of them thoroughly knowledgeable about the field of learning and memory, have found the paper quite provocative.

          • C Wilson

            Your point about reproducibility is well taken. If you were to “find a way for (your) research to pass the reproducibilty test,” as I suggested, the fact of making the arrangement would compromise the independence of the test(s).

            I wrote that because I am aware of the problems with reproducibility in a lot of current research. But I went too far with my suggestion, and you are correct to push back on that point. So, in that vein, I hope others will test your research independently by trying to reproduce it.

            As for your other objection, I think I was more careful than I was on the reproducibility issue. I distinguished between your paper and how it was presented by your university’s public relations operation.

            They described your research for a layman’s audience, and it was reported worldwide in non-specialist outlets. The word “memory” means something different to a non-specialist audience than it does to you. Therefore, in presenting what you did for evaluation by a general audience, I think it was an overreach and a misrepresentation to use a term that’s commonly understood to mean what I wrote earlier when your research didn’t use it in the same way.

            https://www.merriam-webster.com/dictionary/memory

            Your research described a process that seems to have transferred a reflex. In your specialized lingo, whose legitimacy I will not argue, a reflex can count as a memory. But that’s not how it’s generally understood — and again, the press release was aimed not at other specialists, but at the public at large.

            Insofar as I understand what you’ve done, you have not transferred what’s commonly understood to be a “memory.” This doesn’t devalue what you’ve done, but rather it’s a matter of how what you’ve done ought to be understood by those who are not specialists.

            I will allow that your use of a specialized term in a way that’s not understood by laymen to be a reflection of your specialization and excitement, as opposed to any accusation of an intent to deceive. Still, however, one thing has been potrayed as something else, by implication.

            This is a common problem when specialized information is translated into the general language. The result is that unrealistic expectations are set, and misleading conclusions are drawn by a wider audience, at least that portion of which has paid any attention.

            I’m sure you’re quite good at what you do, but in the end I don’t think the general publicity matched the specific reality. Perhaps someday you or others will be able to transfer what’s generally understood as “memory” from one organism to another, but I don’t think you have accomplished it just yet.

          • David Glanzman

            You still misunderstand what our study showed. We did not “transfer…a reflex”. Rather, we what transferred—or, more properly, appeared to transfer—was the learning-induced enhancement of a reflex. This is an important distinction. Note that the definition of the word “memory” in Merriam-Webster, which you cite, includes the following: “the store of things learned and retained from an organism’s activity or experience as evidenced by modification of structure or behavior or by recall and recognition….” Exactly.

            Another example of a learned modification of a reflex that everyone accepts as memory—or at least everyone who has had a university-level introductory course in psychology—is the memory acquired as a result of Pavlovian (aka classical) conditioning. As originally described by the Russian physiologist Ivan Pavlov in the early 20th century, a hungry dog will reflexively salivate when presented with meat. The same dog will not salivate, however, to the sound of a bell, at least prior to training. If the dog is trained by an experimenter who repeatedly pairs the sound of a bell with the presentation of food, eventually the dog will salivate when it hears the bell. This is a form of associative learning—the dog has learned that the bell signals delivery of food. The memory produced in the dog’s brain by the training is reflected in a change in a reflexive response—salivation.

            The learning exhibited by the trained snails in our study, as well as by the recipient snails that received the injection of RNA from the trained donors, differed from that demonstrated by Pavlov in that the trained snails did not learn to associate two stimuli; rather, the snails’ withdrawal reflex was enhanced by training with a single stimulus (tail shocks). The formal term for this type of learning is “nonassociative”. Nonetheless, as in the case of classical conditioning, the memory is indicated by the learned change in a reflex. Your apparent difficulty in accepting what we claim to have transferred between snails in our study as an actual memory indicates to me that you have never had a college class in psychology or, if you have, that you weren’t paying attention.

            Of course, the types of memories that most people care about do not involve alterations in reflexive behavior. Instead, they involve stored life events—my memory of where I was when I learned that President Kennedy had been assassinated—or facts—my knowledge of who the current president of the United States is. Such memories are formally known as “declarative”, because they can be consciously recalled (declared). But humans have other important types of memories that cannot be consciously recalled, for example, my memory of how to ride a bike. I cannot verbally express (declare) that memory; in other words, I cannot verbally convey to someone who has never ridden a bike before how I do it. Such memories are known as “nondeclarative” or “procedural” memories. Pavlovian conditioning and sensitization—the type of memory that we investigated in our study—are examples of nondeclarative memory.

            As a neuroscientist who studies learning and memory, it is my job to try to understand how the brain stores memories. Toward that end, I prefer to begin by attempting to understand how the nervous systems of relatively simple organisms encode simple memories. The implicit assumption underlying this approach, known as reductionism, is that the fundamental mechanisms of simple forms of learning and memory will play critical roles in more complex forms. This approach has a history of success in biology. If the data in our eNeuro study and our interpretation of those data are correct, then our findings are likely—will inevitably, in my opinion—lead to more effective treatments for such human disorders of memory as Alzheimer’s disease and PTSD. You may not find that prospect all that exciting, but I suspect a lot of people will.

          • C Wilson

            We shall see. If what you did is independently reproducible, and further research leads to the useful outcomes you hope for, then you will have been vindicated. I certainly don’t somehow hope you’re wrong so my skepticism is vindicated. I’m not quite that chulish, I promise.

            We don’t know each other, and we’re very unlikely to know each other. All I can do is ask you to take my word for it that I’ve been skeptical before, and then changed my mind to conform with the results.

