Dr. Oded Rechavi: Genes & the Inheritance of Memories Across Generations

Dr. Oded Rahavi on Genetic Inheritance

• Dr. Oded Rahavi is a professor of neurobiology at Tel Aviv University
• His laboratory studies genetic inheritance, including epigenetics and the passing of traits related to experiences
• Evidence in worms, flies, mice, and humans suggests that memories can be passed from one generation to the next
• Genetic modifications can be passed transgenerationally, affecting multiple generations

Understanding DNA, RNA, and Inheritance

• DNA is the genetic material containing instructions in every cell
• The entire set of genes is called the genome, which is present in every cell of the body
• Genes are made of DNA and are contained in chromosomes
• Analogy: DNA is like an Ikea instruction book, with instructions to make everything needed in a house
• RNA is the specific instruction for making one particular protein based on the entire set of possibilities
• Messenger RNA (mRNA) contains information for making proteins, but it only makes up a small percentage of the RNA in a cell

Inheritance of Traits and Knowledge

• Eye color is a well-​​known example of inherited traits
• It is generally believed that knowledge, such as studying architecture, is not inherited through DNA

• However, there is evidence that certain types of knowledge at the cellular and system level can be inherited
  Genome, RNA, and Proteins

• Genome: the complete set of genes or genetic material present in a cell or organism

  • Analogous to an Ikea catalog
• RNA: specific instructions for specific pieces of furniture 
  • Transcribed from the genome
• Proteins: the furniture pieces made from RNA using messenger RNA

Somatic Cells vs. Germ Cells

• Somatic cells: all body cells except germ cells 
  • Different cell types express different genes and assume different identities
• Germ cells: cells that contribute to the next generation (sperm and egg) 
  • Combine to form a fertilized egg, from which the entire body develops
  • Information in the soma should not be transferred to the next generation

Inheritance of Acquired Traits

• Controversial and complex topic
• Lamarckian evolution: the idea that traits acquired during an individual’s lifetime can be passed on to their offspring 
  • Discredited by Darwin’s theory of natural selection
• Inheritance of acquired traits still debated and researched today

Epigenetics and Transgenerational Inheritance

• Epigenetics: the study of changes in gene expression or cellular phenotype that do not involve alterations to the underlying DNA sequence
• Transgenerational epigenetics: the transmission of epigenetic information from one generation to another
• Intergenerational epigenetics: the transmission of epigenetic information between parent and offspring

Lamarck, Darwin, and the History of Inheritance Theories

• Lamarck published his book on inheritance of acquired traits over 200 years ago 
  • Believed in the idea, as did many others at the time
  • Connected the idea to evolution, making it controversial
• Darwin also believed in inheritance of acquired traits, but focused on natural selection as the primary driver of evolution 
  • Giraffe neck example: Lamarck believed stretching necks led to longer necks in offspring, while Darwin believed long-​​necked giraffes survived and passed on their traits

Lysenkoism and the Soviet Union

• Lysenkoism: a political and scientific movement in the Soviet Union that rejected Mendelian genetics in favor of Lamarckian inheritance 
  • Led by Trofim Lysenko, who believed in the inheritance of acquired traits
  • Caused massive starvation and ruined agriculture in the Soviet Union
  • Also ruined science in the country for many years

Paul Kammerer and the Midwife Toad

• Paul Kammerer: a Viennese researcher who conducted experiments on various animals, including the midwife toad

  • Attempted to prove the inheritance of acquired traits
  • Controversial and dramatic experiments, detailed in a book by Arthur Koestler
    Types of Toads and Their Adaptations

• Some toads live underwater, while others live on land

  • Underwater toads develop nuptial pads (black pads on their hands) to help males grip females during mating
  • Land toads do not have these pads
• A scientist claimed he could train toads to live underwater and change their physiology to develop nuptial pads 
  • This discovery made him famous, but it was later found that he faked the results by injecting ink into the toads

