Rechavi Epigenetics Lab Shows Small RNAs Pass Memory Across Generations

Essentials: Genes & the Inheritance of Memories Across Generations | Dr. Oded Rechavi — Andrew Huberman

Andrew Huberman

Research in C. elegans proves small RNAs transmit ancestral viral resistance and alter descendant behavior across generations, bypassing traditional DNA inheritance barriers.

AI-assisted summary of Essentials: Genes & the Inheritance of Memories Across Generations | Dr. Oded Rechavi — original source. Check the original for full context.

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Detailed notes

## Background Published on YouTube on September 10, 2026, by Andrew Huberman on the Huberman Lab channel, this Essentials episode features Dr. Oded Rechavi, a professor at Tel Aviv University studying genetics and epigenetics. The discussion focuses on how DNA, RNA, and epigenetic mechanisms determine transgenerational inheritance, explaining why acquired traits were historically thought non-heritable and detailing *C. elegans* research showing small RNA-mediated transmission of viral resistance and behavior.

## TL;DR The episode explores the longstanding biological boundary between somatic cells and the germline—governed by the Weismann barrier and embryonic epigenetic reprogramming—which historically dismissed the inheritance of acquired traits. Dr. Rechavi demonstrates how non-coding small regulatory RNAs can bypass these barriers in the nematode *C. elegans*, transmitting antiviral immunity and neuronally driven behavioral changes across multiple generations without altering the underlying DNA sequence. While mammals lack the continuous RNA amplification machinery found in worms, parental small RNAs can still influence early developmental and metabolic trajectories as framed by the Developmental Origins of Health and Disease (DOHaD) model. The conversation concludes with the future therapeutic potential of dynamic RNA profiling and lifestyle interventions in reproductive medicine and IVF.

## Atmosphere & style The conversation carries an intellectually rigorous yet approachable tone, enlivened by accessible analogies such as comparing gene expression and epigenetic erasure to marked-up pages in an IKEA assembly catalog. Huberman acts as an engaged, inquisitive guide, while Rechavi delivers clear, grounded explanations that balance groundbreaking paradigm shifts with disciplined scientific caveats. The dialogue feels like an illuminating deep dive into the molecular frontier of genetics, demystifying how environmental experiences might physically echo across generations.

## Key takeaways - [00:24](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=24s) Protein-coding messenger RNA accounts for less than 2% of the human genome, with the vast remainder generating regulatory non-coding RNAs. - [03:43](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=223s) The strict biological separation between somatic cells and germ cells prevents learned skills, neural wiring, and acquired physical modifications from transferring into gametes. - [08:27](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=507s) The Weismann barrier and sweeping epigenetic reprogramming—which erases approximately 90% of chemical tags in early embryos—ensure offspring reset to a baseline genetic blueprint. - [11:46](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=706s) Non-coding regulatory small RNAs serve as key candidates for bypassing traditional inheritance barriers by modulating gene expression across generations without modifying DNA sequences. - [12:35](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=755s) C. elegans is an ideal model for epigenetic research due to its defined 959-cell anatomy, mapped 302-neuron connectome, rapid 3-day life cycle, and robust RNA interference pathways. - [15:40](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=940s) In nematodes, RNA interference (RNAi) operates systemically, allowing silencing signals initiated in somatic tissues or ingested food to enter germ cells and pass to progeny. - [19:49](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=1189s) Parent worms transmit antiviral small RNAs to their offspring, conferring inherited viral resistance across multiple generations even in progeny genetically incapable of synthesizing new small RNAs. - [22:15](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=1335s) Transmitting complex memories across generations requires overcoming a language barrier: translating multi-synaptic brain architectures into discrete molecular instructions within a single fertilized egg. - [26:09](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=1569s) Manipulating small RNAs strictly within parental neurons directly alters germline gene expression (such as saeg-2) and modifies descendant foraging behavior across three generations. - [27:22](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=1642s) Mammals lack the small RNA amplification enzymes found in nematodes, but small unamplified parental RNA signals can still cascade during early embryonic and placental development to alter lifelong metabolic trajectories. - [27:22](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=1642s) In rodent models, paternal exercise prior to mating effectively counteracts and rescues metabolic dysfunction inherited from paternal overfeeding. - [29:44](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=1784s) Unlike static DNA testing, RNA profiles are dynamically plastic and responsive to lifestyle interventions, presenting promising future opportunities for reproductive diagnostics and IVF optimization.

## Detailed walkthrough ### [00:00](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=0s) The Paradox of Inheriting Traits vs. Knowledge

Andrew Huberman opens the conversation by reflecting on a fundamental paradox of human inheritance. Most people intuitively grasp basic genetics: if two blue-eyed parents have a child, there is a very high probability that the child will inherit blue eyes rather than brown eyes. Yet, if an individual spends decades mastering complex architecture, nobody expects their child to be born with innate architectural blueprints etched into their DNA. While that child might grow up immersed in architectural books or drafting tables in the household—the classic domain of nurture—the knowledge itself is not considered heritable.

This sets the stage for the deeper mystery explored by Dr. Oded Rechavi at Tel Aviv University: why are physical features like eye color passed seamlessly across generations, whereas acquired knowledge, experiences, and learned skills appear strictly locked within the individual who lived them? Huberman frames this not merely as an academic inquiry, but as an entry point into revolutionary research showing that, under certain cellular conditions, specific types of biological memories and adaptations can indeed cross generational boundaries.

---

[00:24](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=24s) DNA, the IKEA Catalog Analogy, and RNA

Rechavi begins with the foundational machinery of genetics. DNA constitutes the complete set of instructions housed in virtually every cell of the body, collectively termed the genome. Because human cells contain an enormous quantity of DNA, it must be tightly packaged and condensed with structural proteins—comparable to wrapping thread tightly around a spool—forming chromosomes. Every single cell in an organism shares this identical genetic library, raising an obvious question: if a brain neuron and a skin cell possess the exact same sequence of DNA, how do they perform entirely distinct jobs?

```mermaid flowchart LR accTitle: The IKEA Analogy of Gene Expression subgraph Cell ["Every Cell in the Body"] A["Genome (DNA)<br/>'The Entire IKEA Catalog'"] --> B["Messenger RNA (mRNA)<br/>'Torn-out Instruction Page'"] B --> C["Functional Protein<br/>'Assembled Chair / Furniture'"] end ```

To illustrate cell differentiation, Rechavi presents his signature analogy: the IKEA catalog. The entire catalog sits inside every room of a house, detailing how to build every possible piece of furniture—from kitchen counters to bathroom fixtures. However, an occupant decorating a kitchen does not pull out instructions for assembling a toilet; they selectively tear out the single page explaining how to build a kitchen chair. In biological terms, that single torn-out page of instructions is messenger RNA (mRNA), and the resulting assembled chair is the functional protein. Huberman jokes that while IKEA is certainly not an official sponsor of the podcast, the catalog is an exceptionally clear way to visualize gene expression.

Rechavi emphasizes that protein-coding messenger RNA represents less than 2% of the human genome. The vast remainder of the genome does not simply sit idle; a significant portion of it is actively transcribed into non-coding RNAs that carry out diverse, complex regulatory functions—many of which modern science is only beginning to unravel.

- **The Genome**: Present in identical form across nearly every cell in the human body. - **Chromatin & Chromosomes**: Long stretches of DNA compacted around proteins like thread on a spool. - **The Central Analogy**: DNA is the whole IKEA catalog, mRNA is an isolated instruction sheet, and proteins are the finished furniture. - **Coding vs. Non-coding RNA**: Less than 2% of the genome encodes messenger RNA; much of the rest is transcribed into regulatory non-coding RNAs.

---

[03:43](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=223s) Somatic vs. Germ Cells: Why the Soma Stays Behind

Huberman asks whether there is one critical biological exception to the rule that all cells operate equally, pointing toward the distinction between somatic cells and germ cells. Rechavi affirms that this divide is the most crucial boundary in biology. Somatic cells constitute the entire physical body—cells forming the legs, internal organs, and the brain, including specialized neurons that synthesize dopamine or serotonin. Germ cells, by contrast, consist solely of sperm and egg cells. When a sperm fertilizes an egg, they form a single zygote containing the genetic blueprint from which every somatic tissue of the new organism will develop.

Crucially, standard biological dogma dictates that what transpires in the soma must stay in the soma. Somatic cells do not contribute their own cellular material to the next generation. Rechavi points out that this physical segregation is precisely why acquiring knowledge or skills cannot easily be transmitted to offspring:

> "If I learn about architecture, the information is encoded in my brain. And since my brain cells can't transfer information to the sperm and the egg... what happens in the brain shouldn't be able to transfer to the next generation."

Because learning architecture is encoded within specialized synaptic connections and neural circuits in the brain, there is no conventional biological conduit to copy those neural wiring diagrams into sperm or eggs. Rechavi offers an everyday physical parallel: an individual who spends years lifting heavy weights in the gym cannot pass their newly developed musculature down to their children. Offspring still have to perform the workouts themselves. Even if a somatic brain cell experiences an environmental shift or acquires a localized DNA mutation, that alteration remains trapped within that somatic lineage and cannot travel into the germline.

---

[06:04](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=364s) Lamarck vs. Darwin and the Giraffe's Neck

Huberman and Rechavi turn to historical evolutionary theory, specifically addressing Jean-Baptiste Lamarck's controversial concept of the "inheritance of acquired traits." Huberman notes that within evolutionary biology, Lamarckian ideas have long been treated with skepticism, if not outright hostility. For instance, if two elite endurance runners log tens of thousands of miles before conceiving a child, belief that their children will inherently run faster strictly because of the miles logged—rather than inherited innate genetic predispositions—is classically viewed as Lamarckian nonsense.

Rechavi explains the debate through the quintessential historical textbook example: the length of the giraffe's neck.

| Evolutionary Model | Mechanism for Long Necks | Transmissibility | |:--- |:--- |:--- | | **Lamarckian Evolution** | Individual giraffes continually stretched their necks upward to feed on high foliage; this physical stretching was believed to be directly imprinted and passed down to their progeny. | Acquired somatic modifications are transmitted directly to offspring. | | **Darwinian Natural Selection** | Natural genetic variation produced some giraffes born with longer necks by random chance. When food was scarce, longer-necked individuals reached leaves, survived, and reproduced, while shorter-necked giraffes starved. | Pre-existing heritable variations are selected by environmental pressures. |

Darwinian natural selection triumphed because it matched the physical reality of heritable variation surviving under environmental selection, whereas Lamarck’s concept lacked a credible physical mechanism to explain how an animal’s somatic effort could modify its offspring.

---

[08:27](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=507s) The Two Major Barriers: Weismann Barrier and Epigenetic Reprogramming

Historically, the inheritance of acquired somatic traits was dismissed not just because of Darwinian selection, but because of two formidable biological roadblocks that prevent somatic changes from crossing into future generations:

