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What Can Worms Teach Us?

If you are the world’s safest driver, can you expect your children to be safe drivers as well? Will they avoid dangerous driving situations when they first learn to drive? Short answer: most likely not. Long answer? At least in some organisms, the offspring can inherit some life-saving tips from their parents. For example, in Caenorhabditis elegans, a free-living transparent worm, parents can learn to avoid toxic food source and their offspring learn to avoid that food source without ever encountering that food. In their recent paper, Rebecca Moore and her colleagues described how the offspring inherit this information.

C. elegans moving! Courtesy: Wikipedia
Both in animals and plants, the environment greatly influences physical and behavioral characteristics. These characteristics sometimes can be passed onto the next generation even though the genetic code, the DNA sequence, remain unaltered (read this essay for more information on the genetic code). The biological mechanisms that govern the inheritance of these traits without changes in the genetic code are collectively called epigenetics. Interestingly, epigenetic inheritance can be passed onto several generations. Since not much research has been done to see if behavioral modifications can also be passed onto subsequent generations, the researchers decided to look into it.

But did the scientists choose worms? Once more, there is a short answer and a long answer. The short answer is that like mice or rats or other commonly used animals in research, C. elegans is a model organism. Model organisms are non-human organisms that researchers can use to study biological events.  While these organisms differ considerably from us, when it comes to biology, we share a lot of traits with these organisms. C. elegans, for example, have neurons, skin, gut and other tissues that are are very similar to us in form, functional genetics and molecular pathways. These worms can be easily grown in the lab: they can feed on bacterial plates. Furthermore, these worms don’t need to take care of the offspring and have a short, 4-day  generation time (the average time between two consecutive generations). In contrast, our generation time is between 22 to 33 years! So when studying heritable traits, researchers can look into many generations of C. elegans within a short period. These worms also have another interesting trait, but I will talk about it when I go over the relevant experiments. 

Let’s get on with the experiments then. First, the research team needed to establish an experimental setup where a learned behavior could be passed onto the offspring. The researchers took advantage of the worms’ natural attraction to a type of bacteria—a natural food source for the worms—and chose a specific strain of these bacteria that makes the worms sick. While the worms will check out these toxic bacterial strain initially, they learn to avoid the bacteria over time:  worms showed the avoidance response after four hours of exposure to the bacteria. Unfortunately, these exposed parents failed to pass on this learned avoidance response to their offspring. The next generation—the F1 generation—thus was attracted to the pathologic bacteria just like their parents. 

However, when the researchers then exposed the parent worms to the pathologic bacteria for 24 hours (instead of 4-hour exposure), the F1 generation learned to avoid the virulent bacteria innately (they avoided the bacteria even though they were never exposed to it). This avoidance behavior persisted for four generations; worms from F5 generation, however, didn’t avoid the pathogenic bacteria. So now the researchers had a malleable behavioral trait that they could use to study the underlying epigenetic mechanism. 

But before I get into the mechanisms, I want to go over one set of experiments that highlight one rather strange trait of C. elegans. These worms usually have both male and female reproductive systems (called hermaphrodites), therefore can reproduce through self-fertilization. In nature, males are very rare, but these males can mate with the hermaphrodites when the opportunity arises. This unique feature allowed scientists to ask whether both males and females could pass this avoidance response to their offspring. 

First, however, the research team needed female worms, which they could easily generate due to a specific mutation of a gene (fog-2 gene). This mutation does not affect the males but interferes with sperm production in the hermaphrodites. Because of that, the hermaphrodites carrying the mutation only produce eggs and thus are considered to be females. When scientists mated males that had learned to avoid the pathogenic bacteria (after 24 hours of exposure) to non-exposed females, the F1 generation learned the avoidance behavior. Similarly, F1 generation from a mating between exposed females and non-exposed males learned to avoid the virulent bacteria. So this avoidance behavior could be passed onto the next generation by sperm or egg.

Now, let’s look at what molecular mechanisms govern this inheritance. To make a specific protein, cells need to copy or transcribe the relevant DNA code into an RNA, called a messenger RNA or mRNA. To see what types of genes were transcribed, the researchers compared the mRNA profiles from parents and offspring of the worms that avoided the pathogenic bacteria (experimental group) to the non-exposed worms (control group). Because learning and avoidance require neurons, not surprisingly, a large number of neuronal genes had increased mRNA production in the experimental group. 

Based on this data and subsequent experiments, the researchers identified one specific gene, daf-7, and one type of neurons, the ASI neurons, that are essential for the inheritance of the avoidance response. They found that while worms learn to avoid the pathogenic bacteria after 24 hours of exposure if daf-7 or the ASI neurons are mutated or ablated, but the F1 generation doesn’t learn the avoidance response. 

One epigenetic mechanism involves modifying histone proteins, the proteins that DNA wraps around (read this for more information on epigenetics and histone modifications). Because these modifications determine how DNA is packed, the histone modifications can influence RNA production. The researchers identified a pathway that could lead to histone modification and to the inheritance of the avoidance response. 

If we assume this inheritance can happen in the wild, how does it benefit the worms?  To answer the question,  the researchers placed the worms on a small lawn where the worms could avoid pathogenic bacterial colonies if they choose to (the worms didn’t have that much room on the bacterial plates). They found that the F1 generations that learned the avoidance behavior survived significantly longer than the worms that didn’t know to avoid the pathologic bacteria. So one can imagine that in the wild, learning this avoidance behavior can be advantageous to the worms. 

Is there any advantage as to why the avoidance response is not hard-coded? After all, won’t it be better for the worms if they avoided the pathogenic bacteria all together? Here is the problem: the offspring that learned the behavior avoid that specific bacteria all the time, even when the bacteria is not pathogenic. So if the avoidance response is hard-coded, the worms would end up ignoring a perfectly fine source of nutrition in the wild. But because this avoidance response is not hard-coded—that is the inherited wisdom resets after four generations—the worms in the fifth generation can determine once again whether it’s safe to feed on that bacteria. 

One of the interesting aspects of the paper is that this inheritable avoidance behavior seemed specific to one type of bacteria. When the researchers exposed the worms a pathogenic form of a different type of bacteria, the offspring didn’t learn the avoidance behavior even though the parents did. So, it remains to be seen if the conclusions derived from the paper applies to a wider set of behaviors. That aside, this paper offers us a wonderful story about how epigenetics can help animals adapt and survive in a dynamic environment.

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