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Israeli Scientists Rewrite Basics of Genetics

Nematodes have just upended the Second Law of Biology, researchers at Tel Aviv University reported Thursday in the journal Cell. Using worms, Prof. Oded Rechavi, with Rachel Posner and Itai Toker, have proved for the first time that true epigenetic inheritance does exist.

A worm’s reaction to the environment can pass from generation to generation without change in the DNA itself. The team also discovered exactly how this nongenetic legacy is achieved. In the nerve cells of worms, Rechavi stresses — they achieved this in worms. “We have no idea if what we discovered in worms exists in mammals, let alone humans,” he tells Haaretz, adding, “I hope it does.”

Even so, the discovery could have implications for our understanding of heredity and of evolution, he says. “The discovery of a transgenerational transfer of information from the nervous system is a Holy Grail,” says Toker. “The nervous system is unique in its ability to integrate responses about the environment as well as bodily responses. The idea that it could also control the fate of an organism’s progeny is stunning.”

The Second Law of Biology, aka the Weismann barrier, states that inherited information in the germline (sperm and egg cells) shalt be isolated from environmental influences.

Mutation is change in the DNA sequence itself. Epigenetic change involves control of the DNA (for instance, turning genes on and off) but not change to the DNA itself. The billion dollar question has been whether epigenetic changes can be inherited. “Are epigenetic changes inheritable? First of all, there is a lot of confusion about what epigenetic inheritance is. That is the start of the problem,” Rechavi says.

A famous case of misunderstanding involved the Nazi regime starving the Dutch population as a punishment toward the end of World War II. By the war’s end, 20,000 Dutch had died of starvation. Subsequent research found that the survivors’ children tended to have problems from diabetes to high cholesterol to schizophrenia. “Even the generation of grandchildren has problems,” Rechavi says.

But how could exposure to starvation affect offspring two generations down? The thought was that perhaps the effect was epigenetic. 

Apparently not. “Actually, it doesn’t have to be a purely epigenetic effect, by rigorous definition. Children in the mother’s womb during the famine would therefore be affected directly by the famine. Also, germ cells develop in the fetus; so the generation of grandchildren was also directly starved,” Rechavi explains. “Only after that, in non-exposed generations, can we speak of true epigenetic inheritance.”

Legacy of ancient Greece

Arguing that our bodies can beneficially affect the next generations by passing on reaction to the environment is outrageous, Rechavi acknowledges. In fact, the idea has been around forever: the ancient Greeks thought exactly that thousands of years ago. “It is an intuitive way to look at heredity, but there was no proof,” he says, adding that epigenetic inheritance in mammals remains very controversial.

But in the simple nematode C. elegans, progress was made in recent years. Mechanisms were identified that act in parallel with the DNA. In this new study, Rechavi and colleagues show that the worm’s ability to seek food can be governed by inheritance from the ancestor’s neurons, causing epigenetic silencing of a specific gene in the progeny.

This gene was shown to control the decision of whether to forage (go look for food, leave your safe place) or whether to stay put and avoid the risk. If the worm can’t make the epigenetic control mechanism, the gene over-expresses and the worm can’t seek food.

And what is the mechanism controlling the gene? It turns out to be a type of small RNA molecule made in the worm nerve cells. A worm that can’t make the small RNAs can’t seek food. But if that worm’s mother or even their grandmother could make the small RNA in the nervous system — then the worm can seek food.

The worm inherited the small RNAs from Mama, not via the DNA. Ergo, somehow Mama’s nerve cell conveyed the change to Mama’s germ cells. The epigenetic effect can persist three to five generations in nature, even hundreds of generations if the worms are genetically altered, Rechavi says.

Their discovery upends a basic tenet of biology, the Second Law: Inherited information in the germline is supposed to be isolated from what happens in somatic cells (the cells of the body, not the germ cells) and from environmental influences.

In the lab, nematodes that couldn’t make the small RNAs exhibited defective food identification skills. When the researchers restored the ability to produce small RNAs in neurons, the nematodes moved toward food efficiently once again. This effect was maintained for multiple generations even though the progeny did not have the ability to produce small RNAs themselves.

For biologists, the discovery is shocking. “These findings go against one of the most basic dogmas in modern biology,” Rechavi says. “It was long thought that brain activity could have absolutely no impact on the fate of the progeny.” Evidently the nematode didn’t hear of the Second Law of Biology.

“It’s important to stress that we don’t know yet whether any of this translates to humans,” Rechavi reiterates. “If it does, then studying the mechanism could have a practical use in medicine. Many diseases might have some epigenetically inherited component. Deeper understanding of nonconventional forms of inheritance would be crucial to better understand these conditions and to design better diagnostics and therapies.”

Ruth Schuster