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Unto the Fourth Generation – in Nematodes

An organism is exposed to some new task or stimulus in its environment, and learns a new behavior to deal with it. Does this trait get passed on to its progeny? Of course not. That would be Lamarckianism (or even worse, Lysenkoism), and that’s just not how things work. If you teach your dog a complicated trick, her puppies will not be born knowing it. My own son and daughter displayed a notable lack of organic chemistry knowledge in their younger years, in the same way that my father’s dental degree did not show up in me. And so on.

But wait. There is such a thing as epigenetics, and environmental factors can, in fact, leave marks on things like transcription and gene regulation, and it’s possible that such things could end up being inherited. Indeed, transmission of some of these markers in response to environmental stress has been documented. But how far does such inheritance go? Could it get all the way up to behavioral phenotypes? There have been reports in simple model organisms of such effects, and two new papers in Cell are now proposing mechanisms for them (commentary at Cell here).

One of these, by a team from Princeton, is looking at the behavior of C. elegans nematodes when they encounter what should be a food source (P. aureginosa PA14 bacteria). They go for them initially, even in preference to some other bacterial prey, but then learn that these pathogenic bacteria are in fact not so great and thereafter avoid them. And the progeny of these trained nematodes also avoid the same bacteria. Importantly, nematodes provide no parental care (so there’s no teaching going on), and under lab conditions they’re not passing on any microbiome from the parents, either (both of which factors make studying epigenetic effects on behavior a lot harder in more complex animals).

The paper demonstrates that (1) this avoidance is due to TGF-beta signaling pathways in the nematodes’ sensory neurons and (2) that an RNA mechanism (through Piwi Argonaute) is responsible for the eventual histone marking and transmission of the inherited behavior. It looks like they’re worked out most (maybe all) of the pathway through studies of mutations in the various proteins involved. In addition, they’ve shown that these effects can be transmitted through up to four generations, via either male or female parents, and that the strength of this effect is directly proportional to the virulence of the starting bacteria that the original nematodes were trained on. Moreover, transmission of this behavior is shown to have a positive survival advantage, so there’s the whole package.

The other paper, from researchers at Tel Aviv and McGill, looks at the neuronal effects of small RNA species and their ability to leave inheritable marks. The double-stranded RNA-binding protein RDE-4 turns out to be crucial, and the small RNAs downstream of it are what communicate with the germline:

We propose here that changes in neuronal endo-siRNAs can be communicated to the offspring via regulation of germline RNA and the activity of the germline endo-siRNA inheritance machinery. Through this route, neuronal responses to external stimuli or internal physiological states could be translated into inheritable information and affect the progeny’s behavior and possibly fitness.

So these two papers complement each other very well, and make what looks like a solid case. Various small RNA species are responsive to environmental changes themselves, and can in turn modify germline inheritance. We’re going to have to get used to this idea, and then start looking for what the homologs of these nematode pathways might be doing in higher organisms. All the way, perhaps, up to humans? Perhaps the problem with my example in the first paragraph is just that organic chemistry knowledge has no particular survival advantage. . .!

14 comments on “Unto the Fourth Generation – in Nematodes”

  1. Nick K says:

    I dispute your assertion that a knowledge of organic chemistry has no survival value. After all, it has kept you going all these years!

  2. Anon says:

    So the sins and wisdom of the great-grandparents are visited upon the son? The popular press, religious leaders and armchair sociologists are going to have a field day with this “finding”. Articles in the popular press (Daily Mail!) and David Brooks (NYT) appearing in 3..2..1…

    1. A Nonny Mouse says:

      You could, instead quote the famous Philip Larkin poem.

  3. Joseph says:

    And they shall do kindness for thousands of generations to those who love them and keep their commandments.

  4. electrochemist says:

    Reminds me of the classic experiment on planaria (flatworms) which seemed to show that if some planaria were trained by directional light exposure, and then if their bodies were mascerated and fed to other planaria, those “cannibalistic” planaria retained some of the photoconditioning. This was shown ~ 60 years ago. Was it disproven later?

    1. Derek Lowe says:

      Pretty much. That was James McConnell’s work, but it was very hard to reproduce, and many other labs couldn’t get it to work at all. And there were reports that other variables (more handling, etc.) also affected the planarian light-maze data and the the McConnell experiments were not well-controlled for this. Interestingly, he was a target of the Unabomber in the 1980s.

      1. Earl Boebert says:

        Interesting. Haven’t thought about McConnell in decades. The Worm Runners Digest was a favorite of mine in college.

        1. Anonymous says:

          This blog had me thinking back to the Worm Runner’s Digest, too! I first encountered it as an undergrad while going through an issue of ISI’s Current Contents: was WRD real? I had to go to the library to find out that it was.

          The first McConnell inheritance experiments were based on regeneration (in planaria), not replication of offspring. I wonder if any contemporary groups are taking that approach?

          I’ve provided a link in my handle to a story about WRD.

  5. JG4 says:

    The hair on the back of my neck stood up again. Did the same thing when I read about the Överkalix study years ago.

    Hope to stop by in a couple of weeks.

  6. exoGSK says:

    It’s quite plausible that nematodes could serve as a model system … certainly in the case of upper management

    1. Scott says:

      That is severely insulting… to the nematodes!

  7. Emma Walmsley says:


  8. Kling says:

    Check out Denis Noble (Oxford) lecture here

    Contrarian view of how a blind gene-centric world view is too simplistic. An organism uses DNA for survival, not – DNA uses organism for survival.

  9. Wallace Grommet says:

    Isn’t there an instinctive reaction on the part of some bird species hatchlings when a predatory bird flies overhead? The chicks become immediately silent or some such, as opposed to when ordinary songbirds are visible in flight.

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