Controversies and Fraud in Science

• Fraud and controversy can occur in high-​​profile scientific situations 
  • Most scientists are honest and seeking truth, but some may bend the truth or be wrong without intending to commit fraud
• Example: McConnell’s experiments with flatworms (planaria)
  • Claimed he could teach them associations and transfer memories by feeding chopped-​​up worms to others
  • Results were controversial and difficult to replicate, leading to questions about the validity of the findings

Memory Transfer Experiments

• The idea of transferring memories through molecules was appealing and led to experiments in various animals, including fish and rodents
• The question of whether transferred memories were specific or just a general sensitization remained unresolved

Challenges in Replicating Scientific Findings

• Replication is an important aspect of scientific research, but it can be difficult to achieve in some cases 
  • Factors such as differences in methodology, equipment, or even the individual animals used in experiments can affect replication

• In McConnell’s case, the main issue was not necessarily replicating the entire experiment, but determining the specificity of the transferred memories
  Unabomber and Memory Transfer Research

• Unabomber targeted scientists, including memory transfer researcher

• Researcher’s assistant injured in explosion, ending line of research
• Recently, Mike Levin and Postdoc Talshomrat replicated some memory transfer experiments using advanced equipment
• Mechanism of memory transfer still unclear

RNA and Memory

• McConnell’s experiments suggested RNA could transmit memory
• Idea became popular, but was considered pseudoscience
• RNA can be fed to worms and cause changes, but exact process still unknown

Barriers to Inheritance of Acquired Traits

• Separation of soma (body cells) from germline (sperm and egg cells) 
  • Called the Weismann Barrier
  • Somatic cells can change in response to experience, but germline cells are isolated
• Epigenetic reprogramming
  • Chemical modifications to DNA and proteins are largely erased in sperm, egg, and early embryo
  • Allows for a “blank slate” based on genetic instructions

Epigenetics

• Term originally defined by Conrad Waddington in the 1940s
• Refers to interactions between genes and their products that influence development
• Later, term became associated with chemical modifications to DNA and proteins
• Epigenetic changes can cause differences between genetically identical twins

Methylation and Other Modifications

• DNA can be chemically modified, such as methylation of cytosine
• Proteins that condense DNA, called histones, can also be modified
• Modifications can affect gene expression and function

RNA Molecules and Inheritance

• RNA molecules are considered the most interesting players in inheritance
• Inheritance occurs across cell division or generations through mechanisms other than changes to DNA sequence

• Most modifications are erased in germline cells, but some remain, which could be significant
  Epigenetic Inheritance and Imprinting

• Epigenetic inheritance: environment of parents changes the children

• Imprinting: limited number of genes where it matters whether inherited from mother or father 
  • Occurs through epigenetic inheritance, not changes to DNA sequence
  • In some cases, environment plays no role
• Examples of environmental effects on offspring: 
  • Starvation during pregnancy leading to differences in birth weight, glucose sensitivity, and neurological diseases
  • Stress in male mice/​​rats leading to offspring with higher stress thresholds but memory deficits
  • Nicotine exposure improving tolerance to similar drugs in the next generation

Trade-​​offs in Epigenetic Inheritance

• Some effects of epigenetic inheritance may be trade-​​offs with other traits 
  • Example: offspring of starved worms live longer but are more sick and less fertile
• Caution needed when asking “why” questions in biology

Effects of Metabolic Changes and Nutrition on Offspring

• Numerous examples of overfeeding or starving parents affecting body weight, glucose tolerance, and reproductive success of offspring
• Direct effects on offspring do not necessarily require new biology or epigenetics 
  • Example: starving pregnant women directly affects the baby in utero, not necessarily through epigenetic inheritance