```mermaid flowchart TD accTitle: Two Biological Barriers to the Inheritance of Acquired Traits subgraph Barrier1 ["Barrier 1: The Weismann Barrier"] Soma["Somatic Changes<br/>(Muscle growth, neural learning)"] -- "BLOCKED<br/>No conduit to gametes" --> Germline["Germline Cells<br/>(Sperm & Egg)"] end subgraph Barrier2 ["Barrier 2: Epigenetic Reprogramming"] Germline --> Reprog["Germline & Early Embryo<br/>Chemical modifications erased"] Reprog --> Slate["'Blank Slate'<br/>Only raw DNA sequence passed on"] end ```

The first barrier is the **Weismann barrier**, formulated in the 19th century by German evolutionary biologist August Weismann. Often referred to as the "second law of biology" (with natural selection being the first), it posits that hereditary information flows exclusively from the germline to somatic cells, never in reverse. Somatic cells can alter their gene expression, accumulate cellular damage, or strengthen neural connections during life, but they are completely insulated from communicating these updates to the germline.

The second barrier is **epigenetic reprogramming**. Over a lifetime, an organism's DNA acquires diverse chemical marks—such as epigenetic modifications that dial gene expression up or down in response to diet, stress, or environment. However, during the production of germ cells (spermatogenesis and oogenesis) and immediately following fertilization in the early embryo, the cell executes a rigorous epigenetic reset. These acquired chemical tags are almost completely wiped away, resetting the nascent embryo back to a biological "blank slate" governed purely by the baseline genetic sequence. This dual architecture guarantees that parental somatic wear-and-tear does not accumulate uncontrollably across successive generations.

[09:29](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=569s) Epigenetic Reprogramming and the Psychological Appeal of Lamarckism

In mammals and humans, the genome undergoes sweeping epigenetic reprogramming between generations. Roughly 90% of epigenetic marks and modifications on sperm and egg DNA are wiped clean so the embryo can develop according to the species' baseline genetic blueprint rather than retaining specialized somatic constraints. Andrew Huberman frames this using an IKEA manual analogy: every cell receives the full master instruction book, but as individual cells specialize into liver, skin, or brain cells, specific pages receive penciled-in notes, highlights, and adjustments. Epigenetic reprogramming acts like an eraser that scrubs out all those user-added pencil marks before handing the book down to the next generation. This biological reset ensures that the offspring retain the full developmental potential to build any cell type, rather than remaining restricted to the narrow modifications made in a specific tissue.

```mermaid flowchart TD accTitle: Epigenetic Reprogramming and Generational Erasure subgraph SOMA["Somatic Specialization"] direction TB A["Master Genome (IKEA Manual)"] --> B["Tissue-Specific Epigenetic Marks (Pencil Notes)"] B --> C["Differentiated Cell Types (Brain, Liver, Skin)"] end

subgraph GERM["Generational Reset (~90% Cleared)"] direction TB C -.-> D["Weismann Barrier / Reprogramming"] D --> E["Sperm & Egg Epigenetic Erasure"] E --> F["Reset Master Blueprint for Offspring"] end ```

Despite the strict evolutionary logic of clearing these marks, human psychology strongly resists the idea of biological finality. People instinctively want to believe in the inheritance of acquired traits because it lends personal agency and purpose to life: the idea that improving your own biology, health, or habits could directly upgrade your children's biological destiny. Dr. Oded Rechavi references Erwin Schrödinger's influential 1944 book *What Is Life?*, where the physicist deemed the inheritance of acquired traits scientifically untenable. Schrödinger lamented this reality as "gloomy," because strict Darwinian natural selection implies that regardless of personal striving, offspring inherit only what is hardcoded in the gametes—leaving parents able to provide money and education, but unable to biologically pass down their self-improvement.

- Roughly 90% of epigenetic modifications in mammalian sperm and eggs are erased during reprogramming. - Epigenetic erasure preserves totipotency, ensuring offspring can build any cell type rather than carrying somatic cell restrictions. - In his 1944 book *What Is Life?*, Erwin Schrödinger described natural selection as "gloomy" because it appeared to rule out parental biological influence over inherited traits.

---

[11:46](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=706s) Non-Coding RNA as a Transgenerational Messenger

While nuclear DNA modifications are largely reset, non-coding regulatory RNAs have emerged as prime candidates for bypassing traditional inheritance barriers. Beyond classic messenger RNA (mRNA)—which serves as the template for protein synthesis—cells produce diverse classes of small regulatory RNAs that modulate gene expression without altering the underlying DNA sequence. In recent years, mammalian research has increasingly placed small RNAs at center stage as a viable mechanism for transmitting physiological and environmental information across generations, making it the cutting edge of modern transgenerational epigenetics.

---

[12:35](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=755s) *C. elegans* as a Genetic Model Organism

To untangle these mechanisms definitively, Dr. Rechavi's laboratory turned to the transparent nematode *Caenorhabditis elegans*. Model organisms allow global scientific communities to consolidate resources, standardize genetic nomenclature, and execute precise interventions that are impossible in humans. Despite deep evolutionary divergence, humans and nematodes share a common ancestor, conserved cellular machinery, and many homologous genes, allowing fundamental discoveries in worms to directly inform human biology and disease mechanisms.

*C. elegans* offers unparalleled experimental precision:

| Feature | *C. elegans* Characteristic | Experimental Advantage | |:--- |:--- |:--- | | **Cell Count** | Exactly 959 somatic cells | Precise cellular mapping across every individual | | **Nervous System** | Exactly 302 identified neurons | Globally standardized connectome ("subway map") since the 1980s | | **Optical Clarity** | Completely transparent body | Real-time imaging of neuronal firing and optogenetic control | | **Genomics** | First animal genome fully sequenced (before humans) | Comprehensive catalog of gene expression and silencing pathways | | **Reproduction** | ~250 genetically identical progeny per hermaphrodite | Tight control over nature vs. nurture with robust statistical power | | **Life Cycle** | Rapid 3-day generation time | Hundreds of successive generations can be tracked in a single PhD tenure |

Because laboratory worms are grown on simple agar plates seeded with bacteria, researchers can isolate environmental variables with absolute rigor. Within *C. elegans*, the evidence for transgenerational epigenetic inheritance of acquired traits is so robust and reproducible that it is universally accepted across the epigenetic field.

---

[15:40](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=940s) RNA Interference and Systemic Gene Silencing

Unlike mammals, *C. elegans* lacks an adaptive immune system with specialized immune cells such as T cells and B cells. Instead, the nematode relies on RNA interference (RNAi) to destroy viral pathogens using small RNAs. In 1998, Andrew Fire and Craig Mello discovered that introducing double-stranded RNA (dsRNA) matching a specific gene target triggers an intracellular catalytic pathway that systematically degrades the corresponding mRNA, completely silencing protein production—work for which they received the 2006 Nobel Prize in Physiology or Medicine.

```mermaid flowchart LR accTitle: Mechanism and Spread of RNA Interference in C. elegans subgraph TRIG["Trigger & Processing"] direction TB A["Double-Stranded RNA (dsRNA)"] --> B["Small Interfering RNAs (siRNAs)"] end

subgraph ACTION["Target Destruction"] direction TB B --> C["Target Matching mRNA"] C --> D["mRNA Cleavage / Gene Silencing"] end

subgraph SPREAD["Systemic & Germline Spread"] direction TB B -.-> E["Somatic Spread (Gut, Head, Body)"] E --> F["Germline Transmission (Eggs/Sperm)"] F --> G["Inherited Silencing in Progeny"] end ```

A remarkable feature of RNAi in worms is its systemic spread across biological barriers. Injecting dsRNA into somatic tissues—even locally into the worm's head—or simply feeding worms bacteria engineered to express dsRNA causes the silencing signal to spread throughout the entire body, enter the germline, and persist into subsequent generations. While feeding or injecting synthetic dsRNA is a powerful, highly artificial laboratory tool that cleanly isolates single variables, Dr. Rechavi set out to discover whether natural, non-engineered environmental challenges also prompt small RNAs to transmit inherited adaptations across generations.

- Andrew Fire and Craig Mello published their foundational RNAi discovery in 1998 and received the Nobel Prize in 2006. - Double-stranded RNA (dsRNA) triggers the generation of small RNAs that identify and degrade target mRNA transcripts, blocking protein translation. - RNAi operates systemically in *C. elegans*: silencing signals travel from ingested bacteria in the gut to somatic tissues, enter the germ cells, and are inherited by offspring.

