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

00:00:00.000 | - Welcome to the Huberman Lab Podcast,

00:00:02.280 | where we discuss science and science-based tools

00:00:04.880 | for everyday life.

00:00:05.900 | I'm Andrew Huberman,

00:00:10.400 | and I'm a professor of neurobiology and ophthalmology

00:00:13.320 | at Stanford School of Medicine.

00:00:15.180 | Today, my guest is Dr. Oded Rehavi.

00:00:17.740 | Dr. Oded Rehavi is a professor of neurobiology

00:00:20.200 | at Tel Aviv University in Israel.

00:00:22.520 | His laboratory studies genetic inheritance.

00:00:25.220 | Now, everybody is familiar with genetic inheritance

00:00:27.680 | as the idea that we inherit genes from our parents,

00:00:30.200 | and indeed that is true.

00:00:32.020 | Many people are also probably now aware

00:00:34.280 | of the so-called epigenome,

00:00:35.800 | that is, ways in which our environment and experiences

00:00:39.020 | can change our genome,

00:00:40.320 | and therefore the genes that we inherit

00:00:42.880 | or pass on to our children.

00:00:45.080 | What is less known, however,

00:00:46.800 | and what is discussed today,

00:00:48.440 | is the evidence that we can actually pass on

00:00:51.200 | traits that relate to our experiences.

00:00:54.040 | That's right.

00:00:54.960 | There is evidence in worms, in flies, in mice,

00:00:58.920 | and indeed in human beings,

00:01:00.640 | that memories can indeed be passed

00:01:02.760 | from one generation to the next.

00:01:04.760 | And that turns out to be just the tip of the iceberg

00:01:06.880 | in terms of how our parents' experiences

00:01:08.720 | and our experiences can be passed on

00:01:10.960 | from one generation to the next,

00:01:13.340 | both in terms of modifying the biological circuits

00:01:16.080 | of the brain and body,

00:01:17.240 | and the psychological consequences

00:01:19.620 | of those biological changes.

00:01:21.600 | During today's episode,

00:01:22.520 | Dr. Rehavi gives us a beautiful description

00:01:24.780 | of how genetics work.

00:01:26.480 | So even if you don't have a background in biology or science,

00:01:29.040 | by the end of today's episode,

00:01:30.740 | you will understand the core elements of genetics

00:01:33.820 | and the genetic passage of traits

00:01:35.400 | from one generation to the next.

00:01:37.080 | In addition, he makes it clear

00:01:38.880 | how certain experiences can indeed modify our genes

00:01:42.520 | such that they are passed from our parents to us,

00:01:46.040 | and even transgenerationally across multi-generations.

00:01:49.560 | That is, one generation could experience something

00:01:52.520 | and their grandchildren would still have

00:01:55.180 | genetic modifications that reflect

00:01:57.420 | those prior experiences of their grandparents.

00:02:00.120 | Dr. Rehavi takes us on an incredible journey

00:02:02.800 | explaining how our genes and different patterns

00:02:05.140 | of inheritance shape our experience of life and who we are.

00:02:08.940 | Before we begin, I'd like to emphasize that this podcast

00:02:11.800 | is separate from my teaching and research roles at Stanford.

00:02:14.480 | It is, however, part of my desire and effort

00:02:16.660 | to bring zero cost to consumer information about science

00:02:19.280 | and science-related tools to the general public.

00:02:21.960 | In keeping with that theme,

00:02:23.080 | I'd like to thank the sponsors of today's podcast.

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00:06:00.800 | And now for my discussion with Dr. Oded Rahavi.

00:06:04.360 | Oded, thank you so much for being here.

00:06:06.520 | - Totally my pleasure.

00:06:07.700 | - Yeah, this podcast has a somewhat unusual origin

00:06:12.260 | because I am familiar with your work

00:06:14.620 | but we essentially met on Twitter

00:06:16.540 | where you are known for many things

00:06:20.280 | but lately especially you have been focusing

00:06:25.280 | not just on the discoveries in your laboratory

00:06:28.580 | and other laboratories

00:06:29.860 | but also sort of meme type humor

00:06:33.140 | that relates to the scientific process

00:06:34.780 | and we'll return to this a little bit later.

00:06:36.660 | But first of all, I think it's wonderful

00:06:39.060 | that you're so active on social media

00:06:40.860 | in this positive stance around science

00:06:43.220 | that also includes humor.

00:06:45.140 | But today what I mainly want to talk about

00:06:47.660 | is the incredible questions that you probe in your lab

00:06:51.180 | which are highly unusual, incredibly significant

00:06:54.620 | for each and all of our lives and very controversial

00:06:58.340 | and at times even a little bit dangerous or morbid.

00:07:02.600 | So this is going to be a fun one for me

00:07:04.860 | and for the audience.

00:07:06.260 | Just to start off very basically

00:07:07.660 | you get everyone up to speed

00:07:09.020 | because people have different backgrounds.

00:07:12.700 | I think most people have a general understanding

00:07:14.660 | of what genes are, what RNA is and so on

00:07:17.580 | but maybe you could explain to people in very basic terms.

00:07:21.340 | And I'll just preface all this by saying that

00:07:23.740 | I think most people understand

00:07:24.880 | that if they have two blue-eyed parents

00:07:27.000 | that there's a higher probability

00:07:29.380 | that their offspring will have blue eyes than brown eyes.

00:07:32.340 | Similarly, if two brown-eyed parents

00:07:35.060 | have higher probability that they will have brown eyes

00:07:36.860 | rather than blue eyes and so on.

00:07:39.060 | But that most people generally understand

00:07:41.580 | and accept that if they spend part of their life

00:07:45.040 | let's say studying architecture,

00:07:47.260 | that if they have children

00:07:49.040 | that there's no real genetic reason, we assume,

00:07:53.220 | that their children would somehow be better at architecture

00:07:58.220 | because they contain the knowledge

00:08:00.580 | through the DNA of their parents.

00:08:01.740 | They might be exposed to it in the home,

00:08:03.360 | so-called nature-nurture, there's a nurture in that case

00:08:05.980 | but that they wouldn't inherit knowledge or other traits.

00:08:09.160 | And today I'm hoping you can explain to us why eye color

00:08:13.940 | but not knowledge is thought to be inherited

00:08:16.600 | and the huge landscape of interesting questions

00:08:19.040 | that this opens up including some evidence

00:08:22.080 | that contrary to what we might think,

00:08:25.100 | certain types of knowledge at the level of cells

00:08:27.460 | and systems can be inherited.

00:08:28.960 | So that was a very long-winded opening

00:08:31.160 | but to frame things up, what is DNA, what is RNA

00:08:36.060 | and how does inheritance really work?

00:08:38.580 | - Okay, so DNA is the material, the genetic instructions

00:08:43.580 | that is containing every one of our cells.

00:08:46.540 | We have the set of genes containing,

00:08:49.540 | the entire set is called the genome

00:08:51.620 | and this is present in every cell of our body,

00:08:53.860 | the same set of instructions.

00:08:56.180 | And genes are made of DNA

00:08:59.340 | and they also contain, and chromosomes,

00:09:03.400 | they are containing chromosomes,

00:09:04.600 | chromosomes is the DNA and the proteins

00:09:06.620 | that condense the DNA because we have a huge amount of DNA

00:09:09.900 | in every cell that you need to condense it to.

00:09:11.860 | - Sort of like thread on a spool.

00:09:14.060 | - Right, huge amounts that you have to condense.

00:09:16.940 | And we have the same genome, the same DNA

00:09:19.060 | in every cell in our body.

00:09:21.460 | - Can I just interrupt and I'll do that periodically

00:09:23.680 | just to make sure that people are being carried along.

00:09:28.400 | I sometimes find that even remarkable

00:09:31.400 | that a skin cell and a brain cell, a neuron for instance,

00:09:34.600 | very different functions,

00:09:35.960 | but they all contain the full menu of genes

00:09:39.420 | and the same menu of genes.

00:09:40.680 | - No, it is amazing, it is amazing.

00:09:42.440 | And perhaps it's good to have an analogy

00:09:44.580 | to understand how it works.

00:09:45.660 | So this is, I hope this is not a commercial,

00:09:47.540 | but this is like the IKEA book

00:09:50.000 | that you have in every cell in your body,

00:09:52.240 | the instructions to make everything

00:09:53.600 | that you need in your house, the chairs, the kitchen,

00:09:57.180 | the pictures, but in every room, you want something else.

00:10:01.140 | So in the kitchen, you want things that fit the kitchen

00:10:03.700 | and in the toilet, you want things that fit the toilet.

00:10:05.840 | So you only remove one particular page of instructions,

00:10:10.380 | which is the instruction of how to build a chair.

00:10:12.940 | And this you place in the living room, okay.

00:10:15.880 | And in the toilet, you put in a toilet.

00:10:17.380 | So the DNA is the instruction to make the genome,

00:10:21.740 | is the instruction to make everything.

