Most of the cells in the body are born to take hard knocks. From the harmful effects of infection to ultraviolet rays, the buffeting that cells receive can lead to mutations in DNA—changes that no one wants passed on to the next generation. Luckily, one type of cell lives a pure, protected, safe existence. The cells of the germline—the cells that go on to become sperm or eggs—live a charmed life. 

Until recently, that careful protection—a shield called the Weismann barrier—was thought to be nearly impenetrable. The DNA in our germlines is our most precious resource. If it were mutated willy-nilly by the vagaries of life, far too many dangerous mutations would get passed on to subsequent generations. Germline DNA must be kept safe, subject only to a few mutations, of which few end up entering the population, resulting in slow, gradual change in a species over time. The Weismann barrier implies that the natural selection of Darwin must be correct—that the pre-existing traits of a parent make it either more or less successful and therefore more or less capable of passing those traits down to its offspring. 

But what if germline cells weren’t as protected as we thought? Björn Schumacher, who studies DNA repair and genome stability at the University of Cologne, and Oded Rechavi, who studies epigenetic inheritance at Tel Aviv University, have shown that specific neurons in the nematode worm C. elegans can tweak the DNA of germline cells. Signals from those neurons raise or lower levels of small RNAs. Those tiny bundles of code slip into germline cells, changing the expression of germline DNA—changes which are then passed on to the next generation of worms.

The Weismann Wall

August Weismann proposed in 1893 that only germ cells could pass on information to the next generation. If this was true, he noted, those cells must be protected from bad influences of the war-ravaged cells of the body, or soma. As time went on, this idea evolved into the Weismann barrier, the idea that the DNA of germline cells was inviolate, unaffected by the changes occurring to the rest of the cells in the body. 

In theory, a single nucleotide change to a strand of DNA can be good, bad, or meaningless. But in reality, “the vast and overwhelming probability of a random change in the DNA sequence being beneficial or detrimental leans towards being detrimental,” explains Peter Sarkies, a molecular biologist at Oxford University. “So if you randomly mutate something, it’s much more likely to be damaging than it is to be beneficial.” In normal body cells—somatic cells—a damaging mutation is a bad thing. But it’s also limited in scope. “If you have a problem with your somatic cell, that particular organism may have a malfunction, but that’s only going to be in that cell and then all of its progeny,” Sarkies notes. Those cellular progeny may end up being a tumor, for example. But that tumor—and the DNA in it—don’t get passed on to any offspring the animal may have. 

All cells, somatic or germline, have mechanisms to repair damaged DNA, and even to signal that they need to stop replicating or be destroyed if changes are too drastic. You’d expect those control mechanisms to be especially strong in the germline, Sarkies says. “In an organism which has finite resources of energy, it would spend more energy protecting the replication and the DNA repair in the germline.” The barrier wasn’t thought to be complete, he notes. Information from the germline could still affect the soma, to allow for development into eggs or sperm. But things that affect the soma wouldn’t affect the germline. Like the popular metaphor, what happens in Vegas stays in Vegas. “In other words, something that happens to an adult is not canonically believed to affect the next generation via the germline,” he says. 

The idea of the Weismann barrier was critical for the development of the molecular basis of evolution, says Michael Skinner, who studies environmental epigenetics at Washington State University in Pullman, WA. “The Weissman barrier concept was really good and really appropriate for initial thinking in the early 1900s,” he explains. Unfortunately, Skinner says, the Weismann barrier gained the aura of dogma—that environmental changes must never affect the germline. “And so the dogma, basically, was driving the science. And so if something was outside that dogma, then it was just put down.” 

Nature doesn’t care about dogma, though, and scientists began to realize that perhaps the Weismann barrier wasn’t quite so firm. “We are increasingly realizing that that’s not true,” Sarkies explains. “Nobody’s ever thought that was true in plants. Because in plants, somatic cells can actually become germline cells very easily.” Take a cutting from one plant, place it in the ground, and a whole new plant can grow, complete with a new germline—one derived from somatic cells. 

Animals were not immune from these effects either. Environmental influences could make tweaks to how DNA in cells was expressed—adding molecular tags that changed whether DNA made it through to protein. These are epigenetic effects—changes to cell function that don’t change the underlying DNA. Instead, they can tag DNA to be more or less transcribed, make it more or less tightly packed and accessible, or change how RNA is edited and made into proteins.

But epigenetic changes appear to mostly get stripped away as germline cells matured and joined. “This was always the observation that overall epigenetics are reset,” explains Schumacher. “In [an] oocyte that is now fertilized, that it needs to be reset to undergo not only this complete rejuvenation, but also then completely give rise to the to all lineages of an embryo.”

This is in contrast to genetic inheritance, Rechavi notes, “which once it happens, once you have a mutation or any other change to your DNA in the germline, then that’s permanent.” Epigenetics was thought of as transient, he says, “it starts and ends after a few generations.” 

Worms and Weather

But some epigenetics might be more permanent than others. In work which won the Nobel Prize in Physiology or Medicine in 2006, Craig Mello and Andrew Fire showed that giving C. elegans double-stranded RNA could produce silencing effects on gene translation—binding to messenger RNA and preventing it producing a protein. Those small RNAs, when injected or fed to the worms, could reach the germline and persist into the next generation. 

Schumacher and Rechavi knew that these small RNAs were special. “They can be transported from one cell to another, from one tissue to another, from the soma to the germline, and so it makes them these intermediates that actually contain information,” Schumacher says. “What we really wanted to figure out was, how far can this change a species?” Could these small RNAs—induced by the environment, and released by cells in the soma—make it to the germline, and influence evolution? They were particularly interested in transposons—sequences within DNA that can bounce around to different positions on the genome. 

