Essentials: Genes & the Inheritance of Memories Across Generations | Dr. Oded Rechavi
In a Nutshell
Dr. Oded Rechavi's research shows that small RNA molecules can transmit acquired traits across generations in C. elegans, bypassing the Weismann barrier that was thought to prevent inheritance of learned behaviors. When specific small RNAs are altered in the worm's brain, this changes behavior in descendants for up to three generations through direct RNA transmission to germ cells, without requiring feedback from germline back to brain. The mechanism depends on continuous RNA amplification in worms, which mammals lack, making human applications currently unknown but potentially involving lifestyle interventions or RNA profiling in IVF if similar systems exist.
These notes were generated by AI and may contain inaccuracies.
Welcome to Huberman Lab Essentials, where we revisit past episodes for the most potent and actionable science-based tools for mental health, physical health, and performance. Andrew Huberman, professor of neurobiology and ophthalmology at Stanford School of Medicine, introduces Dr. Oded Rechavi. The discussion focuses on genes, RNA, and the inheritance of memories across generations.
Most people understand that if two blue-eyed parents have children, there's a higher probability the offspring will have blue eyes than brown eyes. However, people generally don't expect that if parents study architecture, their children will inherit genetic knowledge of architecture. The distinction is that eye color is inherited through DNA, while knowledge is not. DNA contains the genetic instructions present in every cell, known as the genome. Genes are made of DNA, and chromosomes consist of DNA and proteins that condense the DNA.
The genome can be compared to an IKEA catalog containing instructions for everything needed. In each cell, only specific instructions are used—like removing one page from the catalog for a particular piece of furniture. The RNA represents these specific instructions, and the protein is the finished product (the chair). Less than 2% of the genome encodes for messenger RNA, while much of the genome produces RNA that performs other functions, some understood and many not.
A crucial distinction exists between somatic cells and germ cells. Germ cells (sperm and egg) are the only cells that contribute to the next generation. Each person develops from a combination of sperm and egg that fuse to create a fertilized egg, from which the entire body develops. Somatic cells (all non-germ cells) should not contribute to the next generation. This separation is considered one of the main barriers to inheritance of acquired traits.
The Weismann barrier, named after August Weismann in the 19th century, describes the separation of the soma from the germline. Only the germline transmits information to the next generation, and this is called the second law of biology. The second major barrier is epigenetic reprogramming, where chemical modifications acquired by cells are largely erased between generations. In mammals and humans, about 90% of these modifications are removed in the sperm, egg, and early embryo.
Lamarck believed in inheritance of acquired traits, proposing that evolution progressed through organisms passing on traits they acquired during their lifetime. Darwin demonstrated that natural selection is the mechanism—organisms with particular heritable qualities survive and become more common. The classic example is giraffe necks: Lamarck proposed giraffes stretched their necks to reach trees and passed on longer necks, while Darwin proposed giraffes with longer necks survived due to genetic advantages.
Resistance to inheritance of acquired traits is based on theoretical grounds due to the Weismann barrier and epigenetic reprogramming. However, people often want to believe in it because it gives life meaning if individuals can biologically change their children's futures. Erwin Schrödinger, in his 1944 book, wrote that inheritance of acquired traits is untenable and called this unfortunate because, unlike Darwinism, it means individuals cannot biologically influence the next generation.
RNA molecules, beyond messenger RNA, have potential to transmit information between generations. Different types of RNA regulate gene expression, and recent research suggests RNA may mediate transmission of acquired traits. This is considered cutting-edge research with much more to understand.
Model organisms allow researchers to study fundamental biological processes that apply to humans. C. elegans (Caenorhabditis elegans) was selected because it's a nematode with exactly 959 cells, of which 302 are neurons. The worm community has created a connectome—a complete wiring diagram of neural connections that is identical across individuals. Worms are transparent, allowing visualization of neural activity, and their genome was the first animal genome sequenced.
C. elegans produces about 250 genetically identical offspring per mother, with a generation time of only 3 days. This allows hundreds of generations to be studied within a single PhD timeline. The environment can be precisely controlled, making it easier to separate nature from nurture. Every worm produces hundreds of progeny, providing excellent statistical power for experiments.