            As for what I studied in college, you’re correct. I didn’t take any psychology classes. The closest I got was sociology, and that was enough. I also took a “neuropsychology of the brain” class, but I was an absolutely miserable student in it. I wonder if the dissection of formaldehyde-soaked sheep’s eyes had anything to do with it.

            They gave me a D-minus and not an F, and in retrospect I think it might have been because they really didn’t want me back there trying to take advantage of the grade-replacement option for those who re-take a class that they failed.

            I honestly wish you the best.

          • David Glanzman

            Thank you for keeping an open mind and for your good wishes. Also, thanks for sharing the story about your experience in the college neuropsychology class. I can see why you would not wish to continue in that field!

          • C Wilson

            Being skeptical doesn’t mean being cynical and ugly. It’s only skepticism, and that’s not something I’ll ever apologize for. In the end, I’m in favor of whatever works. I am always happy to be proved wrong when the result is a good one. People should never root for failure. I sure don’t.

            By the way, I hold no grudges with respect to the neuropsychology class. I’m not as stupid as the D-minus would suggest, but I think it’s fair to say that I was never destined for that field. I genuinely hope that whatever you are working on pans out.

  • TLongmire

    I hestitate to suggest this but if you seek the most efficient method to transfer the RNA couldn’t you replace all the DNA in a sperm with the relevant RNA of this study and inject them in a female earthworm and narrow the variables? I read a study a while back that suggested a single sperm can have surprisingly complex effects upon females.

    • David Glanzman

      First, we don’t know which particular RNA species transmit the memory; we injected whole RNA extracted from the nervous systems of the snails (note: not earthworms). Second, I’m not certain your proposed experiment can even be done; certainly it has not been done in Aplysia, which, by the way are hermaphrodites, as are earthworms.

      • TLongmire

        Shows how much I know but figured a Trojan horse would be more quantifiable if even possible.

  • MindPortal

    Collins and Pinch’s first chapter in The Golem, discussing the earlier planaria “edible memory” experiments was mentioned previously in the comments here. I think the full conclusion of that chapter may be relevant.

    “In spite of the widespread demise of the credibility of the chemical transfer of memory, a determined upholder of the idea would find no published disproof that rests on decisive technical evidence. For such a person it would not be unreasonable or unscientific to start experimenting once more. Each negative result can be explained away
    while many of the positive ones have not been. In this, memory transfer is an exemplary case of controversial science. We no longer believe in memory transfer but this is because we tired of it, because more interesting problems came along, and because the principal experimenters lost their credibility. Memory transfer was never
    quite disproved; it just ceased to occupy the scientific imagination. The gaze of the golem turned elsewhere.” (Collins and Pinch, The Golem, p. 25)

    • David Glanzman

      Thanks for pointing this out, MindPortal. Collins and Pinch’s assessment is fair, I think. Along these lines, I believe that—even had the studies reporting memory transfer been consistently replicable—a major impediment to general acceptance of the idea of memory transfer is that molecular biology had not advanced sufficiently, either theoretically or technically, by the late 1960s to the early 1970s to characterize the molecular basis of memory transfer. Because most behavioral neuroscientists knew nothing about noncoding RNA and its function—the structure of the first noncoding RNA, found in baker’s yeast, was reported in 1965—they perforce hypothesized, incorrectly, that memory was somehow encoded in messenger RNA. Furthermore, epigenetics was unknown at the time. And high-throughput methods for RNA sequencing did not become generally available until the 21st century. By contrast, in the early 1970s neurobiologists succeeded in identifying synaptic correlates of memory in relatively simple organisms such as crayfish and Aplysia. Moreover, in 1973 the first discovery of a form of long-term synaptic plasticity in the mammalian brain—long-term potentiation (LTP) of synapses in the hippocampus—was made by Bliss and Lømo. These advances in our understanding of the synaptic basis of memory may have played a significant role in shifting neurobiologists intellectually away from the idea of memory encoding by molecules.

      There is an article in press in the journal Studies in History and Philosophy of Science by David Colaço that contains an excellent history of the memory transfer episode. Colaço’s article also has an interesting hypothesis regarding why research on memory transfer was abandoned. As soon as the article becomes available online I will post a link to it here.

    • David Glanzman

      Here is the link to Colaço’s article (see my comments below): https://www.sciencedirect.com/science/article/pii/S003936811730211X. Interestingly, he cites the same passage from Collins and Pinch you cite.

      • MindPortal

        Got it. Thank you very much David!
        Todd Stark

  • Crazychromatin1611

    Hi David! The paper says that there were some snails that underwent training but did not sensitize. Would you expect that RNA extracted from those snails would not result in sensitization of naive snails?

    • David Glanzman

      In principle, yes, I would expect the RNA from the non-learners not to produce sensitization in the recipient snails. Notice, however, that the animals used in our experiments are not laboratory-reared, but collected from the wild, specifically, from the Pacific Ocean here in Southern California. Also, the donor and recipient snails used in each round of the experiments were always from the same batch of animals. Therefore, if the trained snails failed to learn due to some health-related problem resulting from the local condition of the ocean, the inability of the recipient animals to exhibit sensitization after the RNA injection would not be informative.

      • Crazychromatin1611

        I see. Thank you for your answer. I found your paper to be very intriguing given my interest in chromatin (as my name might suggest haha) and that I also work on memory engrams. I am definitely looking forward to reading more papers from your lab. Very exciting! :)

        • David Glanzman

          Thanks very much for your interest. However, my lab’s research moves at a snail’s pace (ouch!–sorry), and it will be a while before the next paper. Good luck with your important work on chromatin and memory engrams!

  • SFDrake001

    Mr. David
    is it possible to convey in a similar way memories of each type? Is it possible to transfer memories between generations?

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