00:10:24.020 | This is the IKEA book.

00:10:25.140 | And in every cell, we take just the instructions

00:10:28.380 | for make one particular furniture, and this is the RNA.

00:10:31.500 | This is the RNA, this is the set.

00:10:32.980 | And then at the end, you'll build a chair.

00:10:35.500 | The chair is the protein.

00:10:37.060 | So the DNA, the RNA is our instructions

00:10:40.180 | to make one particular protein

00:10:42.300 | based on the entire set of possibilities.

00:10:45.180 | And this is true for one particular type of RNA,

00:10:49.940 | which won't be the star of this conversation,

00:10:53.220 | which is messenger RNA.

00:10:55.300 | This is the RNA that contains the information

00:10:57.340 | for making proteins.

00:10:58.580 | And in fact, this is just a small percent

00:11:01.180 | of the RNA in the cell.

00:11:03.220 | So we have a very big genome and less than 2% of it encodes

00:11:08.220 | for this messenger RNA.

00:11:10.460 | However, a lot of the genome is transcribed to make RNA

00:11:15.460 | that does other things.

00:11:17.620 | Some of these RNAs we understand

00:11:19.500 | and many of them we don't.

00:11:23.420 | I think it's a beautiful description

00:11:24.780 | and IKEA is not a sponsor of the podcast.

00:11:27.300 | So it's totally fair game to use the IKEA catalog

00:11:31.900 | as the analogy for DNA, the specific instructions

00:11:34.940 | for specific pieces of furniture is the RNA

00:11:37.700 | and the furniture pieces being the proteins

00:11:39.420 | that are essentially made from RNA using messenger RNA.

00:11:43.340 | Okay, thank you for that.

00:11:45.300 | So despite the fact that the same genes

00:11:48.260 | are contained in all the cells of the body,

00:11:51.780 | there is a difference between certain cell types, right?

00:11:55.780 | I would say, is it fair to say

00:11:57.420 | that there was basically one very important exception

00:12:00.380 | which is somatic cells versus germ cells?

00:12:03.380 | And would you mind sharing with us what that distinction is?

00:12:05.860 | Sure, so yes, every cell type is different

00:12:09.980 | because it expresses, it brings into action different genes

00:12:14.140 | from the entire collection and assumes an identity.

00:12:19.340 | And so we have cells in the legs,

00:12:24.020 | we have cells in the brain, we have in the brain,

00:12:26.140 | we have cells that produce dopamine,

00:12:27.820 | cells that produce serotonin and so on.

00:12:30.060 | And we can make different separation, different distinctions

00:12:35.060 | but we can make one very important distinction

00:12:38.340 | between the somatic cells and the germ cells.

00:12:41.300 | The germ cells are supposed to be the only cells

00:12:43.380 | that contributes to the next generation,

00:12:46.620 | out of which the next generation will be made.

00:12:48.820 | So each of us is made just from a combination

00:12:52.420 | of a sperm and an egg, these are two types of germ cells.

00:12:55.700 | And then they fuse and you get one fertilized egg

00:13:00.700 | and out of this one cell,

00:13:02.860 | all the rest of the body will develop.

00:13:05.180 | And what happens in the soma,

00:13:07.260 | which are all the cells that are not the germ cells,

00:13:09.740 | should stay in the soma,

00:13:10.900 | should not be able to contribute to the next generation.

00:13:13.140 | This is very important.

00:13:14.300 | And it's thought to be one of the main barriers

00:13:17.100 | for the inheritance of acquired traits,

00:13:19.140 | the inheritance of memory and so on.

00:13:21.100 | Because for example, like the example that you gave

00:13:24.140 | with learning architecture,

00:13:26.300 | if I learn about architecture,

00:13:28.980 | the information is encoded in my brain.

00:13:31.740 | And since my brain cells can't transfer information

00:13:36.260 | to the sperm and the egg,

00:13:38.140 | because the information is supposed to reside

00:13:40.980 | in synaptic connections between different neurons,

00:13:42.980 | in particular circuits that developed.

00:13:47.420 | So what happens in the brain

00:13:49.340 | shouldn't be able to transfer to the next generation.

00:13:51.900 | Even simpler, a simpler example,

00:13:54.020 | if you go to the gym and you build up muscles,

00:13:56.340 | you know that your kids will have to work out on their own.

00:14:00.340 | It won't, this shortcut won't happen.

00:14:03.100 | This is something that we know intuitively,

00:14:05.780 | even if we don't have any background in biology.

00:14:08.460 | And this is connected to the fact that,

00:14:10.660 | as we said at the beginning,

00:14:11.780 | every cell in the body has its own genome.

00:14:14.500 | And the next generation will only form

00:14:17.940 | from the combination of the genomes in the sperm and the egg.

00:14:21.260 | Even if you somehow acquire the mutation

00:14:25.620 | or a change in your DNA in one of particular brains,

00:14:29.020 | yes, it wouldn't matter because this mutation,

00:14:30.740 | there's no way to transfer it to the DNA of the germ cells

00:14:34.740 | that will contribute to the next generation.

00:14:37.020 | - So despite that, there is, as you will tell us,

00:14:41.580 | some evidence for inheritance of experience, let's call it.

00:14:46.540 | Or, and here we have to be careful with the language, right?

00:14:50.460 | I just want to put a big asterisk

00:14:52.580 | and underline and a highlight that the language

00:14:54.820 | around what we're about to talk about is both confusing

00:14:58.980 | and at the same time fairly simple and controversial, right?

00:15:01.780 | It's a little bit like in the field of longevity,

00:15:05.060 | people sometimes will say anti-aging,

00:15:06.740 | some people say longevity.

00:15:07.940 | The anti-aging folks feel that longevity

00:15:10.020 | is more about longevity clinics, they don't like that.

00:15:12.620 | Anti-aging is related to some other kind of niche clinics,

00:15:16.420 | sometimes FDA approved or a government approved,

00:15:18.620 | sometimes not.

00:15:19.460 | And so there's a lot of argument about the naming,

00:15:20.860 | but it's all about living longer and living healthier.

00:15:23.700 | In this field of acquiring traits

00:15:27.160 | or the passage of information to offspring,

00:15:30.700 | what is the proper language to refer to

00:15:32.780 | what we're about to discuss?

00:15:36.220 | There is this idea and I'll say it so that you don't have to

00:15:39.060 | that dates back to Lamarck and Lamarckian evolution,

00:15:42.940 | very controversial, right?

00:15:44.620 | And maybe not even controversial,

00:15:45.980 | I think it's very like offensive even to certain people.

00:15:48.460 | This idea of inheritance of acquired traits,

00:15:50.420 | the idea that one could change themselves

00:15:53.760 | through some activity, use the example of going to the gym,

00:15:55.980 | we could also use the example of somebody

00:15:57.220 | who becomes an endurance runner,

00:15:58.700 | then decides to have children

00:15:59.980 | within another endurance runner and has in mind the idea

00:16:04.140 | that because they did all this running

00:16:06.860 | and not just because they were biased towards running

00:16:09.120 | in the first place, but because of the distance

00:16:11.940 | they actually ran that their offspring somehow

00:16:13.660 | would be fabulous runners.

00:16:15.020 | Okay, this Lamarckian concept is, we believe, wrong.

00:16:20.020 | So how do we talk about inheritance of acquired traits?

00:16:24.040 | What's the proper language for us to frame this discussion?

00:16:26.660 | - Right, we have to be very careful, as you said,

00:16:28.700 | and there are many complications and many ambiguities.

00:16:31.920 | - And maybe you could tell us why Lamarckian evolution,

00:16:34.100 | for those that don't know, is such a stained thing.

00:16:38.500 | - Right, so--

00:16:39.900 | - It's not polite.

00:16:40.980 | - Right, perhaps we'll start with just to just say

00:16:43.300 | that we can talk about inheritance of acquired traits,

00:16:46.300 | transmission of parental responses,

00:16:47.940 | inheritance of memory, all of these things,

00:16:49.780 | and we can also talk about epigenetics

00:16:52.660 | and transgenerational epigenetics

00:16:54.420 | and intergenerational epigenetics.

00:16:56.200 | There are many terms that we need

00:16:57.340 | to make clear for the audience.

00:17:01.520 | The reason that it's so toxic or controversial

00:17:05.520 | is very complicated and goes a long time back,

00:17:10.120 | even way before Lamarck, so even the Greeks

00:17:13.440 | talked about inheritance of acquired traits.

00:17:15.560 | Lamarck is associated with the term,

00:17:18.540 | but it's probably a mistake, although everyone talks about,

00:17:21.480 | including people who studied.

00:17:23.040 | So Lamarck worked, he published his book

00:17:27.020 | about a little more than 200 years ago,

00:17:30.520 | and he believed in the inheritance of acquired traits,

00:17:34.980 | absolutely, but just like anyone else in his time.