Understanding the Mechanisms of Epigenetic Inheritance

• Important to separate nurture from nature and understand the mechanisms behind epigenetic inheritance
• In humans and mammals, it is unclear what transmits epigenetic inheritance and which molecules are involved
• Further research needed to determine the role of epigenetics in inheritance and the potential implications for human health and development “Remember that this form of notetaking is called the \“style\” of notetaking:

Epigenetic Inheritance in Mammals

• Exposure of mother can affect transmission of genetic information through father’s sperm
• Stressing fathers can affect sperm and next generation
• Epigenetic inheritance through paternal line involves two generations; through maternal line involves three generations
• Evidence for epigenetic inheritance in mammals is scarce and evolving
• In-​​vitro fertilization (IVF) used to separate environment from inheritance
• Controversy exists among scientists regarding epigenetic inheritance
• Psychologists more likely to believe in heritable trauma than population geneticists
• Larger studies needed to understand the extent of epigenetic inheritance

Partner Selection and Inheritance

• Partner selection influenced by various traits, including kindness, resource potential, and aesthetic attractiveness
• Subconsciously selecting for biological traits related to vigor and robustness
• Research on immune compatibility and other factors in partner selection
• Nurturing ability and reliability may be linked to partner selection

RNA and Epigenetic Inheritance

• RNA, particularly non-​​coding RNA, has potential to transmit information between generations
• Field of epigenetics shifting focus to RNA as a key molecule for inheritance

Model Organisms in Research

• Model organisms are organisms that many researchers work on, with a community of researchers creating resources and tools
• Model organisms have informed much of what we understand about human health
• Examples of model organisms include nematodes (worms), fruit flies, and mice
• Studying model organisms allows for a deeper understanding of basic cellular functions and processes

Importance of Model Organisms

• Model organisms are critical for understanding human health and biology
• They provide insights into cellular functions and processes that can be applied to human biology
• Studying model organisms can lead to discoveries that have significant implications for human health and disease”
  Model Organisms in Biology
• E. Coli bacteria, phage (virus of bacteria), flies, worms (C. elegans nematodes), zebrafish (Danio), mice, plants (Arabidopsis), non-​​human primates (macaque monkeys, marmosets, squirrel monkeys)
• Emerging model organisms: planaria (flatworms for studying regeneration)
• Studying these organisms helps us learn about humans due to shared ancestry and functions
• Model organisms have advantages for experimentation, as we can manipulate their genes and study their functions

C. elegans Nematodes

• Small, 1mm long roundworms, found in rotten fruits and leaves
• Not parasites, easy to handle and grow in lab conditions
• Transparent, allowing for observation of neurons firing
• 959 cells in the body, 302 neurons (debate between 300 and 302)
• Neurons have specific names and functions
• Connectome: a map of how neurons are connected to one another
• Powerful tools for manipulating the brain, such as optogenetics
• First animal to have its genome sequenced
• Short generation time (3 days) and large progeny (250 genetically identical offspring)

Inheritance of Acquired Traits in C. elegans

• Experiment aimed to test if worms can produce transgenerational resistance to viruses
• Worms don’t have dedicated immune cells, but use RNA molecules (small RNAs) to defend against viruses
• 2006 Nobel Prize awarded to Andrew Fire and Craig Mello for discovering the mechanism of small RNAs regulating genes
• Injecting worms with double-​​stranded RNA shuts off corresponding genes, leading to the production of small RNA molecules that silence the messenger RNA

• This mechanism is conserved in many organisms, including humans, and has led to the development of drugs using this mechanism
  Motec Genes and Transgenerational Epigenetic Kinetics

• Motec genes: modified transgenerational epigenetic kinetics

  • Affect the function and inheritance of certain traits for multiple generations
• Examples of motec genes: 
  • Met two: involved in methylation of proteins that condense DNA
  • Other genes that affect the production of small RNAs

Duration of Inheritance and Lifespan

• Inheritance duration could be programmed to fit certain environmental factors 
  • Example: worms inherit traits for 3–5 generations, possibly due to cycles of starvation and abundance
• Inheritance duration could also be related to the lifespan of the organism 
  • Humans typically live 80 years, so inheritance of adaptive traits might be more relevant for 1–2 generations