[19:49](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=1189s) Inherited Antiviral Resistance and Small RNA Transmission

Small RNAs likely originated as an evolutionary defense mechanism designed to eliminate viruses and parasitic genomic elements. Dr. Rechavi illustrates this defensive function using an experiment with *C. elegans* and a fluorescent viral reporter. Under normal circumstances, when infected with this virus, worms destroy the pathogen and remain black; if the virus replicates unchecked, the worm glows bright green. To test transgenerational transmission, Rechavi’s team took worms, infected them, and neutralized the genetic machinery required to generate small RNAs in their offspring.

```mermaid flowchart TD accTitle: Transgenerational Antiviral Inheritance in C. elegans accDescription: Workflow illustrating how parent worms pass antiviral small RNAs to genetically deficient progeny to silence viral replication.

subgraph Parents ["Parent Worms (P0)"] A["Infected with Fluorescent Virus"] --> B["Generate Viral-Matching Small RNAs"] B --> C["Neutralize Small RNA Synthesis Genes in Progeny"] end

subgraph Progeny ["Descendant Generations (F1+)"] C --> D["Inherit Small RNAs via Gametes"] D --> E{"Exposed to Virus"} E -->|Lacks Synthesis Machinery| F["Inherited Small RNAs Silence Virus"] F --> G["Worms Stay Black (Protected)"] end ```

Even though the progeny lacked the genes needed to produce small RNAs de novo, they stayed black when exposed to the virus. The offspring silenced the infection purely because they inherited antiviral small RNAs directly from their parents. By sequencing these inherited small RNAs, the researchers confirmed they matched the viral genome precisely. This protective silencing was not a one-off event; it persisted across multiple generations.

- **Fluorescent reporter mechanism:** Worms turn green if the virus replicates; worms remain black if the virus is silenced. - **Genetic knockout control:** Offspring lacking the machinery to produce new small RNAs were still protected as long as their parents were infected. - **Molecular validation:** RNA sequencing confirmed that progeny carried specific small RNAs corresponding to the viral sequence inherited from their parents.

---

[22:15](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=1335s) Neuronal Activity, Memory, and the Language of Inheritance

The conversation turns to whether mammalian small RNAs could mediate the transgenerational transmission of stress, protective adaptations, or complex brain activity. While Rechavi emphasizes that much remains unproven in mammals, *C. elegans* provides clear insights. The brain possesses the unique capacity to integrate environmental cues and internal states to anticipate future conditions—raising the provocative question of whether an organism could biologically "plan" the fate of its descendants without verbal communication, effectively writing parental experience into the offspring's genetic instruction manual.

A fundamental biological challenge is that the nervous system and the germline speak entirely different languages. The brain encodes memories in three-dimensional synaptic architectures—strengthening or weakening connections between neurons. Conversely, heritable information must pass through the strict bottleneck of a single cell: the fertilized egg. Translating complex synaptic wiring into a discrete molecular code within a gamete is a major theoretical hurdle. In simple learning paradigms, such as conditioning *C. elegans* (which have only 302 neurons and thousands of odorant receptors) to avoid an odor by pairing it with starvation, learning might simply involve downregulating a specific receptor rather than complex synaptic remodeling. While mammalian studies have claimed transgenerational inheritance of odor aversion, Rechavi notes that the exact mechanisms by which signals travel from the parent's brain to the germline, and then back from the germline to the offspring's brain, remain incompletely resolved.

---

[26:09](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=1569s) Neuronal Small RNAs Alter Germline Expression and Progeny Behavior

In a 2019 study published in *Cell*, Rechavi’s lab demonstrated that modifying the production of endogenous small RNAs specifically in the worm's brain altered the foraging behavior of descendants up to three generations later, without any direct manipulation of the descendants' brains. This transmission bypassed the need to translate high-level neural networks into germline instructions. Instead, perturbing neuronal small RNAs in the parents directly altered the expression of specific genes within the germline—most notably a gene called *saeg-2*.

```mermaid flowchart LR accTitle: Soma-to-Germline Signaling Axis accDescription: Mechanism showing how neuronal small RNAs travel to the germline to alter progeny behavior across generations.

A["Parent Neurons: Manipulate Endogenous Small RNAs"] --> B["Soma-to-Germline Signal"] B --> C["Germline Expression Altered (saeg-2 Gene)"] C --> D["Transmission via Specialized RNA Transport Machinery"] D --> E["Progeny Foraging Behavior Altered (Up to 3 Generations)"] ```

Because the entire somatic body—including the nervous system—develops directly from the germ cells, molecular changes established in the gametes naturally influence downstream developmental trajectories and somatic secretion. Proving this was a bona fide epigenetic mechanism, the behavioral shift required the physical protein transport machinery responsible for shuttling RNA across generations; removing these transport proteins abolished the effect entirely.

- **Published landmark study:** Rechavi and colleagues demonstrated soma-to-germline behavioral inheritance (*Cell*, 2019). - **Duration of effect:** Neuronal small RNA perturbations changed progeny food-seeking capacity across three generations. - **Key germline target:** The *saeg-2* gene in the germline mediates this behavioral change. - **Requirement for RNA transporters:** The phenotype relies strictly on proteins that physically carry RNA molecules between generations.

---

[27:22](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=1642s) Developmental Origins of Health and Disease (DOHaD)

A crucial difference between nematodes and mammals lies in RNA amplification. *C. elegans* utilize dedicated enzymes to continuously amplify small RNAs, preventing signal dilution across successive cell divisions and generations. Mammals lack an equivalent amplification mechanism. Huberman and Rechavi discuss how unamplified parental RNA signals could still exert organism-wide effects in mammals: a small molecular perturbation occurring during early embryonic cleavage or within placental development can cascade, permanently altering metabolic and physiological trajectories. This principle aligns directly with the Developmental Origins of Health and Disease (DOHaD) framework.

Looking toward future applications, Rechavi discusses how lifestyle interventions might counteract adverse epigenetic inheritance. In rodent models, paternal overnutrition leads to metabolic dysfunction in offspring, but paternal exercise prior to mating effectively rescues this inherited defect, restoring normal metabolic programming in the progeny.

- **RNA amplification distinction:** Nematodes continuously amplify small RNAs; mammals lack this amplification machinery. - **Early developmental cascades:** In mammals, small amounts of inherited non-coding RNAs can alter early embryonic or placental development, triggering widespread downstream physiological effects (DOHaD model). - **Interventional rescues:** Paternal exercise in rodents counteracts and corrects metabolic damage inherited from parental overfeeding.

[29:44](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=1784s) Future Applications: RNA Diagnostics, Plasticity, and IVF

Dr. Oded Rechavi outlines the exciting potential for applying small RNA biology to reproductive medicine, both in the distant future and in the nearer term. Looking far ahead, once the underlying mechanisms are comprehensively understood, it might become feasible to actively engineer or alter the composition of heritable RNAs introduced during in vitro fertilization (IVF). However, a far more immediate and realistic avenue lies in diagnostics. While standard DNA-based screening is already routinely performed for couples planning to have children—such as in Israel, where widespread genetic testing is common to screen for inherited disorders—clinical diagnostics currently ignore the RNA landscape entirely. Deciphering heritable RNA profiles could open up an entire second layer of biological information to identify specific RNA signatures correlated with disease.