00:17:38.560 | Just everyone believed in it.

00:17:40.460 | It seemed obvious to them that it was long before Mendel

00:17:44.540 | and the rules of genetic inheritance,

00:17:47.700 | and also Mendel was long before their understanding

00:17:50.260 | that DNA is the heritable material,

00:17:51.820 | but this happens a long time ago.

00:17:53.420 | Everyone believed in it, including Darwin.

00:17:56.340 | Darwin was perhaps more Lamarck than Lamarck.

00:17:59.140 | - Really?

00:17:59.980 | - Absolutely.

00:18:00.820 | - All right, now we're getting into the meat of it.

00:18:04.340 | - And this is in the origin of the species.

00:18:08.480 | It's in all of his writings.

00:18:10.100 | Lamarck didn't even really make the distinction

00:18:12.120 | between the generations.

00:18:13.300 | He had many other reasons for being wrong,

00:18:15.900 | but he connected the terms,

00:18:17.340 | inheritance of acquired traits to evolution,

00:18:20.300 | and this is some of the reason

00:18:21.680 | that he was very controversial, even in his time.

00:18:24.160 | There were other reasons, for example,

00:18:25.780 | he rejected current-day chemistry

00:18:28.180 | and thought that he can explain everything

00:18:30.260 | based on Aristotelian fluids, earth, wind, fire, and water.

00:18:33.980 | - There's still some people on the internet

00:18:35.340 | that think they can discard with chemistry

00:18:37.340 | and explain everything based on earth, wind, fire, and fire.

00:18:39.740 | - And this wasn't only biology.

00:18:40.780 | It was also the weather and everything.

00:18:42.940 | So that was part of the reason.

00:18:44.780 | But Lamarck, so Lamarck made many mistakes,

00:18:49.440 | but he did have a full theory of inheritance,

00:18:53.680 | which was a big step towards where we are today.

00:18:58.680 | So he had important contributions, nevertheless.

00:19:02.200 | Although he was mistaken about the mechanism,

00:19:04.240 | what he believed, like everyone else, drives evolution

00:19:08.760 | is the transmission of the traits

00:19:10.920 | that you acquire during your life

00:19:12.400 | or the things that you do or don't do.

00:19:15.200 | We talked about use and disuse of certain organs

00:19:18.200 | that shape our organs,

00:19:22.600 | and eventually also the organs of the next generation.

00:19:24.800 | - He sounds a little bit

00:19:25.640 | like the first self-help public figure, right?

00:19:29.400 | Well, this idea, this is heavily embedded

00:19:31.600 | into a lot of the health and fitness space

00:19:34.520 | on Twitter and Instagram and on the internet,

00:19:37.080 | which is that, and it's the idea

00:19:39.800 | that we're sold very early in life,

00:19:42.920 | at least here in the United States and probably elsewhere,

00:19:44.880 | which is that we can become anything that we want to become.

00:19:47.320 | And then that will forever change the offspring,

00:19:51.520 | either because of nature or nurture.

00:19:53.480 | - Right, and this is a very dangerous idea,

00:19:55.680 | as I'll explain in a second, and it led to horrible things.

00:19:58.260 | This is part of the reason that this is such a taboo.

00:20:00.840 | It's not only self-help.

00:20:02.880 | You're helping, you're all this helping yourself.

00:20:05.320 | The problem is when you apply it to others.

00:20:07.360 | And this happened in a very, very dramatic

00:20:09.760 | and horrible way in the recent past,

00:20:13.800 | as I'll tell in a second.

00:20:15.480 | So Lamarck, this is what he believed,

00:20:17.880 | and he thought this is how evolution progresses.

00:20:22.880 | And later, Darwin showed that it's really natural selection,

00:20:27.880 | the selecting of the people, of the organisms

00:20:32.520 | that already contain the particular qualities

00:20:37.520 | are selected based on whether they survive

00:20:41.640 | or not in particular environments,

00:20:43.120 | and therefore the evolution progresses.

00:20:45.840 | They become more common and take over.

00:20:48.000 | This is very different, two different explanations.

00:20:49.680 | The most common way this is contrasted

00:20:52.440 | is the neck of the giraffes.

00:20:53.920 | This is the classic example.

00:20:55.560 | According to Lamarck, the giraffes had to stretch

00:20:58.920 | their necks towards the trees to eat

00:21:01.680 | when the trees were high.

00:21:04.020 | And because of that, they transmitted these traits

00:21:07.200 | long necks to their children who also had long necks.

00:21:09.840 | By the way, he only mentioned this example

00:21:13.480 | a handful of times, he didn't really focus on that.

00:21:15.760 | And according to Darwin, just the giraffe

00:21:18.120 | that happened to be born with the long neck survived

00:21:20.440 | because it ate, so it's heritable materials,

00:21:24.240 | he didn't know about genetics, but take over,

00:21:27.200 | and the rest of the giraffes that have

00:21:28.600 | different heritable materials just die.

00:21:31.880 | So this is natural selection

00:21:33.020 | versus inheritance for quadrates.

00:21:34.680 | There are many reasons why Lamarckism

00:21:38.640 | and inheritance for quadrates became such a bad term.

00:21:41.540 | One of the biggest is what happened in the Soviet Union.

00:21:45.900 | Under Stalin, there was a scientist called Lysenko

00:21:49.780 | who thought that Mendelism, normal genetics,

00:21:53.680 | is bourgeois science, shouldn't be done.

00:21:57.140 | And whoever did normal genetics was either killed

00:21:59.860 | or sent to Siberia.

00:22:03.120 | And he thought that, just like you said,

00:22:05.960 | not only we can become everything that we want,

00:22:07.820 | but we can grow everything that we want

00:22:09.980 | in every field we can take care of.

00:22:11.860 | Frozen field and grow potatoes there and so on.

00:22:15.000 | And this led to massive starvation,

00:22:17.880 | ruined agriculture in the Soviet Union,

00:22:21.820 | also ruined science for many, many years,

00:22:24.120 | and put a very dark cloud on the entire field.

00:22:27.320 | And only probably in the '80s or something like this,

00:22:30.540 | the field started to recuperate for that.

00:22:34.040 | Aside for that, which is a very dramatic thing,

00:22:37.120 | there was also crazy stories around and attempts

00:22:42.120 | to prove the inheritance of quadrates.

00:22:44.680 | Despite the realization of many scientists,

00:22:47.100 | this is something that is very rare

00:22:48.860 | or that normally doesn't happen.

00:22:50.220 | That is not a normal way that inheritance works.

00:22:53.740 | And I can tell you about two such dramatic cases

00:22:57.960 | that will illustrate it.

00:22:59.140 | - Yeah, please.

00:22:59.980 | - So in the beginning of the 20th century, in Vienna,

00:23:03.540 | there was a researcher called Paul Kammer,

00:23:06.660 | was a very famous and also very colorful figure

00:23:10.720 | who did experiments on many different types of animals.

00:23:14.260 | He did experiments on toads that are called

00:23:16.680 | the midwife toad because the male carries the eggs.

00:23:21.680 | And there's a beautiful book about it from Kessler

00:23:28.540 | telling the story of what happened there.

00:23:30.440 | And there are a couple of types of toads.

00:23:34.240 | Some of them live underwater and some of them live on land.

00:23:39.180 | And these toads are different in the shape

00:23:42.740 | and in their behavior.

00:23:43.900 | So of course, the capacity to live underwater is one thing,

00:23:48.560 | but also the morphology and appearance changes.

00:23:52.680 | The toads that live underwater developed

00:23:54.700 | these nubital pads, these black pads on their hands

00:23:57.940 | that allow the males to grab onto the female

00:24:00.840 | without slipping.

00:24:02.220 | - For mating.

00:24:03.060 | - For mating.

00:24:04.600 | And the ones on land don't have them.

00:24:06.600 | He claimed that he can take the toads

00:24:08.620 | and train them to live underwater,

00:24:11.720 | changing the temperature and all kinds of things.

00:24:14.820 | It's a very difficult animal to work with.

00:24:17.660 | Eventually, according to Kammer,

00:24:19.780 | they will acquire the capacity to live underwater

00:24:23.140 | and also change their physiology

00:24:24.740 | and develop these black nubital pads on their heads.

00:24:27.700 | With this discovery, he traveled the world,

00:24:31.100 | became very famous, this was just the beginning

00:24:36.100 | of the previous century, as the person who found the proof

00:24:41.060 | for inheritance of acquired traits,

00:24:42.440 | despite the controversy and so on.

00:24:44.800 | And at the beginning of the realization

00:24:46.940 | of how it actually works with DNA and so on.

00:24:49.040 | Not with DNA, but with natural selection.

00:24:52.720 | DNA came later.

00:24:53.560 | And people didn't believe him.

00:24:58.140 | He was actually under a lot of attacks,

00:25:01.820 | but it seemed convincing.

