New inheritance mechanism unrelated to DNA is discovered by chance

Many of the greatest discoveries have come through chance, although serendipity generally goes to those who work for it. Matthew Eroglu and his research group at the University of Toronto were beginning to study cancer signalling pathways when something strange happened that turned the whole focus of the research on its head. The worms they were using, normally hermaphrodites that reproduce without difficulty, began to become more feminine with each generation until they ended up being sterile. Surprised at something they had never seen before, they shifted all their efforts “to investigate what was causing this inherited effect,” explains Eroglu.

Their work of the following years led to further and even greater surprises. The effect on the worms was due to something that was being inherited and accumulated in the offspring, yet had nothing to do with any nucleic acid (DNA or RNA) or anything related to them, representing a break with what was known until then about animals. That something — and this was the final surprise — turned out to be proteins with an amyloid structure and prion properties, similar to those that accumulate in Alzheimer’s plaques, which could be passed from generation to generation and multiply over time, vampirizing their neighbors.

The research was featured on the cover of the journal Nature Cell Biology. For Tanya Vavouri, group leader at the Josep Carreras Leukaemia Research Institute, an expert in epigenetic processes and their transmission who was not involved in this work, “it is a very good study that reveals a new mechanism of inheritance. It is very novel.”

Although the new finding has not yet been studied or tested in humans, according to Eroglu, “this is an additional mechanism on top of genes that could explain part of our missing heritability,” that is to say, the fact that several traits (such as height or intelligence) and diseases (such as diabetes, neurological disorders or some types of cancer, among others) behave in a more hereditary way than genes have been able to explain until now. Brent Derry, Eroglu’s supervisor, is even more forceful. To him, the discovery “changes what we think about the field entirely.”

The path of research: a tour de force

Caenorhabditis elegans is a transparent worm that lives for just three weeks, reproduces very easily and is the star of many laboratories around the world. More than 99% of them are hermaphrodites that follow a peculiar cycle: when they are larvae, their first 150 sexual cells become sperm; right after that, the remaining half will become female oocytes. When Eroglu and his group deactivated the genes they initially wanted to study, they observed that the number of offspring decreased with each generation, even disappearing altogether if they were raised with a little heat, something that creates a certain amount of stress for these creatures.

Curiously, each generation produced fewer sperm and more oocytes, until finally they only produced the latter. The hermaphrodite worms had become feminized, and this was not something that was transmitted genetically and normally: the changes accumulated, they also occurred with heat in normal, unmodified worms — although in a milder way, because they continued to produce some sperm — and they were also reversible, as they regressed if the worms were raised at slightly lower temperatures. It was a form of epigenetic inheritance added to that of the genes.

Epigenetics can be broadly defined as marks or changes that affect the behavior of genes and can be passed on to daughter cells but do not alter the DNA sequence. And they revolve around the two nucleic acids. When researchers began their almost endless battery of experiments, however, they were unable to identify anything known to play a role.

They only observed one apparent difference, and that was the key. Under a microscope, the feminized worms contained autofluorescent green dots like “glowing blobs,” according to Eroglu, which grew generation after generation. They called them “herasomes,” and inside them was the key to the mechanism: they contained proteins folded in amyloid-like structures, similar to those that accumulate in patients with Alzheimer’s disease (although not the same ones). When they were given substances that hindered their formation, the effect was reduced. When they were injected with amyloids from feminized worms, the animals reproduced the same process and transmitted it for several generations. “It was enough to cause the effect. It is the simplest model that explains the observations,” Eroglu concludes.

Amyloid proteins can be very different, but they are named after a certain structure they form when they fold. And they have a very peculiar characteristic: they have the potential to multiply by “infecting” other similar proteins with which they come into contact. This “vampirization” is the way prions, which are essentially another type of amyloid protein, spread. Although their reputation is terrifying, their characteristics also allow them to play important roles, such as in the storage of hormones or possibly also in the formation of memory. And, as Harvard University professor Craig P. Hunter writes in a text about the new discovery: “In the same way as DNA, amyloids replicate themselves using themselves as a model, which makes them ideal carriers of acquired, inheritable information.” This, which had been seen in yeast, is now being confirmed for the first time in much more complex animals.