Epigenetic Inheritance in Plants

• Epigenetic inheritance is well-​​established in plants 
  • Inheritance of acquired traits has been observed and well-​​controlled in plant studies
• Example: a plant species adapting to grow in a corkscrew form to capture sunlight and nutrients

Stress and Reward Systems

• Stress and reward systems are generic by design 
  • Stress response is the same for various stressors (e.g., a troubling text message or a dark figure in the hallway)
  • Reward system is governed by dopamine circuits, which are involved in anticipation and reward for various stimuli (e.g., ice cream, sex)
• Inheritance of stress resilience or maladaptive traits might also be somewhat generic 
  • Example: inheritance of resilience to viruses in general, rather than a specific virus like COVID-19

Bandwidth of Inheritance and Memory Transmission

• Inheritance can be very specific or very general 
  • Inheritance of memories is an interesting concept to explore

• In worms, researchers have learned about mechanisms that shuttle RNAs between generations

  • Identified genes needed for RNA transfer between generations
  • Identified genes that affect the duration of inheritance responses
    Memory Transfer Between Generations

• Defining memory:

  • Broadest definition: any change in behavior or response due to past experiences or history
  • More interesting: memories encoded in the brain, which can hold more specific and elaborate memories
• Brain’s ability to synthesize information about the environment and internal state, and think ahead 
  • Can plan the fate of offspring using the brain, without direct communication
  • Writing something into the instruction manual based on one’s own experience
• Limitations on memory transfer: 
  • No known mechanism to translate between the language of the brain (synaptic information) and the language of inheritance (molecular information)
  • Next generation has a different brain, even if genetically identical
  • Translation of information from one generation’s brain to the next is highly unlikely
• Possibility of specific memories being transferred: 
  • Example: teaching worms to dislike a certain odor by pairing it with something bad (e.g., starvation)
  • This learning may not involve changes in synapse strength, but rather the removal of a receptor for the odor
  • This type of memory transfer could be possible through an RNA that controls the specific receptor
• Current state of the field: 
  • Need to prove how information transfers from the brain to germ cells, and then from germ cells back to the brain
  • Research has shown that the brain can communicate with the next generation using small RNAs, which can change behavior without translating between languages
  • Example: manipulating the production of small RNAs in a worm’s brain can change the behavior of future generations in finding food
  • This effect depends on the machinery that transfers RNA between generations
  • The gene “sage” is involved in this process, but its exact function is still unknown

Implications and Future Research

• Understanding the mechanisms behind memory transfer between generations could have significant implications for biology and inheritance
• Further research is needed to determine the specific roles of genes like “sage” and the exact processes involved in transferring information between generations

• Exploring the limitations and possibilities of memory transfer could provide valuable insights into the nature of learning, memory, and inheritance
  Germ Cells, Hormones, and Inheritance

• Germ cells affect the soma, including the brain, by secreting certain chemicals

• Changes in germ cells can alter the course of development
• In mammals, heritable information can be transmitted through early developmental changes

Influence of Hormones on Germ Cells

• Germ cells (sperm and eggs) reside in regions rich with hormones
• Hormones can modify somatic cells of the body
• Example: Puberty — a transformation of somatic cells influenced by hormones

Worm Mating Behavior and Stress

• Worms can self-​​fertilize or mate with males
• Mating with males is risky but diversifies the genome
• Stress (high temperatures) can cause worms to mate more with males for three generations
• Stressed worms secrete a pheromone that attracts males

Influence of Age on Mating Behavior

• Worms secrete the pheromone when they are old and running out of fertility
• Similar to humans adjusting their attractiveness as they age to attract a mate or co-parent

Autism and Human Disease

• Children of older fathers (40 and up) have a higher chance of becoming autistic
• Unclear if this is due to epigenetics or DNA damage