00:25:03.140 | At the end, what happened is that they found

00:25:05.760 | that he injected ink to the toads

00:25:09.540 | to make them become blacks, to have these nubital pads.

00:25:13.460 | So he faked the results.

00:25:15.380 | And he couldn't stand up with the accusations

00:25:20.380 | and killed himself.

00:25:21.580 | - Wow.

00:25:22.420 | - In this book by Kessler, it's just maybe it was,

00:25:24.740 | it was the assistant who did it.

00:25:26.620 | - Who killed him?

00:25:27.540 | - No, no.

00:25:28.920 | Who injected it to sort of save him from,

00:25:31.820 | because the samples lost the coloring or something like that.

00:25:34.540 | So it might be, who knows what happened.

00:25:36.140 | - Well, in science, whenever there's a fraud accusation

00:25:39.860 | or controversy, it's not uncommon to see

00:25:42.100 | a passing of responsibility.

00:25:43.860 | - Right.

00:25:44.700 | - There are recent cases, there are ongoing cases now

00:25:46.360 | where it's a question of who did what, et cetera.

00:25:48.520 | Actually, I have two questions before the second story.

00:25:53.520 | I'm struck by the idea that he was traveling and talking.

00:25:55.980 | I'm guessing this was before PowerPoint and Keynote,

00:25:58.660 | but also before transparencies,

00:26:01.220 | which actually were still in place

00:26:02.700 | when I was a graduate student.

00:26:05.260 | For those of you who don't know,

00:26:06.100 | transparencies are basically transparent pieces

00:26:09.160 | of plastic paper that you put onto a projector,

00:26:12.960 | and then you can write on them and do demonstrations,

00:26:15.780 | but can show photographs and things like that.

00:26:18.560 | So how was he giving these talks

00:26:19.980 | and would he travel with the toads?

00:26:21.100 | - So he traveled with the samples.

00:26:22.820 | - I see.

00:26:23.640 | - And I'm basing this on this Kessler book,

00:26:25.480 | which is on its own very controversial.

00:26:27.640 | It's more of a beautiful story than perhaps the truth.

00:26:31.620 | But according to the story there,

00:26:33.760 | he had to stand in one side of the lecture hall

00:26:36.180 | with his hands behind the back,

00:26:37.880 | while others would examine the samples

00:26:40.780 | and pass them around and so on.

00:26:42.700 | - But he cheated, someone cheated.

00:26:44.200 | - He probably did it.

00:26:46.060 | At least that's what most people think.

00:26:50.020 | But this wasn't replicated.

00:26:51.520 | I mean, also, I don't think anyone tried to replicate it.

00:26:54.180 | - Interesting, this is just a point about replication

00:26:56.880 | and actually another tragic example,

00:26:58.940 | not but a few years ago, Sakai,

00:27:01.840 | who as far as we knew was doing very accomplished work

00:27:06.020 | on the growth of retinas, literally growing eyes in a dish.

00:27:10.900 | I think everyone believes that result.

00:27:12.800 | But then there were some accusations about another result

00:27:15.540 | that turned out to be fraudulent and Sakai killed himself.

00:27:19.580 | This was a recent, this was only about five, 10 years ago.

00:27:23.100 | So it still happens.

00:27:24.340 | - Yeah, it happens.

00:27:25.240 | I think it's rare, but it does happen,

00:27:26.940 | especially in this very high profile situation.

00:27:29.780 | - I would argue, I'd love to know what your number is,

00:27:32.020 | but I would argue that 99% of scientists are seeking truth

00:27:36.980 | and are well-meaning, honest people.

00:27:38.460 | - I totally agree.

00:27:39.580 | And I think that even when people are wrong,

00:27:43.700 | it's mostly not because they're evil and trying to act.

00:27:47.380 | Maybe they really want to believe the results

00:27:49.880 | or there are all kinds of ways to be wrong

00:27:52.040 | and even to bend truth without just blatant fraud.

00:27:57.040 | But this is, according to the story,

00:28:01.820 | an example of very bad fraud, which is, I agree,

00:28:04.820 | is rare because most scientists, as you said,

00:28:06.980 | this is also my opinion, are just trying to discover truth

00:28:09.640 | and do the best they can.

00:28:10.620 | - Well, why else would you go into it?

00:28:11.980 | Because it's certainly not a profession to go into

00:28:13.740 | if you want to get rich.

00:28:14.560 | - It's not the money.

00:28:15.400 | - And it's probably not even a profession to go into

00:28:17.420 | if you want to get famous.

00:28:18.460 | If you want to be famous, you should go to Hollywood

00:28:20.380 | or become a serial killer because they'll make specials.

00:28:23.280 | Please don't.

00:28:24.480 | But please don't do either.

00:28:26.920 | No, Hollywood, I suppose, for some is fine.

00:28:28.980 | But in any case, okay, so Kammerer around 1907, 1906.

00:28:33.980 | - This is slightly before,

00:28:35.900 | the controversy broke out after the First World War.

00:28:40.200 | - Okay, great.

00:28:41.660 | So Kammerer is gone.

00:28:43.720 | His toads, with their either ink or whatever, neuprofen pads,

00:28:48.560 | they have to go back to mating on land.

00:28:51.040 | - Yeah. - Yeah, okay.

00:28:51.960 | I'd like to take a quick break

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00:30:06.220 | - So this is, forget about that.

00:30:09.080 | We also had the Lisenko episodes.

00:30:11.160 | That's a very big thing.

00:30:12.820 | And then in the US, there was, in the '70s and '80s,

00:30:16.540 | a researcher named McConnell,

00:30:18.740 | who did very different experiments.

00:30:20.260 | And he was also a character.

00:30:21.580 | He worked on, so he was a joker type of thing,

00:30:25.720 | and he published many of his results

00:30:27.820 | in a journal that he published

00:30:30.020 | that was called Worms Breeders Gazette

00:30:32.060 | and had many cartoons and things like that.

00:30:33.940 | - So he started his own journal?

00:30:35.780 | - Yes.

00:30:36.620 | - That's one way to publish a lot.

00:30:37.980 | - But he also published in very respected journals

00:30:42.160 | in parallel.

00:30:43.000 | But he was a psychologist, American psychologist,

00:30:45.580 | and he worked on a worm, a flat worm,

00:30:49.900 | which is called planaria, which is very interesting.

00:30:52.380 | It's different than what we'll discuss today,

00:30:55.540 | different type of worm.

00:30:57.300 | You know, worms are very common.

00:31:01.080 | So four out of five animals on this planet sees a worm.

00:31:03.800 | - Really?

00:31:04.640 | - Yes, numerically.

00:31:05.460 | It's just count the individuals.

00:31:06.500 | So we are the exception.

00:31:09.940 | But I'll talk about a very different worm later.

00:31:12.860 | This is a flat worm.

00:31:13.700 | This is called planaria.

00:31:15.560 | And it is remarkable in many ways.

00:31:17.400 | It was also a model that many people worked on,

00:31:20.080 | including the fathers of genetics,

00:31:23.000 | the people who started genetics, like Morgan.

00:31:24.800 | They worked on it in the beginning,

00:31:25.820 | but it's very, very hard to study genetics in this worm

00:31:29.020 | because unlike us, unlike what we explained before

00:31:32.120 | about how we all develop from sperm and an egg,

00:31:35.600 | these worms, most of the time, reproduce just by fission.

00:31:40.200 | They tear themselves apart.

00:31:42.120 | So they have a head and a tail,

00:31:44.400 | and the part of the head would just tear itself apart

00:31:46.760 | on the tail, grow a new, the head will grow a new tail,

00:31:50.080 | the tail will grow a new head.

00:31:51.480 | You can even cut them to 200 pieces.

00:31:53.340 | Each piece will grow into a new worm.

00:31:55.240 | - Wow.

00:31:56.080 | - And they have centralized brains with lobes and everything

00:32:00.560 | and even degenerate eyes.

00:32:04.120 | He studied these worms,

00:32:05.660 | and he said that he can teach them certain things,

00:32:09.020 | associations, by pairing all,

00:32:12.320 | I don't remember exactly what he did.

00:32:14.380 | I think it was either lights or electricity with--

00:32:18.480 | - Shock them, I think.

00:32:19.320 | - Which would shock them with other things.

00:32:21.080 | And he could train them to learn

00:32:22.880 | and remember particular things.

00:32:24.280 | - Like they might get shocked on one side of the tank.

00:32:26.600 | - Exactly.

00:32:27.440 | - And then avoid that side of the tank.

00:32:29.520 | - Yes.

00:32:30.340 | - And then I guess the question is

00:32:31.180 | whether or not they're ripped apart cells

00:32:34.080 | and their subsequent generations

00:32:35.980 | will know to avoid that side of the tank

00:32:37.560 | without having ever been exposed to the shock.

00:32:40.080 | - Right.