These transposons—the subject of another Nobel Prize, this one for Barbara McClintock in 1983—can have drastic effects when they change position. One gene inserted into another can inactivate its victim, cutting off a potentially important sequence. They can create duplications, or change how a cell develops. “Transposons must be silenced in the germline, because they can cause havoc,” Schumacher says. “But they also appear to be drivers of genome evolution.” Normally, small RNAs in the germline prevent the bouncing of transposons. But if the soma affected those small RNAs, allowing those transposons to leap, they could have effects on germline DNA itself, far beyond simple epigenetics. 

Using C. elegans, Schumacher, Rechavi and their colleagues introduced a stressor—they turned up the heat on the worms. “They’re very adapted to temperature,” Schumacher explains. Temperature sensing, he notes, is something the somatic cells do. The nematodes are happiest at 20° Celsius. The scientists turned up the heat to a balmy 25-26°C. 

Those neurons sent signals via small RNAs. Those RNAs entered the worms’ germline cells. Rechavi has shown that under higher temperatures, these small RNAs could change how worms mated. C. elegans is androdiecious. It can fertilize itself, or it can mate with other male worms—opting for new genes over stable known DNA. When the weather got warm, Rechavi showed that worms released a male-attractive pheromone—mating out instead of self-fertilizing. That pheromone was transferred to the worm’s offspring via small RNAs—even when the offspring were raised at cooler temperatures. 

Now working together, Schumacher and Rechavi have sequenced the RNA of single worms to identify how these changes are happening. “There’s neuronal sensing of the temperature changes,” Schumacher says. “And that directly affects small RNA responses that then have an effect on germline adaptations. So we can directly link the environment sensing to these changes in small RNAs, and how that impacts the genome.” 

A Hole in the Wall

Studies of epigenetics like Schumacher’s and Rechavi’s have shown that Weismann barrier is not a wall. Instead, it’s a tightly controlled filter, like the filter between the blood and the brain, Schumacher notes. “Not impenetrable, it’s just really well controlled,” he says. “That’s why it’s so important to figure out how access is controlled, what kind of factors can pass through and then have an impact.”

The results raise enough questions for any one scientist’s lifetime. The small RNAs could already be in the germline, and only their levels could be changed by signals from neurons. But small RNAs could potentially come from other cells into the germline cells from the body. After all, in the previous work that won Fire and Mello the Nobel, small RNAs injected into C. elegans made it into reproductive cells. 

Schumacher and Rechavi also aren’t sure why some epigenetic changes might be passed on, while others might be stripped and cleared when the fertilized ovum resets. They also aren’t sure what effect these small RNAs are having on the behavior or function of future generations of worms—whether this makes them more or less capable of dealing with high temperatures, for example. 

So far, the changes to the small RNAs appear to be temporary. The effect Schumacher and Rechavi says “lasts for at least three generations,” Rechavi says. “Eventually, it flips back.” But those small RNAs have already done their job, mobilizing transposons. “Once the genome is changed because of these epigenetic changes, once transposons mobilize, the genome is forever different, and this never goes back,” he explains. 

This is, of course, in C. elegans, a tiny worm relatively far from a human. But human oocytes are known to show epigenetic changes as they age, Schumacher notes. “I think it’s conceivable that we will discover mechanisms that could be equivalent even in humans,” he says. “Of course, they are so much more complex, and that’s why it’s so important that we work out the biology in worms first.” 

Sarkies also suspects that limited, tightly controlled communication between body and germline is possible across many organisms. What Rechavi and Schumacher have shown, he says, “is really exciting, because it’s actually the molecular mechanism of this.” It’s also a direct connection between the epigenome and the genome, “and I think people haven’t really been thinking in that way.” 

The findings stand in contrast to how many scientists think of genetic inheritance, Rechavi says. “The dogma in biology is, first of all, that the germline is isolated from the soma, and that the activity of the brain is limited to that very same generation,” he notes. “Here we show that the parents’ brain affects…the children and grandchildren and so on.” 

If the soma—the experiences of the body—can affect the genetics passed down to future generations, “I think it fundamentally change[s] how we think about evolution, because it’s supposed to just depend on selecting random changes in the genome,” Schumacher says. “But now we are essentially saying there could be, there could potentially be, something like adaptive evolution. Adaptive evolution is a very controversial concept that has mostly been investigated in bacteria and never been found anywhere else. But here we actually find the first hint that something like that could exist.” 

The findings also suggest that the germline genome isn’t just less protected, it’s also less stable than previously thought. Of course, we’ve always known the genome needs to change, because without genetic change, humans wouldn’t exist, Schumacher says. “But it seems that the way it changes, or when it changes is not just random. There are certain conditions under which it changes more than in other conditions.”

Those options, however, are random, and small RNAs that allow transposons to move around aren’t necessarily going to produce good things. Evolution itself will have the last word. “We don’t know if it’s adaptive,” Rechavi says. “It could be a form of stress-induced mutagenesis, but yes, natural selection will still decide whether this is kept or not.” 

Epigenetic, evolution, long and slow, could be a shortcut to adapt to current environmental conditions. “We have to start breaking down this genetic determinism dogma,” Skinner says. “It’s a combination of epigenetics and genetics that regulates biology.” Genetic inheritance, the Weismann barrier, and science itself aren’t rigid, purely protected and stable. Instead, just as science changes in response to the pressures of new findings and ideas, so organisms—and their germlines—might change in response to the stresses of life.