Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog from the publishers of Science Translational Medicine . All content is Derek’s own, and he does not in any way speak for his employer.

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. . .!