00:32:40.920 | So without ever been exposed to the shock

00:32:43.040 | or whether the new generation,

00:32:46.240 | the new heads will be able to learn faster.

00:32:49.360 | That's another, the subtlety that you might have, okay?

00:32:52.320 | And this is what he said happened.

00:32:55.200 | He said he can teach them certain things,

00:32:56.680 | remove, cut off their heads,

00:32:58.440 | and new heads with all the brain will grow.

00:33:03.840 | And that it will contain the memory.

00:33:05.760 | This was the start of the controversy,

00:33:07.600 | not the end of it, only the beginning.

00:33:10.000 | Then he said something even much wilder,

00:33:12.240 | which is he can train them to learn certain things

00:33:16.040 | and then just chop them up,

00:33:17.760 | put them in a blender and feed them to other worms

00:33:21.560 | because they are cannibalistic, they eat each other.

00:33:24.280 | And that the memory will transfer through feeling.

00:33:26.800 | This sounds--

00:33:27.640 | - Such a dramatic feel.

00:33:28.820 | - Yeah.

00:33:29.660 | (laughs)

00:33:30.680 | And by the way, this opened the field.

00:33:33.120 | So people did experiments that not only in planaria

00:33:35.560 | but in goldfish and certain rodents

00:33:38.720 | and did these memory brain transfer essays,

00:33:42.320 | implanting brain.

00:33:43.640 | And this is back when they had an idea

00:33:47.620 | that some memories could be molecular,

00:33:49.560 | could have a molecular form, which is very appealing.

00:33:51.880 | It's almost like science fiction.

00:33:53.520 | You can have a memory in a tube.

00:33:55.120 | And like the way we think about memory normally,

00:33:57.920 | which is something that is distributed in neuronal circuits

00:34:02.200 | and encoded in the strength

00:34:03.720 | of particular synapses and so on.

00:34:06.040 | But the idea that you can take a memory

00:34:07.920 | and reduce it into a molecule

00:34:10.080 | and transfer it around is very, very interesting.

00:34:13.480 | So this is why it attracted so many people.

00:34:15.120 | This ended up in a catastrophe.

00:34:17.380 | So there was an NIH investigation.

00:34:19.880 | No one can replicate anything.

00:34:21.260 | It was a big mess.

00:34:22.720 | Although there were always scientists who said,

00:34:24.720 | "Yes, we can replicate this and this."

00:34:26.040 | So they were in the back.

00:34:28.820 | McConnell stuff was different.

00:34:32.240 | Again, people thought that they couldn't,

00:34:35.100 | that there are problems replicating,

00:34:36.740 | but it wasn't necessarily, but some people replicate,

00:34:38.760 | but it wasn't necessarily about replicating the whole thing.

00:34:41.980 | But the question was,

00:34:44.220 | did the memory that transfer is specific

00:34:46.540 | or is it an overall sensitization that transmits and so on?

00:34:49.420 | - Right, like you could imagine that what gets transmitted

00:34:51.380 | is a hypersensitivity to electricity

00:34:53.860 | as opposed to the specific location

00:34:55.880 | that the electricity was introduced.

00:34:57.420 | Or even more than that,

00:34:58.720 | even just hypersensitivity in general,

00:35:01.800 | you're more vigilant and you'll learn anything faster.

00:35:04.100 | That's also a possibility.

00:35:05.700 | But his problem wasn't the accusation.

00:35:07.760 | It was much worse that he was targeted by the Unabomber,

00:35:10.720 | this terrorist who sent letters with bombs

00:35:13.440 | to many scientists for 15 years.

00:35:16.360 | And his assistant, again, it's the assistant,

00:35:19.240 | I think exploded and this is how his line of research ended.

00:35:22.560 | Just recently, a few years ago,

00:35:26.440 | a researcher from Boston, Mike Levin,

00:35:30.760 | and his postdoc, Tal Shomrat,

00:35:34.480 | replicated some of McConnell's experiment

00:35:37.100 | with the cutting of the head,

00:35:38.320 | but using very fancy equipment and automated tracking.

00:35:42.300 | And they could say that they can replicate

00:35:44.140 | some of his experiments.

00:35:47.840 | - Really?

00:35:48.800 | And they don't open packages in that laboratory?

00:35:51.620 | - They have interesting stories.

00:35:53.080 | You should have Mike over.

00:35:54.340 | - Yeah, I'm familiar with a bit of his work.

00:35:56.860 | I didn't realize they had done that experiment.

00:35:58.780 | - They published it a few years ago.

00:36:01.140 | And this is very interesting,

00:36:01.980 | but of course they don't know how it happens.

00:36:05.220 | The mechanism is unclear.

00:36:06.700 | McConnell went a step further than this.

00:36:08.940 | And what's fascinating is that these are experiments

00:36:11.740 | that were done in the '70s and '80s.

00:36:13.580 | He said that he can not only transfer the memories

00:36:16.820 | through chopped animals,

00:36:20.020 | but he can take the other animals that learned

00:36:22.740 | and break it down into different fractions.

00:36:25.380 | So just the DNA, just the RNA, just the fats,

00:36:28.940 | the proteins, the sugars.

00:36:30.580 | And he said that the fraction that transmit the memory

00:36:33.260 | is the RNA.

00:36:34.100 | And this is very, very interesting

00:36:36.260 | because it was a long time before everything

00:36:38.100 | that we know about RNA today.

00:36:40.860 | I'll soon go into my research, explain what we do,

00:36:44.640 | and then you'll see that you can actually feed worms

00:36:46.680 | with RNA and have many things happen.

00:36:49.860 | This is, everyone knows this is true.

00:36:52.900 | So this is why it was so appealing to go back to that

00:36:55.380 | and study.

00:36:56.220 | By the way, at the time it became popular knowledge.

00:36:59.300 | Everyone knew these experiments.

00:37:00.940 | There's a Star Trek episode about it from '84.

00:37:03.940 | There are comics books about it, books about it.

00:37:06.340 | So this was very, and people were eating RNA

00:37:08.900 | because they thought that there was RNA in memory.

00:37:10.500 | This was, of course, complete nonsense.

00:37:12.580 | But this was, it made a lot of noise in these years,

00:37:16.420 | which is part of the reason it was so toxic

00:37:19.500 | until recently.

00:37:20.560 | You couldn't touch it because it was considered

00:37:22.900 | pseudoscience, likely Senco, like camera and all of this.

00:37:26.920 | So this was just something you didn't want to touch at all.

00:37:29.820 | And then we go back to these studies

00:37:34.300 | about inheritance of memory or inheritance of acquired traits

00:37:37.780 | in other organisms, in mammals, in humans.

00:37:42.780 | And aside from the dark clouds that these episodes left,

00:37:48.720 | there were also theoretical problems

00:37:50.700 | of why this can't happen.

00:37:53.560 | Barriers that have to be breached for this to happen.

00:37:57.800 | And you can talk about many different types of barriers.

00:38:01.460 | And you can also narrow it down to two main barriers.

00:38:07.440 | First barrier, we mentioned it,

00:38:09.140 | this is the separation of the soma from the germline.

00:38:11.640 | - Right, the somatic cells,

00:38:13.400 | they can change in response to experience.

00:38:15.540 | The sperm and the egg, the so-called germ cells cannot.

00:38:19.740 | That's the idea.

00:38:20.580 | - Or they are isolated on what happens in the soma, okay?

00:38:23.720 | The man who first thought about this barrier

00:38:27.000 | is called Weizmann, August Weizmann.

00:38:28.700 | This was in the 19th century.

00:38:30.140 | So it is called today the Weizmann barrier.

00:38:33.500 | Separation of the soma from the germline,

00:38:35.040 | only the germline transmit information

00:38:36.980 | to the next generation.

00:38:38.460 | And this is also called the second law of biology.

00:38:40.760 | So this is very, very fundamental.

00:38:42.300 | So natural selection is the first one,

00:38:43.820 | this is the second one because it's so important

00:38:46.080 | to how we work, to how our bodies work.

00:38:49.680 | Weizmann, by the way, thought that if you will have

00:38:52.620 | direct influence of the environment on the germ cells,

00:38:55.800 | then perhaps this could transfer to the next generation.

00:38:58.840 | So he wasn't as strict as his barriers suggest,

00:39:03.840 | but this is not how most people remember it, okay?

00:39:08.920 | But he thought that this is unnecessary.

00:39:11.260 | It's possible that natural selection can expand everything.

00:39:14.000 | And he compared to a boat, which is in the ocean,

00:39:18.040 | it is sailing and it has a sail open.

00:39:20.560 | So you don't have to assume that it has an engine.

00:39:22.600 | The wind is blowing, you don't have to assume other things.

00:39:25.080 | The natural selection might be enough.

00:39:26.960 | So this barrier is still standing, but not entirely.

00:39:33.160 | It is reached in some organisms.

00:39:35.560 | We'll go into that in a second.