How do they achieve this particular effect on sex? Apparently, amyloids can ultimately upset the ratio of two proteins that are key to the development of sex cells and that normally alternate in the life of the worm like a seesaw. The first produces sperm, and the second produces oocytes. Once the movement is broken, it will only produce the latter.

The picture on the cover of the magazine in which the article was published was the phone background Eroglu had on his mobile device for years: a shot he took himself of a worm at the moment it switches from making sperm to making eggs. As his university put it, “a perfect metaphor for his discovery. While researching one thing, he discovered another.”

What is its evolutionary value? Does it occur in humans?

The vast majority of these worms reproduce by themselves, in a hermaphroditic manner. When the environment becomes stressful or threatening, it can be beneficial to change this routine: if instead of being self-sufficient, they breed with others, they increase the diversity in their genes and with it the possibilities of finding responses to the new threat. In this case, the accumulation of amyloids feminizes the worms to a greater or lesser extent by making them produce less sperm, urging them to mate with the males they find. It would be a type of adaptation similar to that suggested by Lamarck, the naturalist for whom evolution occurred through changes that organisms generated when adapting and then transmitted —like giraffes stretching their necks—, and not by chance and Darwinian selection.

Epigenetics has offered Lamarck a posthumous glimmer of hope, albeit of relative value. Nature seems to conspire against him and tends to erase most of these types of marks when the daughter organisms are formed. And it does so especially in animals like us, which also take many years to reproduce and not a few weeks like worms, giving time for the possible marks to fade away.

In reality, there are very few reports of such changes transmitted to humans, and they are still being questioned. Some of the best-known works are those that found metabolic changes in the grandchildren of those who suffered a great famine in the Netherlands during World War II. For Vavouri, however, although “there is an epidemiological observation, the mechanisms that cause them have not yet been proven.”

Possible epigenetic changes transmitted after Holocaust trauma have also been publicized, but these studies have been criticized for their methods and interpretations, and their biological significance seems irrelevant. “There are many factors that can influence and confuse this type of study where the psychological comes into play,” explains Vavouri. “Moreover, the differences are very small and their significance is difficult to accept.”

However, the problem of missing heritability remains, the fact that the letters in genes do not explain part of the inheritance pattern observed for many traits or diseases. Could amyloid proteins be the door that helps to close this knowledge gap?

Eroglu admits that it is not known what could cause the accumulation of these proteins or whether they play a role in us, but he also points out that “amyloid aggregates have been observed in human oocytes, although we do not know what they do or what their relevance might be,” and that “at least one group is investigating whether this amyloid inheritance occurs in rats.” This group is led by Gail Cornwall, a researcher at the University of Texas. Asked about this work and its implications, she says that she was “excited.” Amyloid proteins “are an ideal mechanism for organisms to try out new phenotypes [observable traits] before genetically modifying them. One might think that nature would not eliminate such a powerful adaptation mechanism in higher organisms,” she explains by email.

For Vavouri, however, “there are many examples in nature where what may seem logical does not happen in reality. Without going any further, scientists think of many logical hypotheses that are later not confirmed. It is interesting to investigate, but we still do not know if it happens in humans or even in mammals or what it could mean.” For the researcher “it is a mechanism that already has value even if it is not tested in humans. The world is much bigger than us and this type of discovery could even affect us in other ways.”

According to Eroglu, “none of this contradicts the fact that genes determine the vast majority of inheritance. However, there are traits that are not fully explained by variation in their sequence.” In the university’s press release, he adds: “There’s this alternate inheritance mechanism on top of DNA. Who knows what you could do? Could we discover something that, in fact, doesn’t change sex but changes some other traits? Or predict diseases that we couldn’t base on DNA alone?”

The final paragraph of their paper, albeit with caveats, was accepted by the journal’s editors, and reads: “The major implication of this is that stably heritable proteins may act as a reservoir of yet unexplored phenotypic modifiers that are independent of gene sequence, a potential source of ‘missing’ heritability. Though speculative, the breadth of familial traits associated with amyloid perturbations that largely cannot be attributed to genomic sequence variation (for example, type 2 diabetes, some cancers, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and the autism spectrum) is suggestive of this notion.”

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