• DNA fragmentation kits available for sperm analysis at home or in clinics
  Adaptive Autistic Traits and Offspring

• Engineering and hard science phenotype parents may have a higher probability of offspring on the autism spectrum

  • Possible gene copy issue or selection for partially on the spectrum parents

Older Fathers and Autism

• Intuition: less fidelity, less DNA maintenance, and some damage that passes on 
  • Sperm generated once every 60 days
  • Damage may be at the level of germ cells not having proper machinery
  • DNA repair machinery could be defective or work less well in older people, leading to constant production of germ cells with more mutations

DNA Repair Machinery

• Many types of DNA repair 
  • Some use other copies of DNA to correct
  • Some recognize lesions on DNA and remove them
  • Elaborate and complicated system
• Tractable system that can be modified through pharmacology or other means

Three Parent IVF

• Legal in the UK and other countries, but not in the US
• Addresses chromosomal abnormalities and mitochondrial genome deficits in older females’ eggs 
  • Takes nucleus from mother’s egg and places it into cytoplasm of younger woman with healthy mitochondrial DNA
  • Sperm fertilizes the egg, then implanted into the mother
  • Has been done several times in cases of mitochondrial damage or mutations

Potential Applications of Understanding Transgenerational Inheritance

• Change parent inheritance by having the parent exercise 
  • Experiments in rodents show overfeeding creates problems for next generations, but exercise corrects parent inheritance
• Manipulate inheritance at the source 
  • Change composition of heritable RNAs by eating RNAs
  • In vitro fertilization could change composition of RNAs in introduced material
• Use for diagnostics 
  • DNA-​​based diagnostics for genetic disease
  • Look at RNA for correlations with disease
  • Potential to change RNA profile through lifestyle changes (e.g., exercise)

Memory in C. elegans

• Memory within one generation 
  • Worms forget after 2 hours
• Experiment: teach worms association, freeze them, thaw them, and see if they still remember 
  • Idea: if memory is kept, it’s in the absence of electrical activity

• Actual experiment: teach worms association, place them on ice, and observe memory kinetics

  • Worms don’t forget even after 10 times longer than control worms
  • Not just physical response, but changing internal state of worms affecting memory kinetics
  • Research on cold tolerance in C. elegans nematodes
    Worms, Memory, and Cold Tolerance

• Worms can become cold tolerant if acclimated to lower temperatures for at least 5 hours

  • Cold tolerance involves changes in lipid metabolism and other factors
• Cold-​​tolerant worms forget learned associations when placed on ice 
  • Indicates that internal state change, not just temperature, affects memory
• Researchers identified genes that change when worms become cold tolerant 
  • Mutating these genes causes worms to remember longer even off ice
  • Genes expressed in just one pair of neurons out of 302
  • Manipulating these genes in neurons can extend memory

Lithium and Memory

• Lithium is a drug used to treat bipolar disorder 
  • Its mechanism of action is not entirely clear
  • It is an atom created in the Big Bang and has a fundamental effect on the brain
• Researchers found that worms grown on lithium remember longer than control worms 
  • Lithium switches the forgetfulness mechanism on and off in cold-​​tolerant worms
  • This is connected to cold tolerance

Memory Instilling Events

• In medieval times, children were thrown into cold water after learning to help them remember lessons 
  • Memory instilling events involve the release of adrenaline
  • These events can apply to learning other types of information as well
• The role of lithium and cold in memory experiments may involve an internal state switch 
  • This switch highlights important events that occurred before the switch
  • It is unclear if this is an RNA-​​dependent mechanism

Dr. Oded Rechavi’s Research

• Dr. Rechavi’s research focuses on genetics, inheritance, the epigenome, and transgenerational passage of traits
• His work explores the use of model organisms and the history of experiments in these fields
• Dr. Rechavi is also involved in transforming science at the level of publishing and social media