00:39:37.320 | The other barrier is the, now we have to understand

00:39:42.320 | the other barrier, we have to talk about epigenetics.

00:39:44.940 | We have to define epigenetics and what it is.

00:39:47.140 | And epigenetics is another term which people misuse

00:39:52.180 | horribly and say about everything that is epigenetics.

00:39:55.480 | Even people from the field, okay?

00:39:58.620 | The word itself, that the term was defined in the '40s

00:40:04.500 | by Waddington, Conrad Waddington.

00:40:07.260 | And he talked about the interaction between genes

00:40:10.460 | and their products that in the end bring about the phenotype

00:40:15.460 | or the consequences and how genes influence development.

00:40:19.380 | Later, people discovered mechanisms that are,

00:40:23.500 | that change the action of genes, the different mechanisms,

00:40:27.900 | and started talking about these as epigenetics.

00:40:30.640 | For example, the DNA is built out of four basic elements.

00:40:35.640 | These are the A, T, G, and C, right?

00:40:40.280 | And they can be chemically modified.

00:40:42.580 | So in addition to just the information that you have

00:40:45.620 | in the sequence of the DNA, you also have this information

00:40:48.960 | in the modification of the bases.

00:40:51.780 | The most common modification that has been studied

00:40:54.900 | more than others is modification of the letter C

00:40:58.040 | of cytosine, methylation, addition of a methyl group

00:41:01.640 | to this C.

00:41:03.340 | And this can be replicated, so after the DNA,

00:41:08.340 | the cells divide and replicate their genetic material.

00:41:13.940 | In certain cases also, these chemical modifications

00:41:17.180 | can be added on and replicate and be preserved.

00:41:20.260 | - For those who aren't as familiar with thinking

00:41:23.080 | about genes and gene structure and epigenetics,

00:41:26.300 | can we think of these, you mentioned the four nucleotide

00:41:29.500 | bases, C, G, A, D, but could we imagine that through things

00:41:33.920 | like methylation, it's sort of like taking

00:41:35.400 | the primary colors and adding, changing one of them

00:41:39.040 | a little bit, changing the hue just slightly,

00:41:41.860 | which then opens up an enormous number of new options

00:41:45.120 | of color integration.

00:41:46.960 | - Absolutely, just more combinations, more ways,

00:41:49.240 | more information.

00:41:50.740 | There are the modifications of the DNA,

00:41:52.600 | and also there are the modifications of the proteins

00:41:55.180 | which condense the DNA that are called histones.

00:41:58.160 | So they are also modified by many different chemicals.

00:42:03.140 | Again, methylation is a very common modification

00:42:06.340 | of acetylation, even serotonin,

00:42:08.440 | the serotonination of histones.

00:42:11.440 | - Serotonin.

00:42:12.280 | - Right, this is a new paper from Nature

00:42:13.660 | from a few years ago.

00:42:14.500 | - Can change DNA.

00:42:16.440 | - Not the DNA itself, but the protein that condenses it.

00:42:19.000 | - Essentially how, in the analogy I used before

00:42:22.440 | of how the threat is wrapped around the spool essentially.

00:42:25.920 | - Yes, and this determines the degree of condensation

00:42:30.660 | of the DNA, whether the gene is now more or less accessible

00:42:34.860 | and therefore can perhaps be expressed more or less.

00:42:38.020 | This is one way to affect the gene expression

00:42:42.940 | and bring about the function of the gene.

00:42:45.260 | There are many additional ways, it's not the only one.

00:42:48.020 | So when all of this was starting to be elucidated,

00:42:51.940 | people talked about epigenetics,

00:42:53.340 | they started talking about these modifications,

00:42:55.320 | forgot the original definition.

00:42:57.120 | And when people said epigenetics,

00:42:58.720 | they talk about methylation and things like that.

00:43:00.920 | - And again, to just frame this up

00:43:02.620 | so we can imagine two identical twins,

00:43:04.960 | so-called monozygotic twins.

00:43:06.440 | We could go a step further and say that they're monochorionic

00:43:10.120 | or they were in the same placental sac

00:43:12.000 | 'cause twins can be raised in separate sacs,

00:43:13.840 | slightly different early environments.

00:43:15.440 | Let's say those two twins are raised separately.

00:43:17.720 | One experiences certain things.

00:43:20.440 | The other things, they eat different foods, et cetera.

00:43:23.860 | And there is the possibility through epigenetic mechanisms

00:43:26.720 | that through methylation, acetylation,

00:43:28.900 | serotonin production, et cetera,

00:43:32.040 | that the expression of certain genes in one of the twins

00:43:35.240 | could be amplified relative to the other, correct?

00:43:37.560 | - So we know that even totally identical twins,

00:43:40.400 | genetically they're identical,

00:43:41.900 | but they look different and they are all different.

00:43:44.160 | We all experience it.

00:43:46.400 | And this can happen because of these epigenetic changes.

00:43:51.160 | Or it can happen because of other mechanisms

00:43:52.880 | because genes respond to the environment.

00:43:54.600 | Genes don't exist in a vacuum.

00:43:56.380 | Genes need to be activated by transcription factors.

00:44:01.420 | And there's a whole, there's a lot of machinery

00:44:05.560 | that is responsible for making genes function.

00:44:08.520 | So we are a combination of our genetic material

00:44:13.160 | and the environment.

00:44:15.080 | So when people talk about epigenetics

00:44:16.840 | and talk just about the modification,

00:44:18.880 | they're also not exactly right.

00:44:20.800 | My definition of epigenetics is inheritance,

00:44:24.640 | which occurs either across cell division

00:44:28.240 | or more interestingly also for this podcast now,

00:44:31.440 | across generations.

00:44:32.680 | Not because of changes to the DNA sequence

00:44:36.600 | but through other mechanisms.

00:44:38.920 | I think this is the most robust definition

00:44:43.080 | that allows you to understand what you're talking about.

00:44:45.760 | And then again, and then the question is,

00:44:49.880 | if this happens, then what are the molecules

00:44:52.720 | that actually transmit information across generations?

00:44:56.280 | Are they these chemical modifications

00:44:59.000 | to the DNA or to the proteins that condense the DNA?

00:45:02.160 | Or are there other agents that transmit the information?

00:45:06.200 | And which molecules can do it?

00:45:08.200 | And I actually think that the most interesting players today

00:45:11.640 | are RNA molecules, okay?

00:45:13.560 | But before I go into that, I just want to say

00:45:15.800 | that when we talk about the barriers

00:45:17.240 | to epigenetic inheritance

00:45:18.480 | or the barriers to inheritance of acquired traits,

00:45:21.720 | in addition to the separation of the soma

00:45:24.400 | from the germline that we discussed,

00:45:25.600 | the other main barrier,

00:45:27.240 | it's called epigenetic reprogramming,

00:45:30.040 | which is that we acquired our cells,

00:45:33.800 | the genetic material in our cells

00:45:36.400 | acquires all kinds of changes,

00:45:38.240 | these chemical changes, modifications we discussed.

00:45:42.560 | But these modifications are largely erased

00:45:47.040 | in the transition between generations.

00:45:49.120 | So in the germline, in the sperm and the egg,

00:45:53.000 | and also in the early embryo,

00:45:55.120 | most of the modifications are removed

00:45:57.960 | so we can start a blank slate

00:46:00.160 | based on the genetic instructions.

00:46:02.440 | And this is crucial.

00:46:03.360 | Otherwise, according to the theory,

00:46:06.560 | it's not clear that actually true

00:46:07.680 | because in some organisms, it doesn't really happen.

00:46:10.840 | We will not develop according to the species'

00:46:15.600 | typical genetic instructions.

00:46:18.040 | So to preserve this, we erase all these modifications

00:46:22.000 | that start anew.

00:46:23.160 | And this is in mammals and in humans.

00:46:26.160 | This is largely true.

00:46:27.000 | Most of the modifications in the sperm and in the egg

00:46:30.920 | are removed, so about 90% of them.

00:46:33.160 | Some remain, which could be interesting.

00:46:36.160 | So the idea, if I understand correctly,

00:46:38.320 | is that there's some advantage to wiping the slate clean

00:46:43.320 | and returning to the original plan.

00:46:45.800 | In the context of the IKEA furniture analogy,

00:46:50.280 | the instruction book is the one that's issued to everybody,

00:46:54.160 | okay, or every cell, right?

00:46:56.040 | Only certain instructions are used for certain cells,

00:46:58.160 | say a skin cell or a neuron or a liver cell

00:47:00.440 | or any other cell for that matter.

00:47:04.120 | Through the course of the lifespan of the organism,

00:47:06.880 | those specific instructions are adjusted somewhat.

00:47:09.180 | Okay, so maybe like IKEA furniture,

00:47:12.040 | sometimes they send you seven, not eight

00:47:14.560 | of particular screws, or they send you the proper number,

00:47:18.200 | but you put them in the wrong place

00:47:19.880 | and it sort of changes the way

00:47:20.940 | that the thing works a little bit.