The fundamental advantage of RNA over DNA is its dynamic plasticity. DNA sequences are fixed and immutable, meaning parents or clinicians can only screen and choose between different embryos. In contrast, RNA profiles respond dynamically to physiological states and environmental interventions. Dr. Rechavi paints a speculative yet grounded scenario: in the future, if specific RNA profiles correlate with optimal health outcomes, a clinician might advise a parent, "maybe you should run on the treadmill a little bit" to favorably reshape their small RNA profile prior to harvesting sperm or eggs for IVF. While Dr. Rechavi emphasizes the heavy caveat that this remains theoretical "science fiction" today and has not yet been demonstrated in humans, the inherent malleability of RNA offers vast diagnostic and therapeutic promise.

```mermaid flowchart TD accTitle: DNA versus RNA Screening and Intervention Comparison

subgraph DNA_Path["DNA-Based Screening (Fixed)"] D1["Fixed Genome Sequence"] --> D2["Genetic Screening for Disease"] D2 --> D3["Embryo Selection Only"] end

subgraph RNA_Path["RNA-Based Screening (Plastic)"] R1["Dynamic RNA Profiles"] --> R2["RNA Diagnostic Screening"] R2 --> R3["Lifestyle Interventions (e.g., Exercise)"] R3 --> R4["Optimized Profiles for IVF"] end ```

- **Current Screening vs. RNA Screening**: Genetic DNA testing identifies static disease risks, whereas RNA profiling could reveal real-time physiological states and regulatory health signatures. - **The Plasticity Factor**: Unlike the hardcoded DNA genome, small RNA repertoires shift in response to physical activity and environmental conditions. - **Scientific Caveat**: Dr. Rechavi stresses that all human reproductive applications remain hypothetical, as research has yet to determine how these transgenerational RNA mechanisms operate in human biology.

---

[31:06](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=1866s) Concluding Remarks and Acknowledgements

Andrew Huberman concludes the discussion by thanking Dr. Rechavi for guiding listeners through the intricate biology of the genome, RNA function, and the groundbreaking transgenerational research coming out of his laboratory at Tel Aviv University. Huberman highlights the profound value of using model organisms like *C. elegans* to uncover conserved biological principles that challenge classical dogmas of inheritance. Dr. Rechavi expresses his gratitude in return, noting that exploring the frontiers of non-DNA inheritance and epigenetics makes it an exceptionally fascinating time to study genetics.

## Notable quotes > [03:43](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=223s) If I learn about architecture, the information is encoded in my brain. And since my brain cells can't transfer information to the sperm and the egg... what happens in the brain shouldn't be able to transfer to the next generation. — Dr. Oded Rechavi

> [03:43](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=223s) what transpires in the soma must stay in the soma. — Dr. Oded Rechavi

> [08:27](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=507s) hereditary information flows exclusively from the germline to somatic cells, never in reverse. — Dr. Oded Rechavi

> [09:29](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=569s) Roughly 90% of epigenetic marks and modifications on sperm and egg DNA are wiped clean so the embryo can develop according to the species' baseline genetic blueprint rather than retaining specialized somatic constraints. — Andrew Huberman

> [22:15](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=1335s) The nervous system and the germline speak entirely different languages. — Dr. Oded Rechavi

> [22:15](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=1335s) translating complex synaptic wiring into a discrete molecular code within a gamete is a major theoretical hurdle. — Dr. Oded Rechavi

> [29:44](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=1784s) maybe you should run on the treadmill a little bit — Dr. Oded Rechavi

> [29:44](https://www.youtube.com/watch?v=1_iNTFSw4Nc&t=1784s) DNA sequences are fixed and immutable, meaning parents or clinicians can only screen and choose between different embryos. In contrast, RNA profiles respond dynamically to physiological states and environmental interventions. — Dr. Oded Rechavi

## Mentioned Andrew Huberman, Dr. Oded Rechavi, Tel Aviv University, IKEA, Jean-Baptiste Lamarck, Charles Darwin, August Weismann, Erwin Schrödinger, What Is Life?, Caenorhabditis elegans, Andrew Fire, Craig Mello, Cell, Developmental Origins of Health and Disease (DOHaD)

## Video description In this Huberman Lab Essentials episode, my guest is Dr. Oded Rechavi, a professor at Tel Aviv University who studies genetics, epigenetics and the inheritance of acquired traits. We discuss how DNA, RNA and epigenetic mechanisms determine what information can pass between generations, and why acquired traits are generally not thought to be inherited. We also explain research in C. elegans showing how small RNAs can transmit antiviral resistance and influence behavior across generations, what these findings might mean for mammals and humans, and potential future applications for reproductive health and diagnostics.

Show notes: https://go.hubermanlab.com/HbTfdok

Full episode with Dr. Oded Rechavi: https://youtu.be/CDUetQMKM6g

Watch more Huberman Lab Essentials: https://youtube.com/playlist?list=PLPNW_gerXa4OGNy1yE-W9IX-tPu-tJa7S&si=a1_sA7rUT-fE0OM5

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Timestamps 00:00:00 Oded Rechavi 00:00:24 DNA, Genome, RNA & Proteins 00:03:43 Somatic vs. Germ Cells; Inheritance 00:06:04 Lamarck vs. Darwin, Inheritance of Acquired Traits 00:08:27 Weismann Barrier, Epigenetic Reprogramming 00:11:46 RNA & Transgenerational Inheritance 00:12:35 Model Organisms, C. elegans 00:15:40 Inheritance of Acquired Traits in C. elegans 00:16:03 RNA Interference, Small RNAs & Gene Silencing 00:20:08 Viral Resistance Across Generations 00:22:15 Small RNAs, Mammals & Inherited Effects 00:23:23 Brain Activity, Memory & Heritable Information 00:26:09 Neuronal Small RNAs & Behavior Across Generations 00:27:22 Germ Cells, Development & Heritable RNA 00:29:01 Future Applications, Exercise, IVF & RNA Diagnostics 00:31:06 Acknowledgements

#hubermanlab #hubermanlabpodcast #science

Disclaimer & Disclosures: https://www.hubermanlab.com/disclaimer

[Source](https://www.youtube.com/watch?v=1_iNTFSw4Nc)

中文简报

Rechavi实验室研究显示小RNA可跨代传递记忆 在线虫中的研究证明，小RNA能绕过传统DNA遗传屏障，跨代传递祖先的抗病毒能力并改变后代行为。 本期内容探讨了体细胞与生殖细胞系之间长期存在的生物学边界——这一由魏斯曼屏障和胚胎表观遗传重编程所维持的边界，在历史上否定了获得性性状的遗传。Rechavi博士展示了非编码小调控RNA如何在秀丽隐杆线虫（C. elegans）中绕过这些屏障，在不改变底层DNA序列的情况下，跨多代传递抗病毒免疫以及由神经驱动的行为改变。尽管哺乳动物缺乏线虫体内存在的持续RNA扩增机制，但在“健康与疾病的发育起源”（DOHaD）模型框架下，亲代小RNA仍可影响后代早期的发育与代谢轨迹。对话最后探讨了动态RNA谱分析和生活方式干预在生殖医学及体外受精（IVF）领域的未来治疗潜力。 编码蛋白质的信使RNA占人类基因组的比例不足2%，其余绝大部分生成调控性非编码RNA。 (0:24) 体细胞与生殖细胞之间严格的生物学隔离，阻止了习得技能、神经回路以及后天身体改变向配子的转移。 (3:43) 魏斯曼屏障以及清除早期胚胎中约90%化学标记的大规模表观遗传重编程，确保了后代重置为基线遗传蓝图。 (8:27) 非编码调控性小RNA通过在不改变DNA序列的情况下跨代调控基因表达，成为绕过传统遗传屏障的关键候选机制。 (11:46) 秀丽隐杆线虫（C. elegans）凭借其确定的959个细胞解剖结构、已测绘的302个神经元连接组、3天的快速生命周期以及强大的RNA干扰通路，成为表观遗传学研究的理想模型。 (12:35)

Reading summary

Dr. Oded Rechavi and Andrew Huberman discuss how non-coding small RNAs challenge classical genetic dogmas by transmitting physiological adaptations and behavioral shifts across generations without altering the underlying DNA sequence. While evolutionary biology established strict cellular barriers to prevent somatic experiences from altering germ cells, research in model organisms demonstrates that specific RNA-mediated pathways can cross generational lines. Biological Roadblocks to Inheriting Acquired Traits (8:27) Standard genetic dogma historically favored Darwinian natural selection and rejected Jean-Baptiste Lamarck's model of acquired trait inheritance, relying on two major biological defenses. The first is the Weismann barrier, which posits that hereditary information flows exclusively from germ cells to somatic body cells, preventing physical modifications—such as muscular hypertrophy or learned knowledge—from altering the gametes. The second barrier is generational epigenetic reprogramming. In mammals, approximately 90% of acquired chemical modifications on sperm and egg DNA are wiped clean during gametogenesis and early embryogenesis. This reset acts as an eraser that returns the developing organism to a totipotent, baseline genetic blueprint, preventing parental somatic wear and localized adaptations from accumulating unchecked in offspring. Small RNAs as Transgenerational Messengers (15:40) To evaluate how parental experiences might bypass these barriers, Rechavi's laboratory focused on the nematode Caenorhabditis elegans. Nematodes rely on RNA interference (RNAi) as an immune defense, utilizing small regulatory RNAs derived from double-stranded RNA to target and degrade viral messenger RNA transcripts, as originally characterized by Andrew Fire and Craig Mello. Rechavi observed that these RNAi silencing signals can spread systemically from somatic tissues into the germline. When parent worms were exposed to a viral pathogen, they produced matching small RNAs that were passed down to their progeny. Descendants that were genetically engineered to lack the cellular machinery required to make small RNAs remained fully protected against the virus across generations, demonstrating that the inherited RNA molecules themselves conferred transgenerational antiviral immunity. Neuronal Signaling Altering Descendant Behavior (26:09) A key challenge in transgenerational biology is explaining how information stored within complex three-dimensional neural circuits could be condensed into a single-cell gametic code. Rechavi’s laboratory investigated this by selectively altering endogenous small RNA production within the nervous systems of parent nematodes. As published in Cell in 2019, this localized neuronal perturbation generated a soma-to-germline signal that altered the expression of the saeg-2 gene within the germline. This molecular change shifted the foraging behavior of descendant worms for up to three generations. The behavioral transmission strictly required specialized RNA transport proteins, proving that parental neuronal states can guide progeny behavior by modifying germline gene expression without recreating high-level synaptic architecture. Mammalian Relevance and Potential Clinical Applications (27:22) A critical distinction between nematodes and mammals is that nematodes possess enzymes that actively amplify small RNAs, whereas mammals do not. Even without amplification, Huberman and Rechavi note that small amounts of inherited non-coding RNAs can trigger downstream developmental cascades during early mammalian embryonic or placental cleavage, aligning with the Developmental Origins of Health and Disease (DOHaD) model. For instance, rodent studies show that metabolic disorders in offspring caused by paternal overnutrition can be rescued if the father undergoes regular exercise before mating. These findings suggest future applications in human reproductive medicine and in vitro fertilization (IVF). While conventional clinical diagnostics rely entirely on static DNA sequences to screen embryos, dynamic small RNA profiling could eventually monitor real-time parental physiological states. Because RNA is plastic, Rechavi suggests parental interventions such as exercise could hypothetically optimize heritable RNA profiles prior to IVF collection. Rechavi emphasizes that while small RNA-mediated transgenerational inheritance is proven in model organisms like C. elegans, human reproductive applications and epigenetic therapies remain theoretical, as researchers have not yet mapped the precise mechanisms governing small RNA transmission across mammalian generations.