In 2006, Andrew Fire and Craig Mello received the Nobel Prize for discovering RNA interference in C. elegans. They showed that injecting double-stranded RNA shuts off genes matching that sequence. The silencing effect spreads throughout the worm's body, including germ cells, and transmits to subsequent generations. This mechanism is now used in drugs and is called gene silencing.
Experiments demonstrated that worms can transmit natural traits across generations via small RNAs. Worms were infected with a fluorescent virus that turns them green if replication succeeds. When the machinery for making small RNAs was disabled in descendants, they still inherited protective small RNAs from infected parents. These small RNAs matched the viral genome and could be identified through RNA sequencing.
While RNA can transmit information from various tissues, the brain presents unique challenges. The brain stores information in synaptic connections between neurons, while heritable information must pass through the bottleneck of a single fertilized egg cell. The question remains whether brain activity and learned information can be translated into molecular forms that transmit across generations.
Despite having only 302 neurons, C. elegans can learn simple associations. Worms can be taught to dislike odors they previously preferred by pairing them with starvation. This learning might involve changes in synaptic strength or removal of specific odor receptors. Such changes could theoretically be transmitted if RNA controls the relevant receptor expression.
People have shown things like that not in C. elegans but in mammals. Studies claim that when an organism learns something, a particular receptor is methylated or changes in the next generation, transmitting the response. While this could be true, the evidence needs to be more convincing. The key challenge is proving how exactly the information transfers from the brain to the germ cells, and then from the germ cells back to the brain where the receptor needs to operate. This remains the current state of the field and something that needs to be proven.
In C. elegans, research has shown that the brain can communicate with the next generations using small RNAs, changing behavior without requiring any translation between languages. The system is very simple: if you take a worm and change the production of small RNA just in its brain, the next generations will have different behavior even though their brains are untouched. This was published in a 2019 Cell paper.
The research demonstrates that manipulating the production of endogenous natural RNAs in the worm's brain changes their amount, which affects the capacity of worms in the next generation to find food. This effect persists not only in one generation but three generations down the road. The mechanism works by perturbing the production of these small RNAs in the brain, which ultimately affects the expression of a gene in the germline called sage-2.
Controls show that manipulating activity of the sage-2 gene also affects behavior, and this gene works in the germ cells. The information needs to go from the brain to the germline but does not need to go back from the germ cells to the brain to affect behavior. This is confirmed as a true epigenetic effect because it continues for multiple generations and requires the machinery that transfers RNA between generations. Without the protein that physically carries the RNA between generations, the effect does not occur.
It has to be RNA. The actual RNAs that change in the next generation can be sequenced and identified. While it seems unusual that changing germ cells affects behavior through sperm and egg, the germ cells affect the soma including the brain in many ways by secreting certain chemicals, and other cells develop from the germ cells. Some information could be transmitted over the course of development or altered because of changes that occur in the germ cells.
In mammals, one explanation for how heritable information transmits is that it affects something very early in development. The secret to worm inheritance is their capacity to amplify these small RNAs all the time, which keeps the effect going and prevents dilution. In mammals, no such amplification mechanism is known.
The question arises how a small amount of RNA without amplification can affect the entire organism. One possibility is that you perturb something in the very beginning when you have just a few cells, or even in the placenta that develops during pregnancy, and this later throws everything off. This leads to many problems with metabolism and other functions, and relates to the concept of the developmental origin of health and disease, where many functions are established early in development.
Assuming similar mechanisms are discovered in humans, which is unknown, many interventions could be possible before attempting to change inheritance. For example, parental inheritance could be changed by having the parent exercise. Experiments in rodents show that overfeeding creates problems for the next generations, but if the rodent is allowed to exercise, it corrects the parental inheritance.
If the mechanism involves RNAs, future possibilities include changing the composition of heritable RNAs. In IVF, the composition of RNAs in the material introduced could potentially be altered. Before that, diagnostics could be developed. DNA-based diagnostics are currently done for most couples in Israel to look for genetic disease, but no one is looking at RNA at the moment. If the mechanism is better understood, this would provide another level and a whole new world to examine.
The beauty of RNA is that unlike DNA, it is plastic. With DNA, you have your genetic material and perhaps can choose another embryo, but with RNA, future interventions might suggest lifestyle changes such as running on the treadmill to change the profile of RNAs, which could then be used for IVF. This correlates with healthy profiles of RNAs. This is a level that no one looks at now and holds great potential, with the disclaimer that we don't know how it works in humans at all.
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