00:47:22.640 | Once that, assuming furniture could reproduce,

00:47:27.280 | but here in the analogy of the furniture as the cell

00:47:29.720 | or the organ in that mates with another organism,

00:47:34.080 | that needs to be replicated.

00:47:36.080 | And so the idea is to take the instruction book,

00:47:38.160 | go through and erase all the pen and pencil marks,

00:47:41.160 | erase all those additional little modifications

00:47:43.080 | that the owner used or introduced to it

00:47:46.520 | and return to the original instruction book.

00:47:48.080 | - Right, because if you want to bring back

00:47:49.560 | the instruction book, you want it to have all the potential

00:47:51.840 | to make all the furnitures.

00:47:52.760 | You don't want it to be restricted

00:47:54.080 | to the ones that you made in the particular room.

00:47:57.320 | - So it's essentially the opposite of acquired traits

00:48:00.320 | and characteristics based on your,

00:48:03.520 | what we say in biology geek-speak,

00:48:05.360 | lineage-based experience,

00:48:06.360 | but what your parents experienced, right?

00:48:07.800 | In some ways, we want to eliminate all that

00:48:09.840 | and go back to just the genes they provided.

00:48:11.880 | - Yes, but it's more complicated.

00:48:15.160 | It's more complicated than that

00:48:16.280 | because we have some very striking examples,

00:48:18.320 | even in mammals, where some of the marks are maintained.

00:48:23.320 | For example, the classic example is imprinting.

00:48:27.040 | Imprinting is a very interesting phenomenon.

00:48:31.360 | The way DNA works is that you inherit a copy

00:48:36.240 | for every chromosome from your mother and your father,

00:48:40.000 | and then you have in every cell of your body

00:48:42.720 | two copies, if you're a human, of every chromosome, okay?

00:48:46.480 | And then, so every gene is represented twice.

00:48:49.940 | These are called alleles, the different versions of the genes.

00:48:53.720 | And the thought is that once you,

00:48:57.240 | in the next generation, the two copies that you inherited

00:49:00.280 | are equal.

00:49:02.840 | It doesn't matter whether you acquire them

00:49:05.340 | from your mother or from your father, right?

00:49:08.120 | There are some situations where it does matter.

00:49:10.320 | There is a limited number of genes

00:49:12.860 | that are called imprinting genes,

00:49:14.860 | where it does matter whether you inherit it

00:49:16.560 | from your mother or your father.

00:49:18.800 | And this is happening through epigenetic inheritance,

00:49:22.160 | not because of changes to the DNA sequence,

00:49:23.960 | but because of maintenance

00:49:26.320 | of these chemical modifications across generations.

00:49:29.520 | - And as I recall from the beautiful work

00:49:32.080 | of Catherine Dulac at Harvard,

00:49:34.820 | that especially in the brain,

00:49:37.560 | there is evidence that some cells contain

00:49:39.920 | the complete genome from mom

00:49:42.380 | or the complete genome from dad.

00:49:44.720 | - And it can also switch during your life.

00:49:46.740 | So her work showed that early on in your life,

00:49:50.840 | it's different whether you express the maternal

00:49:53.440 | or paternal copy than when you're more mature.

00:49:57.560 | So parents and children take notes.

00:49:59.640 | For those of you that are saying,

00:50:00.840 | oh, the child is more like you or more like me,

00:50:04.000 | that can change across the lifespan.

00:50:05.580 | And if you're thinking about your parental lineage

00:50:08.040 | and wondering whether or not you quote unquote inherited

00:50:11.000 | some sort of trait from mother or from father,

00:50:14.600 | it can be of course both,

00:50:16.040 | or it can be just one or just the other,

00:50:18.080 | which I think most parents tend to see

00:50:22.240 | and describe in their children from time to time.

00:50:24.840 | That's just like the father,

00:50:26.600 | or that's just like the mother for instance.

00:50:28.320 | - Right, right.

00:50:29.280 | But it's important to know that in this situation,

00:50:33.600 | the environment played no role.

00:50:35.920 | This was just whether it passed to mother or the father.

00:50:39.240 | It's not that something that happened

00:50:40.640 | to the mother or the father affected it.

00:50:43.080 | So this is slightly different.

00:50:44.200 | The question is now,

00:50:45.360 | can the environment change the heritable material?

00:50:49.380 | So it's very important to understand

00:50:52.640 | that there is a difference between nurture and nature.

00:50:56.080 | And this is very confusing.

00:50:57.680 | People are, it's a little subtle.

00:51:01.040 | So for example, people tell me,

00:51:02.840 | I'm growing horses for many years.

00:51:04.520 | And I just know that this horse has a particular character.

00:51:09.360 | It's very different from the other horse.

00:51:12.080 | And so this is epigenetic inheritance.

00:51:13.720 | No, it could be just genetically determined.

00:51:16.580 | Yes, this horse inherited a different set

00:51:18.920 | of genetic instructions.

00:51:19.960 | So it is different.

00:51:21.020 | Doesn't have to be about epigenetics.

00:51:24.260 | Epigenetic inheritance means that the environment

00:51:28.060 | of the parents somehow changed the children.

00:51:31.680 | And there are these two main barriers

00:51:35.160 | that are fears, bad bottlenecks,

00:51:37.240 | that we have to think what type of molecule

00:51:40.600 | and how they can be breached.

00:51:42.620 | So one possibility is that there's really

00:51:44.240 | this limited number of chemical modifications that survive,

00:51:47.560 | which is about 10% or so.

00:51:49.700 | That could be very interesting.

00:51:51.040 | - Not a small number.

00:51:52.100 | - Not a small number, but perhaps, perhaps, okay?

00:51:55.620 | This is one possibility.

00:51:57.180 | The other possibility that there are other mechanisms.

00:51:59.920 | The situation now in humans is that it's just really unclear

00:52:06.160 | what transmit, if it can transmit,

00:52:09.160 | and which molecule does it.

00:52:10.560 | We'll talk later about other organisms

00:52:13.620 | where it is a lot more clear.

00:52:15.960 | But in humans and mammals in general,

00:52:19.220 | there are many examples for environments

00:52:23.080 | that change the children.

00:52:25.240 | Whether you need to invoke an epigenetic mechanism

00:52:30.580 | to explain this phenomena, this is unclear.

00:52:33.640 | First of all, because it's how to separate

00:52:35.440 | nurture from nurture.

00:52:36.840 | And second, because the mechanism is just not understood.

00:52:41.800 | So there are classic examples.

00:52:43.920 | For in humans, there were periods of famine,

00:52:47.180 | starvation in different places in the world,

00:52:50.040 | in the Netherlands, in China, in Russia,

00:52:52.400 | where people did huge epidemiological study

00:52:54.920 | to study the next generation.

00:52:56.400 | And so that the children of women who were starved

00:53:00.700 | during pregnancy are different, different in many ways.

00:53:05.700 | They have different birth weight, glucose sensitivity,

00:53:10.840 | and also some neurological higher chances

00:53:16.720 | of getting some neurological diseases.

00:53:18.720 | And this has been shown in very large studies.

00:53:23.720 | - Is there ever an instance of which starvation

00:53:27.300 | or hardship of some kind, some challenge,

00:53:30.020 | sensory challenge or survival-based challenge

00:53:34.300 | led to adaptive traits?

00:53:36.340 | - Yes, there are in different organisms.

00:53:39.220 | It could be as a result of a trade-off.

00:53:42.400 | So there could be a downside as well.

00:53:44.360 | But for example, there are two examples that come into mind.

00:53:47.400 | One of them is that if you stress male mice or rats,

00:53:51.440 | I don't remember.

00:53:55.680 | This is work of Isabel Mansoui in the ETH in Switzerland.

00:53:59.280 | If you stress the males,

00:54:01.280 | you can do it in many different ways.

00:54:04.000 | I don't remember exactly how they did,

00:54:05.320 | but you can separate them from their mothers.

00:54:08.240 | You can do social defeat, all kinds of things.

00:54:11.360 | Then the next generations are less stressed.

00:54:14.120 | They show less anxiety.

00:54:15.560 | - So their threshold for stress is higher.

00:54:17.960 | - Yes.

00:54:18.800 | However, I think they have memory deficits

00:54:20.520 | and other metabolic problems.

00:54:22.360 | - Which may be an advantage for dealing with stress.

00:54:24.720 | - Could be, it could.

00:54:25.680 | - I don't have any direct evidence of that,

00:54:27.200 | but there's some simmering ideas that our ability

00:54:30.760 | to anchor our thoughts in the past, present or future

00:54:33.440 | seems very adaptive in certain contexts.

00:54:35.960 | In other contexts, it can keep us ruminating

00:54:37.840 | and not adaptively present to our current challenges.

00:54:41.680 | - Another example is that nicotine exposure.