精炼阅读摘要

特拉维夫大学的Oded Rechavi博士与Andrew Huberman深入探讨了表观遗传学前沿，指出尽管魏斯曼屏障与表观遗传重编程阻隔了绝大多数后天性状的继承，但在秀丽隐杆线虫等模式生物中，特定小调控RNA能够跨越体细胞与生殖细胞的界限，将抗病毒免疫和神经适应性传递给后代，为理解环境信息如何跨代传导提供了突破性机制。 经典遗传屏障：魏斯曼界限与表观重编程 (8:27) 传统生物学长期对拉马克主义关于“获得性性状遗传”的假设持怀疑态度，因为达尔文的自然选择理论更好地解释了生物通过随机基因突变适应环境的机制。这种隔离在生物学上由两大关键屏障维系：首先是19世纪由August Weismann提出的“魏斯曼屏障”，它确立了遗传信息只能从生殖细胞（精子与卵子）流向体细胞，而无法从体细胞反向写入生殖系的生物学定律；无论是后天锻炼出的肌肉还是大脑中习得的建筑学知识，都仅局限于体细胞及神经突触内，缺乏物理通道将线路图复写至配子。 另一道屏障是严格的表观遗传重编程。虽然所有细胞共享一套完整的基因组DNA（类似于一本庞大的IKEA家具装配手册），并在分化为不同器官时添加了差异化的化学修饰标签（类似在手册上做铅笔笔记），但在哺乳动物生成精子、卵子以及受精卵发育初期，大约90%的表观修饰会被彻底清除。这种擦除机制确保了胚胎重新回到全能的空白蓝图状态，防止亲代积累的后天损耗代代叠加。物理学家Erwin Schrödinger在1944年的著作《生命是什么？》中曾感叹这种自然选择机制十分“阴沉”，因为父母无法通过自身努力直接在生物学层面提升后代的先天蓝图。 模式生物突破：小RNA与系统性抗病毒防御 (12:35) 为了在分子层面验证后天性状是否可能跨代传递，Rechavi团队采用模式生物秀丽隐杆线虫（Caenorhabditis elegans）进行研究。线虫具有极其精确的实验优势：成虫仅包含959个受控体细胞、302个神经元构成的固定连接图谱、完全透明的身体以及3天一代的发育周期。线虫缺乏哺乳动物以T细胞和B细胞为核心的适应性免疫系统，主要依赖RNA干扰（RNAi）机制进行抗病毒防御——Andrew Fire与Craig Mello于1998年发现双链RNA可诱发小RNA靶向降解匹配的mRNA，并因此获得2006年诺贝尔生理学或医学奖。 在线虫体内，RNAi具有罕见的全身扩散特性，体细胞产生的沉默信号能跨越组织边界进入生殖系。Rechavi实验室通过荧光病毒报告系统证实，感染病毒的亲代线虫会合成特异性小RNA；即使通过基因敲除使后代丧失从头合成小RNA的酶系，这些后代依然能够依靠从亲代配子中继承的抗病毒小RNA成功抑制病毒复制并存活，且该保护效应在后续多个世代中持续存在。这证实了小RNA可作为超越DNA序列的跨代信息载体。 跨越语言障碍：神经元小RNA重塑后代行为 (26:09) 将神经系统中的学习与记忆跨代传递面临着巨大的理论困难：大脑记忆编码于高维的三维突触连接结构中，而遗传信息必须通过单细胞受精卵的狭窄瓶颈，两者之间缺乏直接的转译语言。在线虫的简单模型中，某些学习可能仅表现为特定化学受体的下调，但高级神经活动如何告知生殖细胞仍是未解之谜。 Rechavi团队在2019年发表于《Cell》杂志的研究跨越了这道鸿沟。研究人员特异性改变了亲代线虫神经元内的内源性小RNA表达，结果发现这种神经扰动并未试图复写神经元连接，而是通过体细胞向生殖细胞发送信号，直接改变了生殖系中特定基因（如saeg-2）的表达水平。由于后代的所有体细胞均由受精卵发育分化而来，生殖系的预设改变使未接受过任何脑部操作的后代在长达三代的时间内表现出不同的觅食行为。进一步实验表明，该现象完全依赖于跨代转运RNA的物理转运蛋白，从而确证了神经系统能够通过RNA转运系统主动调节后代行为。 哺乳动物差异、发育起源与辅助生殖展望 (27:22) 线虫与哺乳动物之间存在一项关键差异：线虫体内拥有特异性酶系，能够持续扩增复制小RNA以防信号随细胞分裂而稀释，而哺乳动物缺乏这种RNA扩增机制。尽管如此，根据健康与疾病的发育起源（DOHaD）模型，未被扩增的微量亲代非编码RNA在早期胚胎卵裂或胎盘形成的关键窗口期，仍可能触发深远的级联反应，永久改变后代的代谢轨道。啮齿动物实验证实，雄性亲代过度喂养会导致后代出现代谢障碍，但若雄性在交配前进行体育锻炼，则能有效逆转这种不利的表观遗传表型。 对于人类医学应用，Rechavi指出小RNA的最大优势在于其动态可塑性。目前的孕前筛查（例如以色列普遍推行的婚前基因检测）完全局限于静态且不可更改的DNA序列，临床仅能用于胚胎筛选；而RNA则会随生理状态和生活方式迅速改变。Rechavi设想，未来生殖医学或可利用RNA检测评估精子和卵子的即时健康指纹，甚至指导父母在试管婴儿（IVF）取样前通过运动等手段优化RNA状态。不过，Rechavi明确提醒，目前这类人类干预策略仍处于理论推想的“科幻”阶段，尚无确凿的人体临床证据。 Oded Rechavi的研究打破了体细胞与生殖系绝对隔离的传统教条，证明了非编码小RNA能够充当跨越世代的环境信使。然而，由于哺乳动物缺乏RNA扩增酶系且经历深度的胚胎表观重编程，线虫实验中的跨代记忆遗传机制能在多大程度上外推至人类复杂的生理与认知层面，仍是当代生命科学有待解决的核心问题。

Source quotes

[3:43] Dr. Oded Rechavi: If I learn about architecture, the information is encoded in my brain. And since my brain cells can't transfer information to the sperm and the egg... what happens in the brain shouldn't be able to transfer to the next generation. [3:43] Dr. Oded Rechavi: what transpires in the soma must stay in the soma. [8:27] Dr. Oded Rechavi: hereditary information flows exclusively from the germline to somatic cells, never in reverse. [9:29] Andrew Huberman: Roughly 90% of epigenetic marks and modifications on sperm and egg DNA are wiped clean so the embryo can develop according to the species' baseline genetic blueprint rather than retaining specialized somatic constraints. [22:15] Dr. Oded Rechavi: The nervous system and the germline speak entirely different languages. [22:15] Dr. Oded Rechavi: translating complex synaptic wiring into a discrete molecular code within a gamete is a major theoretical hurdle. [29:44] Dr. Oded Rechavi: maybe you should run on the treadmill a little bit [29:44] Dr. Oded Rechavi: DNA sequences are fixed and immutable, meaning parents or clinicians can only screen and choose between different embryos. In contrast, RNA profiles respond dynamically to physiological states and environmental interventions.

Original transcript

[0:00] Welcome to Huberman Lab Essentials, [0:02] where we revisit past episodes for the [0:04] most potent and actionable science-based [0:06] tools for mental health, physical [0:08] health, and performance. [0:11] I'm Andrew Huberman, and I'm a professor [0:13] of neurobiology and opthalmology at [0:16] Stanford School of Medicine. And now for [0:18] my discussion with Dr. Oded Rakavi. [0:21] Oded, thank you so much for being here. [0:22] >> Totally my pleasure. Today, what I [0:24] mainly want to talk about is the [0:27] incredible questions that you probe in [0:29] your lab, which are incredibly [0:31] significant for each and all of our [0:32] lives. I think most people have a [0:34] general understanding of what genes are, [0:36] what RNA is, and so on. But maybe you [0:38] could explain to people in very basic [0:40] terms. And I'll just preface all this by [0:43] saying that I think most people [0:44] understand that if they have two [0:45] blue-eyed parents that there's a higher [0:48] probability that they their offspring [0:50] will have blue eyes than brown eyesh. [0:52] Mhm. [0:53] >> But most people generally understand and [0:55] accept that if they spend part of their [0:57] life um let's say studying architecture [1:00] that if they have children that there's [1:03] no real genetic reason we assume that [1:06] their children would somehow be better [1:11] at architecture because they contain the [1:13] knowledge through the DNA of their [1:15] parents. They might be exposed to it in [1:16] the home so-called nature nurture [1:18] nurture in that case but that they [1:19] wouldn't inherit knowledge. Today I'm [1:21] hoping you can explain to us why eye [1:24] color but not knowledge is thought to be [1:26] inherited and the huge landscape of [1:28] interesting questions that this opens up [1:30] including some evidence that contrary to [1:34] what we might think uh certain types of [1:36] knowledge at the level of cells and [1:38] systems can be inherited. [1:39] >> So DNA are the is the material the [1:43] genetic instructions that is contained [1:45] in every one of our cells. We have the [1:47] set of genes containing the entire set [1:50] is called the genome and this is present [1:52] in every cell of our body. The same set [1:54] of instructions. Genes are made of DNA [1:57] and chromosomes that are containing [2:00] chromosomes. Chromosomes is the DNA and [2:01] the proteins that condense the DNA [2:04] because we have a huge amount of DNA in [2:05] every cell that you need to condense it [2:07] to. [2:07] >> Sort of like um thread on a on a spool, [2:10] >> right? Huge amounts that you have to [2:11] condense. And we have the same genome, [2:14] the same DNA in every cell in our body. [2:17] It's good to have an analogy to to [2:19] understand how it works. This is like [2:20] the IKA book that you have in every cell [2:22] in your body, the instructions to make [2:25] everything that you need in your house, [2:26] the chairs, the the kitchen, the [2:28] pictures, but in every room, you want [2:30] something else. So in the kitchen, you [2:32] want things that fit the kitchen, and in [2:34] the toilet, you want things that fit the [2:35] toilet. So you only remove one [2:38] particular page of instructions, which [2:39] is the instruction of how to build a [2:41] chair. H and this you place in the [2:43] living room. Okay. And the toilet you [2:45] put in the toilet. So the genome the is [2:47] the instruction to make everything. This [2:49] is the care book. And in every cell we [2:52] we take just the instructions for make [2:53] one particular furniture. And this is [2:55] the RNA. And then the end you'll build a [2:58] chair. The chair is the protein. This is [3:00] true for one particular type of RNA [3:02] which is messenger RNA. And in fact this [3:04] is just a small percent of our of the [3:08] RNA in the cell. So we have a very big [3:10] genome and less than 2% of it encodes [3:14] for this messenger RNA. However, a lot [3:17] of the genome is transcribed to make RNA [3:19] that does other things. Some of these [3:21] RNAs we understand and many of them we [3:23] don't. I think it's a beautiful [3:25] description and IKEA is not a sponsor of [3:27] the podcast. So it's totally fair game [3:30] to to use the IKEA catalog as as the [3:32] analogy for DNA. The specific [3:34] instructions for specific pieces of [3:36] furniture is the RNA and the furniture [3:38] pieces being the proteins that are that [3:40] are essentially made from RNA using [3:42] messenger RNA. Right. [3:43] >> Okay. Despite the fact that the same [3:45] genes are contained in all the cells of [3:47] the body, is it fair to say that there [3:48] is basically one very important [3:51] exception which is sematic cells versus [3:53] germ cells. And would you mind sharing [3:55] with us what that distinction is? [3:57] >> So yes, every cell every cell type is [3:59] different. We have cells in the legs. We [4:02] have cells in the brain. We have in the [4:03] in the brain we have cells that produce [4:05] dopamine, cells that produce serotonin [4:07] and so on. But we can make one very [4:09] important distinction between the [4:10] somatic cells and the germ cells. The [4:13] germ cells are supposed to be the only [4:14] cells that contribute [4:16] to the next generation that out of which [4:18] the next generation will be made. So [4:21] each of us is made just from a a [4:23] combination of a sperm and an egg. These [4:25] are two types of germ cells. And then [4:28] they fuse and you make you you you get [4:30] one fertilized egg and out of this one [4:34] cell all the rest of the body will [4:35] develop and what happens in the soma [4:38] which is which are all the cells that [4:39] are not the the germ cells should stay [4:41] in