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Lamarck Rescued by RNA? New "Level of Organization" Found for Epigenetic Inheritance

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Here’s the bottom line from a new paper in PNAS: “To our knowledge, these results demonstrate for the first time that a somatic tissue of an animal can have transgenerational effects on a gene through the transport of double-stranded RNA to the germline.” Whoa!

The triumphalist history of Darwinism shows Charles Darwin trouncing Lamarck’s “inheritance of acquired characteristics” with the new theory of natural selection. The narrative is often given a decisive coup-de-grace with the retelling of experiments in 1891, when August Weismann cut off the tails of multiple generations of mice, proving that acquired characteristics are not inherited. If Lamarckism were true, bodybuilders would have muscular sons. That doesn’t happen, so ha ha! Lamarck’s theory is falsified and defunct. Long live Darwin!

What’s usually left out of this narrative is that Lamarckism did not go out the exit so quietly. In fact, Darwin himself became more Lamarckian in subsequent editions of The Origin. There continue to be Lamarck fans (example at The Mermaid’s Tale) and detractors (example at Real Clear Science). Scientific controversies are rarely decisive. Historians of science like to point out that some of the most clear-cut cases, like the demise of caloric theory and phlogiston theory, did not convince everyone due to one crucial experiment.

The new paper in PNAS is muddying the waters again. Since the word “epigenetics” entered the vocabulary, more old-school geneticists have had to backpedal from the Central Dogma (DNA makes RNA makes protein) to varying degrees. These days, it is common to see admissions of “epigenetic inheritance” and “lateral gene transfer” adding to the neo-Darwinist recipe. What’s new about the PNAS paper is experimental verification of a mechanism for inheritance of acquired characteristics in certain cases. It may only apply to roundworms. It may be limited in what it can accomplish. But it happens; and rather than following Darwin’s rule of random variations, it involves information transfer.

The germline is separated from the rest of the body, or soma, during early development in most animals, consistent with the suggestion that environmental effects on soma throughout the lifetime of an animal cannot influence inheritance through the germline. However, some environmental changes can cause effects that last for three or more generations, even in the apparent absence of changes in the genotype… These transgenerational epigenetic effects are presumably initiated either by direct changes within the ancestral germline or by the transfer of information from ancestral somatic cells to the ancestral germline.

The researchers found an agent of information transfer in the form of double-stranded RNA (dsRNA). Previous work showed that dsRNA from neurons can travel from one somatic cell to another, silencing genes. This is the first time this process is observed to affect the germline, at least in the lab roundworm Caenorhabditis elegans.

Here, we show that neuronal mobile RNAs can enter both somatic and germ cells to trigger gene silencing. Although silencing in somatic tissues is not detectably inherited despite multigenerational exposure to neuronal mobile RNAs, silencing in the germline is inherited for many generations after a single generation of exposure to neuronal mobile RNAs.

How many is many? “Inherited silencing due to the ancestral production of neuronal mobile RNAs persisted for >25 subsequent generations,” they found. In short,

We found that neurons can transport forms of dsRNA into the germline to cause silencing that can last for many generations, and that such transgenerational silencing is restricted to the germline with distinct genetic requirements for initiation and maintenance.

Requirements? Maintenance? That doesn’t sound like Darwin’s “random variations.” It almost sounds like a designed mechanism to help subsequent generations adapt to environmental changes. Watch out for that word information:

Mobile RNAs that enter the germline can provide an organism with the ability to transfer gene-specific regulatory information from somatic cells across generations and could be one mechanism by which the environment elicits transgenerational effects in animals. Although restricted to the germline, transgenerational silencing by mobile RNAs could underlie effects of the environment across generations in some cases. For example, expression of some genes within the germline can affect longevity, and transgenerational silencing of such genes might underlie the longevity that results from ancestral starvation in C. elegans. Thus, additional experiments are needed to determine the role of mobile RNAs, if any, in the transport of such experience-dependent information from somatic cells to subsequent generations in C. elegans.

