The Inheritance of Memories: Genes Across Generations | Dr. Oded Rechavi 

Dr. Oded Rechavi (@OdedRechavi) is a professor of neurobiology at Tel Aviv University and an expert in how genes are inherited, how experiences shape genes, and remarkably, how some memories of experiences can be passed via genes to offspring

Andrew Huberman and Oded Rechavi discuss the tenets of genetic inheritance and the relationship to metabolism, stress, and trauma. They also discuss the heritability of traits, the mechanism behind epigenetics, and how stressors and memories can be passed on to the generations of offspring.

Host: Andrew Huberman (@hubermanlab)

DNA: genetic instructions contained in all of our cells; the entire set is called the genome We have the same genome and DNA in every cell in our body

RNA: instructions to make one particular protein based on the entire set of possibilities There are many types of RNA, for example, messenger RNA contains the information for making proteins

Helpful IKEA analogy for understanding DNA and RNA: the catalog is the DNA; the specific instructions for specific pieces of furniture are RNA; the furniture pieces are the proteins made from RNA using messenger RNA Every cell type brings into action different genes and assumes an identity

Somatic cells vs germ cells: Germ cells are the cells that contribute to how the next generation will be made – for example, the sperm and the egg Somatic cells (all the cells that are not germ cells) are not expected to contribute to the next generation – for example, the muscle you build isn’t inherited by your kids, they have to workout Somatic cells can change in response to experience, but germ cells cannot – this is the second law of biology (a barrier separates somatic cells and germ cells)

Controversial theory of inheritance of acquired traits (Lamarck): transmission of traits acquired in life are passed to offspring – for example, if parent is an endurance runner and the kids will also be endurance athletes Darwin later progressed the idea of evolution with natural selection, instead of inheritance of acquired traits

Epigenetics: in addition to information from the sequence of DNA bases, you also have information about the modification of the bases There are modifications of DNA and also modifications of proteins that condense DNA For example, the expression of certain genes can be amplified in one twin vs the other Rechavi’s definition of epigenetics: inheritance that occurs across cell division or across generations, not because of changes to DNA sequence but through other mechanisms

“We are a combination of our genetic material and the environment.” – Dr. Oded Rvachi

Epigenetic reprogramming: genetic material in our cells acquires chemical changes and modifications which are largely erased between generations so we start a blank slate and develop according to genetic instructions There is some advantage to starting fresh each generation – you return to the original and start new

There is evidence that some cells contain a complete genome from one parent or the other, and this can actually switch during your life

Examples of hardship leading to adaptive traits If you stress male mice, the next generation shows less anxiety maybe because the stress threshold increased Nicotine exposure in mice improves the tolerance of drugs (not just nicotine) in next generation Starving or overfeeding changes body weight and glucose tolerance of next generation

“The fact that there is an effect, that something transmitted [information] is clear. The question is, how miraculous is it and whether you need new biology and epigenetics to explain.” – Dr. Oded Rechavi There doesn’t necessarily need to be new biology to explain what’s happening

Evidence of epigenetics becomes much more scarce when you travel 2-3 generations through a lineage Some communities agree with epigenetics, while some are more resistant – for example, geneticists are resistant while psychologists embrace it Psychologically, you can understand why people want to believe it – it gives your life meaning to think that you can change the biology of your kids

Model organism: a non-human organism with a short generation time used to study specific traits, diseases, or phenomena in its entirety – for example some worms, flies, fish, and plants

We learn about humans from model organisms because we share a lot of genes with model organisms

Advantages of using c. elegans (worm) for inheritance: Always has 959 cells in the body, of which 302 are neurons Each neuron has a name, many with known function We’ve had a clear map of neurons since the 80s and it’s mostly the same across all c. elegans C.elegans are transparent so you can see neurons fire You can activate and silence genes using optogenetics (shining different light) C.elegans is the first organism to have its genome sequenced so you can easily manipulate and study to see what genes do Each mother has about 250 offspring Generation time is 3 days, lifespan is about 3 weeks

“There is obvious and clearcut evidence of inheritance of acquired traits in worms.” – Dr. Oded Rechavi Example: RNA interference – if you inject worms with double-strand RNA, you don’t only see silencing action in a cell you injected it in but it spreads all over the worm’s body; even if you inject in somatic cells, you see the silencing effect in the germ cells and immediate progeny (kids) Additional evidence: worms infected with the virus will destroy the virus even when they can’t make their own gene to destroy it (they inherited the ability from the parent)

In worms – transmission of resistance to viruses through RNAs affects multiple next generations without getting diluted for 3-5 generations They amplify small RNA in every generation

Most of the time these heritable effects seem adaptive on the surface but you have to understand evolution to make a definitive statement

Memory : change of behavior in response to what happened in the past The brain is capable of holding specific and elaborate memories The brain can synthesize information about the environment and internal state, and importantly, think ahead

What transfers may be a general sensitivity to something

The brain uses a different language than the language of inheritance – it keeps information in synapses; heritable information goes through the bottleneck of one cell (fertilized egg) Heritable information has to be molecular, inherited through the fertilized egg

Challenges in understanding heritability of memory: We don’t know the mechanism that may translate between the language of the brain and the language of inheritance The wiring of the brain and particular neuronal circuits is different in offspring Some specific memories could transfer after learning

True epigenetic effect in c.elegans: it was shown that the brain can communicate with the next generation using small RNAs and this can change behavior without using any language Disrupting the production of small RNA in the brain affects expression of genes in germ line

Heritable information in mammals may transmit by affecting something early on in development

Interestingly, worms can be trained to become cold tolerant – you can manipulate the genes of these worms to improve their memory (worms don’t usually have any memory) Remember from previous episodes on learning and memory, people used to seek out extreme cold after bouts of learning to help solidify

Worms are hermaphrodites When you mate, you dilute your genome in half – this is important evolutionarily On the other hand, you diversify your genome The safest choice for worms is to self-mate to avoid the risk

If you take the hermaphrodite female worm and stress it with high temperatures, the next generation mates more with males Pheromones are released which draw males to produce offspring Stress at high temperatures compromises the production of sperm in hermaphrodites so they don’t make enough sperm or optimal sperm which hinders self-mating so the next generations adjust

If you don’t stress worms with temperature, pheromones are only secreted when the worm is old

Higher rates of autism in children of older men: likely defective DNA repair machinery

Three-parent IVF (not legal in the US): some eggs in older females don’t produce healthy embryos so you take sperm from the father, the nucleus from the mother, and put it into the cytoplasm of a younger donor, then the egg implants into the mother In the future, you might be able to change RNA at the source and change the composition of the RNA In the near future, this may be useful for DNA-based diagnostics

Neuronal Small RNAs Control Behavior Transgenerationally ( Cell ) Transgenerational Inheritance of an Acquired Small RNA-Based Antiviral Response in C. elegans ( Cell )