the soma should not be able to [4:43] contribute to the next generation. This [4:44] is very important and is sought to be [4:46] one of the main barriers for the [4:48] inheritance of acquired traits, the [4:50] inheritance of memory and so on because [4:52] for example like the example that you [4:54] gave in with learning architecture if I [4:57] learn about architecture the information [5:00] is encoded in my brain and since my [5:03] brain cells can't transfer information [5:07] to the sperm and the egg because the [5:10] information is supposed to reside in [5:12] synaptic connections between different [5:13] neurons. in particular circuits that [5:16] developed. H so what's what what happens [5:20] in the brain shouldn't be able to [5:21] transfer to the next generation. Even [5:23] simpler a simpler example if you go to [5:25] the gym and you build up muscles you [5:27] know that your kids will will will have [5:30] to work out on their own. It won't this [5:32] short out won't won't happen. This is [5:34] something that we know intuitively even [5:36] if we don't have any background in [5:37] biology. This is connected to the fact [5:39] that as we said at the beginning, every [5:41] cell in the body has its own genome and [5:44] the next generation will only form from [5:46] the combination of the genomes in the [5:48] sperm and the egg. Even if you somehow h [5:52] acquire the mutation or a change in your [5:54] DNA in one of particular brain cells, it [5:57] wouldn't matter because this mutation, [5:59] there's no way to transfer it to the DNA [6:01] of the of the germ cells that will [6:03] contribute to the next generation. There [6:05] is this idea and I'll say it so that you [6:06] don't have to that dates back to Lamar [6:10] and Lamarian evolution very [6:11] controversial right um and maybe not [6:13] even controversial I think it's very [6:15] like offensive even to certain people [6:17] this idea of inheritance of acquired [6:18] traits the idea that one could change [6:21] themselves through some activity use the [6:23] example of going to the gym we could [6:24] also use the example of somebody who [6:25] becomes an endurance runner then decides [6:28] to have children with another endurance [6:29] runner and has in mind the idea that [6:32] because they did all [6:34] running and not just because they were [6:36] biased towards running in the first [6:38] place but because they of the distance [6:40] they actually ran that their offspring [6:41] somehow would be fabulous runners. This [6:43] Lamarian concept is we believe wrong. So [6:48] how do we talk about inheritance of [6:50] acquired traits? What's the proper [6:52] language for us to frame this [6:53] discussion? Lamak this is what he [6:55] believed and and he thought this what is [6:58] this is how evolution progress [7:00] progressed and and later [7:02] um Darvin showed that it's really [7:05] natural selection the selecting of the [7:07] organisms that already contain the [7:09] particular qualities are selected based [7:11] on the whether they survive or not in [7:12] particular environments and therefore [7:14] their um evolution progresses they [7:17] become more common and take over. This [7:19] is very different two different [7:20] explanations. Most common way this is [7:22] contrasted is the neck of the giraffes. [7:24] This is the classic example. According [7:26] to to Lamach, the giraffes had to [7:29] stretch their necks towards the trees to [7:32] eat when the tree when the trees were [7:34] high. And because of that the they [7:36] transmitted these traits long necks to [7:38] their children who also had long necks. [7:40] And according to Darin just that the a [7:42] gerat happened to be born with a long [7:44] neck survived because it ate. So it's [7:47] genetic heritable material. didn't know [7:49] about genetics but take over and the [7:52] rest of the giraffes that have different [7:54] heritable materials just die. So this is [7:56] natural selection versus inheritance [7:57] acquired traits. And then we go back to [8:00] to to these uh studies about inheritance [8:02] of acquired traits. There were also [8:04] theoretical problems of why of why this [8:07] can't happen barriers that have to be [8:10] breached for this to happen. And you can [8:12] narrow it down to two main barriers. The [8:14] first barrier we mentioned it this is [8:16] the separation of the soma from the [8:17] germa [8:18] >> right the sematic cells they can change [8:20] in response to experience the sperm and [8:22] the egg the so-called germ cells cannot [8:26] >> that's the idea [8:27] >> or they are isolated from what happens [8:28] in the soma [8:29] >> okay the man who who first thought about [8:33] this barrier is called wiseman August [8:34] wiseman this was in the 19th century so [8:37] it is called today the wiseman barrier [8:40] separation of the s from the germ line [8:41] only the germ line transmitting [8:43] information from it to the next [8:44] generation and this is also called the [8:46] second law of biology. So this is very [8:48] very fundamental. So natural selection [8:49] is the first one. This is the second one [8:51] because it's so important to how our [8:53] bodies work. The other main barrier it's [8:56] called epigenetic reprogramming [8:58] which is that we acquired our diff our [9:02] cells the the genetic material in our [9:04] cells acquires all kinds of chemical [9:06] changes but these modifications are [9:09] largely erased in the transition between [9:12] generations. So in the germ line in the [9:15] in the the the sperm and the egg and [9:17] also in the early embryo most of the [9:20] modifications are removed. So we can [9:23] start a blank slate based on the genetic [9:25] instructions and this is crucial [9:28] otherwise [9:29] according to the theory it's not clear [9:31] that actually true because in some [9:32] organisms doesn't really happen. [9:35] We will just we will not develop [9:37] according to the [9:39] species typical genetic instructions. [9:42] Mhm. So to preserve this we erase all [9:44] these modifications that start a new and [9:46] this is in in mammals and in humans this [9:49] is largely true. Most of the [9:50] modifications on the in the sperm and in [9:54] the egg are removed. So about 90% of [9:56] them. [9:56] >> So the idea if I understand correctly is [9:59] that there's some advantage uh to wiping [10:02] the slate clean and returning to the [10:04] original uh plan in in the context of [10:08] the IKEA furniture analogy. The [10:10] instruction book [10:11] >> is the one that's issued to everybody, [10:13] okay? Or every cell, right? Only certain [10:16] instructions are used for certain cell, [10:18] say a skin cell or a neuron or a liver [10:20] cell or any other cell for that matter [10:23] through the course of the lifespan of [10:25] the organism. Those specific [10:26] instructions are adjusted somewhat. [10:28] Okay. So, maybe the idea is to take the [10:30] instruction, but go through and erase [10:32] all the pen and pencil marks, erase all [10:34] those additional little modifications [10:35] that the the owner used or introduced to [10:38] it and return to the original [10:40] instruction, [10:40] >> right? Because if you want to bring back [10:42] the instruction book, you want it to [10:43] have all the potential to make all the [10:45] furniturees. You don't want it to be [10:46] restricted to the ones that you made in [10:47] the particular room. So, part of the [10:50] resistant resistant to the idea is based [10:53] on the theoretical grounds because of [10:56] these barriers. [10:58] And because of the of the controversies [11:00] on the other hand, people really want to [11:03] believe it because it sorts of gives [11:06] your life meaning if you can change your [11:10] biology [11:12] through changing of of your kids through [11:14] changing your biology. So [11:15] psychologically I can understand why [11:17] many people want this to happen. Even [11:19] shreddinger the famous physicist so he [11:21] wrote a very important book in 44 and he [11:25] talks about the heritable material. also [11:26] talks about evolution and he said [11:28] inheritance of a quiet trait is [11:29] untenable. doesn't happen and it and he [11:32] writes this is very very sad or [11:34] unfortunate because unlike Darvinism or [11:37] natural selection which is gloomy [11:39] doesn't matter what you do the next [11:41] generation will be born based on the [11:43] instruction in this the sperm and the [11:45] egg it doesn't m you can't influence it [11:47] of course you can give your kids money [11:48] and education but you can't biologically [11:50] influence it however there's one [11:52] additional thing to to mention which is [11:55] there are also other mechanisms that [11:56] might transmit information including [11:58] transmission between generations of RNA [12:02] and there are different types of RNA not [12:04] just messenger RNA which encodes for the [12:08] information for making protein but also [12:10] other RNAs that regulate gene expression [12:13] and I think that in recent years also in [12:15] the malian field RNA as the molecule [12:20] that has the potential to transmit [12:21] information between generation took [12:23] center stage. So I think this is the [12:25] cutting edge a lot more to understand [12:28] and know but RNA has a lot of potential [12:30] for doing that as we'll explain uh soon [12:33] but we have to go to worms first. Many [12:35] if not most of our listeners are focused [12:37] on humans and human biology and health [12:39] etc. But I cannot emphasize enough the [12:43] importance of model organisms and the [12:45] incredible degree to which they've [12:47] informed us about human health [12:48] especially when it comes to very basic [12:51] functions in cells. Before we start to [12:54] go into the description about worms per [12:55] se, could you just explain to the a [12:58] general audience what a model organism [13:00] is and why you've selected or elected to [13:04] work on a particular type of worm to [13:07] study these fascinating topics that [13:10] there's zero question also take place in [13:12] in humans at some level. [13:14] >> Model organisms mean that it's an it's a [13:16] an organism. there's a a huge community [13:19] of researchers that combine sources to [13:22] create all the the resources and the [13:23] tools and understanding that [13:25] accumulates. We learned about every [13:27] aspect of biology through them