That’s fine for roundworms, but we can’t expect higher organisms to act Lamarckian, can we? The authors consider the possibility that a similar import mechanism for dsRNA (SID-1) works in mammals, but realize that mammals have extra protections against germline changes:

The presence of a mammalian homolog of the dsRNA importer SID-1 that is also required for the uptake of dsRNAs into cells raises the possibility that dsRNA generated from distant somatic cells — potentially in response to environmental influences — may be imported through SID-1 into the mammalian germline to trigger transgenerational epigenetic changes. Consistent with this possibility, small RNAs have been found in circulation in mammals; dsRNAs have been detected in mammalian germ cells; and injection of RNAs into the early mouse embryo can trigger epigenetic silencing. However, even if RNAs from somatic cells are transported to the germline in mammals, they may not always initiate transgenerational inherited effects because they have to escape mechanisms that reprogram epigenetic information in each generation. Additional studies are required to determine whether specific mechanisms prevent environmental influences from triggering transmission of information in the form of mobile RNAs from somatic cells to the germline.

It’s too early to tell, in other words, if this mechanism works for mammals. But consider these evidences that support the possibility: (1) Cases of epigenetic inheritance in humans are already known. (2) Mammals have a homologue of the SID-1 mechanism for importing dsRNA into germ cells. (3) Epigenetic information doesn’t have to reside in the chromosomes; it can be transferred to the zygote via cytosolic proteins in the sperm or egg cells.

Before concluding that mammals need not apply, because they reset all the epigenetic codes each generation, more research will be needed. But if this mechanism for transferring environmental cues to the germline works for roundworms, why would it not work for other organisms? Why would a sophisticated system with “requirements” for “initiation” and “maintenance” be found only here in the animal kingdom?

A news item from the University of Maryland, where the research was conducted, does not restrict this mechanism to roundworms.

For more than a century, scientists have understood the basics of inheritance: if good genes help parents survive and reproduce [classic neo-Darwinism], the parents pass those genes along to their offspring. And yet, recent research has shown that reality is much more complex: genes can be switched off, or silenced, in response to the environment or other factors, and sometimes these changes can be passed from one generation to the next.

The phenomenon has been called epigenetic inheritance, but it is not well understood. Now, UMD geneticist Antony Jose and two of his graduate students are the first to figure out a specific mechanism by which a parent can pass silenced genes to its offspring. Importantly, the team found that this silencing could persist for multiple generations — more than 25, in the case of this study.

They say that this finding “could transform our understanding of animal evolution.” That’s a euphemistic way of saying it could undermine it, turning it from chance to design. No more hoping for beneficial mutations by chance; look instead for organized systems for transferring information from the environment to the organism and its progeny, so that it can robustly adapt to change.

“For a long time, biologists have wanted to know how information from the environment sometimes gets transmitted to the next generation,” said Jose, an assistant professor in the UMD Department of Cell Biology and Molecular Genetics. “This is the first mechanistic demonstration of how this could happen. It’s a level of organization that we didn’t know existed in animals before.

A new “level of organization” is design language, even if the researchers can’t let go of the Darwin paradigm completely:

The team’s biggest finding was that dsRNA can travel from body cells into germ cells and silence genes within the germ cells. Even more surprising, the silencing can stick around for more than 25 generations. If this same mechanism exists in other animals — possibly including humans — it could mean that there is a completely different way for a species to evolve in response to its environment.

“This mechanism gives an animal a tool to evolve much faster,” Jose said. “We still need to figure out whether this tool is actually used in this way, but it is at least possible. If animals use this RNA transport to adapt, it would mean a new understanding of how evolution happens.”

Think about that. There’s nothing there about chance variation and unguided processes. There’s a “tool” the animal can “use” to “adapt.” That sounds like a pre-programmed plan for robustness in a world of change: a plan to keep the population stable when famine, drought, heat, cold, or other factors threaten. Once again, RNA plays the role of a messenger. Like the messenger RNA (mRNA) that ferries genetic information to the ribosome, the dsRNA ferries epigenetic information to other cells and to the next generation. One might imagine an email blast going out, “Attention, all cells: silence gene #59348h; famine detected!” This implies that both sender and receiver understand the protocols and have the necessary infrastructure to get the message out.

We’re not out to support Lamarck or Darwin. Neither of them could account for new genetic information, body plans, or hierarchical design. What’s intriguing is this “level of organization” that biologists “didn’t know existed in animals before.” Here is a new avenue where design-based research can take the lead.

Image: Caenorhabditis elegans, by Sindhuja Devanapally via University of Maryland.

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