including [13:29] many important diseases. And the reason [13:31] that we can learn a lot also about [13:33] humans by studying these animals is that [13:36] we all evolve from the same ancestor. We [13:39] share a lot of our functions with them [13:41] and also a lot of our genes. They [13:43] sometimes have things that are much more [13:45] apparent in them that we can study. [13:46] Another important reason to sending them [13:48] of course is you can you can actually [13:50] experiment on them. We can't do this to [13:52] humans. The things that we do to these [13:53] animals and we can change their genes do [13:57] all kinds of things for them. The [13:58] community of people that study segance [14:00] has literally numbered and named each [14:02] neuron so that two laboratories on [14:04] opposite sides of the world can publish [14:06] papers on the same neuron knowing that [14:08] it's the same neuron in the two [14:10] different laboratories. Something that [14:12] is extremely hard to do in any mamalian [14:15] model. mouse or certainly in humans and [14:19] has posed huge challenges that u give [14:21] great advantages to studies of things [14:23] like sea elegance. [14:24] >> Celigance neatode always has 959 cells [14:27] out of which 302 are neurons. We have a [14:31] me a conneto since the 80s [14:35] like a subway map that tells us which [14:37] neuron talks with which other neurons [14:39] and it is the same. Not only that, the [14:41] worms are transparent. So we can [14:44] actually see the neurons fire using [14:47] particular tools and we can activate [14:49] genes and silage genes using [14:51] optogenetics. On top of that we have [14:54] great understanding of the genetics of [14:56] the worm of of the genome. This is [14:59] circans is the first animal to have its [15:01] sequ it its genome sequenced before [15:04] humans. And we know that and each worm [15:06] produces each mother produces about 250 [15:09] babies which are almost genetically [15:11] identical. And we know where we grow [15:13] them. The environment is very [15:15] controlled. So we grow them in the plate [15:17] with just bacteria. So we can easily [15:20] separate between nature and nurture. The [15:22] generation time in silicance is 3 days. [15:25] Three days. So you can do hundreds of [15:27] worm generations in one PhD. This is [15:30] very important. Not only that, every [15:32] worm will produce hundreds of progeny. [15:34] So you will have that are genetically [15:35] identical. So you will have great [15:37] statistics for your experiments. In the [15:38] worm, we now have very obvious and [15:43] clearcut proof that there is inheritance [15:46] of acquired traits. So much so that I [15:49] don't think that anyone pretty much in [15:51] the epigenetic field argues against it. [15:54] What was the first experiment that you [15:56] did on Celeans that confirmed for you [16:00] that inheritance of acquired traits is [16:02] real? We said to test whether worms can [16:07] produce transgenerational resistance to [16:09] viruses. These worms don't have [16:11] dedicated immune cells like we do. They [16:13] don't have T- cells or B cells. They [16:16] defend themselves from viruses using RNA [16:19] that destroy viruses. And these are [16:21] called small RNAs. 2006 two researchers [16:25] that were studying segance Andrew Fire [16:28] and Craig Melo got the Nobel Prize for [16:31] showing that there is a mechanism that [16:33] regulate genes [16:35] that happens through small RNA. What [16:38] they've shown is that if you inject the [16:42] worms with RNA molecules which are which [16:46] are double stranded, they shut off the [16:48] genes that match in sequence to this [16:50] RNA. So, it's sort of like taking the [16:53] specific instructions for the coffee [16:55] table from your IKEA uh handbook and you [16:59] insert a copy of that into the book and [17:02] in doing so you prevent the expression [17:05] of uh you sort of erase the original [17:07] page. [17:08] >> Perfect explanation. They found that [17:10] double strand RNA, RNA that has two [17:12] strands, is what starts the response [17:15] leading to the production of small RNA [17:17] molecules which are the ones that [17:18] actually find the messenger RNA and [17:21] leads to its destruction. Silence it so [17:23] you don't get proteins in the end. For [17:25] that they got the Nobel Prize after [17:27] people found that this is conserved in [17:29] many organisms including humans and [17:31] there are now drugs this was only in [17:33] 2006 that the Nobel Prize the paper was [17:36] published in 98. There are now drugs [17:38] that use this mechanism. It is called [17:40] RNA interference. RNA interferes in the [17:44] expression of a gene in the in the [17:45] function of a gene. And it's al also [17:48] called gene silencing because these RNAs [17:50] enforce the silencing of genes instead [17:52] of the genes being expressed. They are [17:54] silenced and you don't manifest their [17:56] function. They've shown two very [17:58] important things. You don't only see the [18:02] action in the cell that you injected or [18:04] in the tissue that you injected, but you [18:06] see it all over the worm's body. It [18:08] spreads. This includes also the germ [18:12] cells. So if you inject the double [18:13] strand RNA just to summatic cells, even [18:17] to the head, you will get also the [18:20] effect in the germ cells and in the next [18:22] generation. Later they've shown that you [18:25] can just take worms and feed them on [18:28] bacteria that produce this double strand [18:31] RNA and that the double and the [18:34] silencing would move from the site of [18:36] injection from the gut where the [18:38] bacteria are eaten to the rest of the [18:40] body and also to the next generation and [18:42] this is not controversial at all. This [18:44] is being done routinely every day by any [18:46] segance biologist in the world. This is [18:49] has been replicated a million times. [18:52] When I started my work, I wanted to see [18:54] whether in addition to artificial double [18:56] strand RNA, some natural traits can can [19:00] also transmit across generations because [19:02] of RNA because of smallerness, [19:04] >> right? because um injecting RNAi or um [19:07] in inter short shorter interfering RNAs [19:09] that is or um you know putting [19:14] worms into an environment with an [19:15] abundance of inhibitory RNAs as an [19:17] experiment is very different than worms [19:19] experiencing something and then passing [19:21] on that acquired trait to their [19:23] offspring and it's a world apart in my [19:26] opinion because one is an extreme [19:28] manipulation that illustrates an [19:29] underlying principle. The other is [19:31] something that in theory occurs in the [19:33] passage of of generations just naturally [19:36] >> we're going from the less artificial to [19:37] the more artificial the advantages just [19:40] like with model organisms that the more [19:42] artificial it is the easy it is to you [19:45] know exactly what you did just now [19:47] introduce one factor and you can follow [19:49] the result so this is always the [19:50] tradeoff in fact this is probably the [19:52] reason that these small evolved in the [19:54] first place to get rid of viruses and [19:58] other parasitic genomic elements and [20:02] this is a mechanism to fight [20:04] We demonstrated this very clearly [20:08] using a fluorescent virus. If the virus [20:11] replicates successfully, the worms just [20:13] turns green. And if the virus is [20:15] destroyed, the worm stays black. This is [20:18] very simple. It's a clear cut off. We [20:19] took worms, we infect them with a [20:21] fluorescent virus, they destroy it. This [20:24] also has been done in the past. But then [20:26] what we did is we neutralized [20:29] the machinery that makes small RNAs in [20:33] the descendants of the worms. So they [20:36] cannot make small RNAs from the start on [20:39] their own because they just don't have [20:41] the genes that you need to to make these [20:43] small. And then we ask what will happen [20:45] when we infect these worms with the [20:46] vows? Will they be green or black? They [20:50] can't make their own small RNAs. So they [20:53] can't protect themselves on their own. [20:55] The only way for them to stay black for [20:58] them not having the virus replicate is [20:59] if they inherit the small RNA from their [21:01] pets. And this is exactly what happens. [21:03] All the worms progeny although they [21:05] don't have the gene that is needed for [21:08] making the small RNAs are black. They [21:10] science the virus and this also [21:11] continues for additional generations. [21:13] Okay. So the the parent worms [21:15] effectively [21:17] put something into the genetic [21:19] instructions of the offspring that would [21:21] afford them um this let's call it an [21:23] advantage in this case but afford them [21:26] an advantage if they were to be [21:28] confronted with the same thing that the [21:29] parents were [21:30] >> right and we know exactly what this [21:31] advantage is the the advantages are [21:35] small RNAs that match the viral genome [21:39] then just chop up the virus in the next [21:41] generation and we can identify these [21:43] small RNA [21:45] in the the inhibitory RNAs in the [21:47] descendants although they don't have the [21:49] machinery to make it just because they [21:51] inherit it we can identify them by [21:52] sequencing RNA sequencing which is like [21:54] DNA sequencing you actually get the [21:57] actual sequence of the RNA molecules and [21:58] we can see that they correspond to the [22:00] virus and they have they inherit in [22:02] small RNAs only if their their parents [22:04] were infected with them. It is true that [22:06] also in mammals RNAs and small RNAs are [22:11] a linding candidate for something that [22:13] could mediate the transmission of of [22:16] stress protection or also of harmful [22:18] effects that transmit between [22:20] generations perhaps RNA do it and it's [22:22] very interesting to think about it when [22:24] we talk about inheritance of memories [22:26] can brain activity of some sort transmit [22:30] at least in these words I said no I I [22:32] said this disclaimer multiple times in [22:34] in members we don't Now times will tell [22:36] in worms we know a lot. H so can worms [22:39] transmit brain activity to to do they [22:42] have the specificity to do I think that [22:43] any tissues that transmit transfer to [22:46] transmit RNA to the next generation and [22:48] affect the next generation is [22:49] interesting. The gut muscles everything [22:51] but the brain can synthesize [22:55] information about the environment and [22:57] about internal states and can also think [23:00] ahead. And the most provocative thing [23:02] you can say is that you could plan how [23:04] somehow the fate of your of your nation [23:07] using your brain you know after taking [23:09] many things into the code. This is [23:11] >> without talking to them [23:12] >> right without talking. [23:13] >> All right. Again we go back to this [23:14] instruction manual. It's like writing [23:16] something into the instruction manual [23:17] based on your own experience. [23:19] >> Right? We have to understand that the [23:21] brain [23:22] uses a different language than the [23:25] language of inheritance. It keeps [23:27] information in synapses in the [23:30] connections between different neurons. [23:31] When you learn something, you make you [23:33] make some connections stronger and some [23:34] con other connections weaker and you [23:36] wire the nervous system in a different [23:38] way. On the other hand, heritable [23:41] information of any sort has to go [23:43] through a bottleneck of one cell, the [23:46] fertilized egg, because we all start [23:48] from just one cell. So the question is [23:51] can you or do you translate the [23:53] information this 3D structure [23:54] information of synapses and the [23:57] connection between brains in the [23:58] architecture of the brain. Can you [24:00] somehow translate it to heritable [24:02] information to a molecular form? You can [24:04] teach worms even though although they [24:06] have just 302 neurons you can teach them [24:07] simple things about the world. For [24:09] example you can take an odor that the [24:11] worms like. The worms have thousands of [24:13] odor ant receptors and they can [24:15] recognize many many many molecules. They [24:18] can smell them so they can find food or [24:19] avoid enemies. You can take an order [24:22] that the worms like and pair it to [24:24] something bad like starvation and then [24:27] the worms will learn to dislike this [24:29] order. [24:31] We don't know that this learning [24:33] involves necessarily changing in the [24:35] strength of sinapses. It's a possibility [24:38] but it doesn't have to be the case. It [24:40] could be that just the receptor for this [24:42] particular Odo [24:44] is being removed when they and this is [24:47] how they live. Now they won't have the [24:48] receptor. They won't smell. They won't [24:50] like the order. This is a possibility. [24:52] This type of thing you can perhaps not [24:54] that anyone has showed it convincingly [24:57] transmit to the next generation because [24:59] all it would take is an RNA that will [25:01] control this particular receptor. Okay. [25:03] People have shown things like that not [25:05] in segance but people have shown things [25:07] like this in mammals. [25:10] They said that you learn certain thing [25:12] and then [25:14] just in the next generation thus a [25:15] particular receptor would be metated or [25:18] would change and this would transmit the [25:20] response. And on the one hand it could [25:23] be true. On the other hand you need to [25:27] understand they'll need to prove and [25:29] this wasn't done convincingly enough [25:31] yet. How exactly does the information [25:33] transfer from the brain to the germ [25:35] cells and then in the next generation [25:37] from the germ cells back to the brain to [25:38] where the receptor need receptor need to [25:41] operate and this is a challenge. This is [25:43] the current state of the field that this [25:45] is something that needs to be proven. [25:47] What we did in C elegance is we showed [25:49] that the brain can communicate with the [25:52] next generations using small RNAs and [25:54] that this can change behavior and it [25:57] doesn't require any translating between [25:59] any language. It is very simple. What [26:01] we've shown is that if you take a worm [26:04] and you change the production of small [26:06] RNA just in its brain [26:09] in the next generations their behavior [26:11] will be different even though you don't [26:13] mess with their brains. This is a paper [26:14] that we published in 2019 in cell. We [26:18] show that you just manipulate the [26:20] production of endogenous natural RNAs in [26:23] the worm's brain that are always made, [26:25] but you you change their amount and this [26:27] changes the capacity of the worms in the [26:30] next generation to find food not only in [26:32] one generation but three generations [26:34] down the road. And the way that it works [26:37] is that perturbing the production of [26:39] these small RNAs in the brain affects in [26:42] the end the expression of a gene in the [26:45] germ line. One gene is called sage 2. We [26:49] can do all kinds of controls where we [26:50] manipulate activity of the gene and see [26:52] that this also affects behavior. And [26:55] this gene works in the germ cells. The [26:58] information needs to go from the brain [27:00] to the germs. It doesn't need to go back [27:02] from the germ cells to the brain to [27:03] affect behavior. And this depends. We [27:06] know that this is a true epigenetic [27:08] effect because it goes on for multiple [27:09] generations. And also because it [27:11] requires the machinery [27:14] that transfers RNA between generations. [27:16] If you don't have the protein that [27:17] physically carries the RNA between [27:19] generation, doesn't happen. [27:20] >> So it has to be RNA. [27:22] >> It has to be RNA. We can also find the [27:24] RNAs in the next generation that change. [27:26] We sequence the actual RNAs that change [27:28] in the next generation. So it sounds [27:31] weird that you change germ cells and it [27:33] changes behavior sperm and egg. But if [27:35] you think about it, the germ cells [27:36] affect the soma including the brain in [27:39] many ways by secretreting certain [27:42] chemicals and also because the other [27:45] cells develop from the from the germ [27:48] cells. So some information could be [27:50] transmitted over development or the [27:52] course of development could be altered [27:54] because of changes that occur in the [27:56] germ cells. For example, in mammals, one [27:58] of the explanations for how heritable [28:01] information transmits is that it just [28:03] affects something very own in [28:05] development. I I I told you that the [28:08] secret to worms inheritance is that they [28:10] have the capacity to amplify these small [28:12] RNAs all the time. This is what keeps it [28:14] going and prevents the dilution. In [28:17] mammals, we don't know of such an [28:19] amplification mechanism. So, you ask how [28:20] can a little bit of RNA or something [28:23] without amplifying affect the entire [28:25] organism? And it could be that you just [28:28] perturb something in the very beginning [28:30] when you just have a few cells or even [28:32] if in the placenta that develops in [28:35] pregnancy and this later throws [28:37] everything off and because of that you [28:39] have many problems metabolisms and so [28:41] on. And this is called the idea of the [28:43] develop developmental origin of health [28:45] and disease that many of the things [28:47] occur dur many of the of the functions [28:50] occur early on in development [28:51] >> in terms of the work in either segans or [28:55] in other model organisms but in [28:56] particular in segans where do you see [28:59] this going next? [29:00] >> So assuming that we will discover [29:04] similar things in in humans which we [29:06] don't know that this is the case but [29:07] let's say we we find it. I think there [29:09] are many things you can do before you [29:11] change it. You could also change a [29:14] parent inheritance by having the the [29:17] parent exercise. For example, and some [29:19] things like this have been done. For [29:21] example, there are experiments in in [29:23] rodents where they show that overfeeding [29:26] the u the rodent creates problems for [29:29] the next generations for the for the [29:31] children. However, if you let the the [29:34] the rodent exercise, then it corrects [29:37] the parent inheritance. So this is one [29:39] possibility and you can also manipulate [29:41] it at the source you can change if it's [29:44] RNAs let's say you could in the future [29:46] perhaps if we understand how it works [29:48] actually change the composition of the [29:50] heritable RNAs if you do IVF if you [29:52] vital fertilization you could perhaps [29:55] change the composition of the RNAs in [29:57] the the stuff that you introduce [30:00] but way before that what you could do [30:02] perhaps even in the not so far future is [30:05] use this for diagnostics DNA based [30:08] diagnostics for every couple that wants [30:10] to have a kid in Israel. This is done [30:12] for for most couples. You can look at [30:14] the DNA and look for genetic disease. [30:17] But no one look is looking at the RNA at [30:19] the moment. If we understand how it [30:21] works better, we'll have another level, [30:23] a whole new world to look at. And [30:25] perhaps there will be some RNAs that [30:27] correlate with disease. The beauty is [30:29] that this unlike DNA, it's plastic. So [30:31] with DNA, this is your DNA. Perhaps we [30:33] can choose another embryo. But here you [30:35] could say perhaps or again in the future [30:38] this is science fiction doesn't happen [30:39] now but if we understand this and it's [30:41] true we can say maybe you should run on [30:44] the treadmill a little bit this will [30:45] change the profile of your RNAs and then [30:47] we will use it for IVF. This seems more [30:50] because just it correlates with healthy [30:52] profiles of RNAs. This is a level that [30:55] no one looks at now and holds great [30:57] potential again with a disclaimer that [31:00] we don't know how it works in humans at [31:02] all [31:02] >> yet. Yes. But of course this is why why [31:05] why it's so interesting [31:06] >> today. You've taken us on an amazing [31:08] journey through the genome RNA in [31:12] particular the work in your laboratory [31:14] which is just incredible and also this [31:16] introduction of model organisms. So [31:18] thank you so much. [31:19] >> Thank you. [31:20] >> It's been a real pleasure. [31:21] >> Pleasure was all mine. Thanks a lot.