00:54:45.200 | This is, I think, the work of Oliver Ando from UMass.

00:54:49.440 | If I'm not mistaken, these are not my studies,

00:54:52.760 | but they improve the tolerance to exposure

00:54:57.160 | to similar drugs in the next generation.

00:54:59.580 | The interesting thing here is that it's very nonspecific.

00:55:03.760 | So you treat them with nicotine,

00:55:05.760 | but then in the next generation,

00:55:06.840 | they are more tolerant to nicotine,

00:55:08.480 | but also to other, I think, cocaine.

00:55:11.800 | - That sort of makes sense to me because, yeah,

00:55:13.920 | obviously nicotine activates the cholinergic system,

00:55:17.520 | the dopaminergic system, epinephrine, et cetera.

00:55:20.180 | And you can imagine that there's crossover

00:55:23.300 | because other drugs like cocaine, amphetamine,

00:55:25.480 | mainly target the catecholamines,

00:55:27.120 | the dopamine and norepinephrine.

00:55:28.800 | - In this particular study, if I remember correctly,

00:55:31.660 | they show that this happens, this heritable effect,

00:55:34.880 | even if you use an antagonist

00:55:36.600 | to block the nicotine receptor.

00:55:38.560 | - Wow.

00:55:39.400 | - So it's something more about clearance of xenobiotics

00:55:42.800 | and hepatic functions that is transmitted

00:55:46.620 | and is very nonspecific.

00:55:48.440 | - What I love about all the examples you've given today,

00:55:50.600 | and especially that one is, and I hope that people,

00:55:53.720 | if you're just listening, I'm smiling,

00:55:55.120 | because biology is so cryptic sometimes.

00:55:58.480 | The obvious mechanism is rarely

00:56:01.400 | the one that's actually at play.

00:56:03.360 | And people always ask, well, why?

00:56:06.080 | Why is it like this?

00:56:06.920 | And I always say, the one thing I know for sure

00:56:08.520 | is that I wasn't consulted the design phase.

00:56:11.120 | And if anyone claims they were,

00:56:12.660 | then you definitely want to back away very fast.

00:56:16.200 | - And there could be so many trade-offs, so many trade-offs.

00:56:18.840 | So for example, we studied,

00:56:20.500 | and also many other people studied,

00:56:23.240 | effects, these are in worms.

00:56:26.220 | We'll go deep into that in a second,

00:56:28.080 | but show that when you starve them,

00:56:30.640 | the next generations live longer.

00:56:34.120 | And this, I think, could be a trade-off

00:56:36.560 | with other things like fertility.

00:56:40.880 | So the next generations are more sick and less fertile,

00:56:45.600 | and perhaps because of that, they live longer.

00:56:47.360 | So there could be, it's not necessarily a good thing.

00:56:50.080 | - I don't want to draw you off course,

00:56:51.640 | 'cause this is magnificent,

00:56:52.960 | what you're doing and splaying out for us here.

00:56:55.880 | But do you recall, there was a few years ago,

00:56:57.360 | it actually ended very tragically.

00:56:58.800 | It was an example, I think it was down in San Diego County,

00:57:01.520 | there was a cult of sorts that were interested

00:57:03.940 | in living forever.

00:57:06.560 | And so they castrated,

00:57:08.840 | the male self castrated themselves in the idea

00:57:11.360 | that somehow maintaining some prepubescent state

00:57:15.080 | or reverting to a pseudo prepubescent state

00:57:18.020 | would somehow extend longevity.

00:57:19.320 | The idea that sexual behavior somehow limited lifespan.

00:57:22.480 | This has been an idea that's been thrown around

00:57:24.160 | in the kind of more wacky longevity communities.

00:57:27.040 | They also shaved their heads.

00:57:28.000 | They also wore the same sneakers,

00:57:29.580 | but then they also all committed suicide, right?

00:57:31.580 | As the Hale Bopp Comet came through town.

00:57:34.480 | But that's just but one example of many cults

00:57:37.660 | aimed at sort of, that obviously was not life extension,

00:57:40.820 | that was life truncation,

00:57:41.880 | but aimed at kind of eternal life

00:57:44.840 | or some sort of through caloric restriction.

00:57:47.440 | That's right.

00:57:48.280 | This cult also was very into the whole idea

00:57:50.460 | that by through caloric restriction,

00:57:51.880 | we can live much longer,

00:57:52.720 | which may actually turn out to be true.

00:57:54.860 | I think it's still debated,

00:57:57.160 | hence all the debate about intermittent fasting, et cetera.

00:58:00.000 | But also it is known that if you overeat,

00:58:02.660 | you shorten life.

00:58:04.060 | This is clear.

00:58:05.040 | It's known that big bodied members of a species

00:58:07.860 | live far shorter lives than the smaller members,

00:58:11.820 | a Great Dane versus a Chihuahua, for instance.

00:58:14.340 | So there is some like sort of shards of truths

00:58:17.200 | in all of these things.

00:58:18.420 | But it seems to me that the real question is like,

00:58:20.820 | what is the real mechanism

00:58:22.300 | and why would something like this exist?

00:58:24.740 | Right.

00:58:25.580 | Because infections are very dangerous in biology, right?

00:58:27.720 | Right, but very interesting also.

00:58:29.660 | And so when it comes to metabolic changes and nutrition,

00:58:34.660 | there are numerous examples

00:58:36.860 | where you either overfeed or starve

00:58:40.260 | and get effects in the next generations.

00:58:42.640 | Many of them, sometimes the effects contrast

00:58:45.180 | depending on the way you do this.

00:58:46.880 | Again, these are none of,

00:58:48.700 | we don't do any of that in mammals,

00:58:50.620 | but people show that starving or overfeeding the mothers,

00:58:54.060 | all the fathers changes the body weight

00:58:56.140 | of the next generation and also the glucose tolerance

00:59:00.140 | and other, and also reproductive success.

00:59:04.400 | And so the fact that there's an effect,

00:59:08.720 | that something transmits, this is clear.

00:59:10.940 | The question is, how miraculous is it?

00:59:14.020 | And whether you need new biology

00:59:15.420 | and epigenetics to explain it.

00:59:17.520 | What do I mean by that?

00:59:19.020 | If you affect the next generation,

00:59:22.240 | it doesn't necessarily has to go through the oocyte

00:59:25.880 | or the sperm and involve the epigenome.

00:59:28.580 | You change the metabolism of the animal as it develops,

00:59:33.580 | and obviously it will affect it.

00:59:36.720 | When you, for example, starve women that are pregnant,

00:59:41.720 | as happened during this famous starvation studies,

00:59:46.680 | the baby's already in utero,

00:59:49.820 | exposed directly to the environment.

00:59:51.720 | So it's not even a heritable effect.

00:59:53.700 | The baby is itself affected.

00:59:55.820 | It's a direct effect, very interesting, important,

00:59:58.460 | and has many implications.

00:59:59.660 | And it will be separate from the genetics.

01:00:02.300 | You'll have to take it into account

01:00:03.500 | to understand what's going on.

01:00:05.620 | It doesn't require necessarily new biology

01:00:08.240 | and new biology of inheritance.

01:00:11.900 | Not only is the embryo affected,

01:00:14.920 | the embryo while in utero already has germ cells.

01:00:18.080 | So it's also the next generation is directly exposed.

01:00:22.120 | And you don't need any new biology necessarily to explain it

01:00:25.440 | and it doesn't have has to involve epigenetics

01:00:28.580 | or epigenetics, et cetera.

01:00:29.540 | - It's clear to me that in the female fetus,

01:00:32.820 | the total number of eggs that she will someday produce

01:00:36.400 | and potentially have fertilized by sperm exist.

01:00:39.800 | But in males with a 60 day sperm cycle,

01:00:42.740 | leads me to the question, do fetal males,

01:00:47.100 | males as fetuses, living as fetuses in their moms

01:00:49.780 | already start producing sperm

01:00:51.280 | or it's the primordial cells that give rise to sperm?

01:00:54.740 | - So I'm not an expert.

01:00:56.300 | So I don't want to go into the details

01:00:58.860 | of exactly when in mammals.

01:01:00.940 | But yes, exposure of the mother also affect

01:01:04.500 | eventually the transmission of the father,

01:01:08.140 | of genetic information for the sperm's father.

01:01:10.820 | And there are also many examples

01:01:12.360 | of just stressing the father's affecting the sperm

01:01:15.860 | and affecting the next generation.

01:01:17.320 | There, if you go to the F2 generation,

01:01:19.300 | if you go two generations down the road,

01:01:21.460 | not to the kids, but to the grandkids,

01:01:23.820 | then it is a real epigenetic effect

01:01:26.340 | because you examine something that happens

01:01:31.340 | although the next generation was never exposed

01:01:34.460 | to the original challenge.

01:01:36.520 | So when we say about epigenetic inheritance

01:01:39.380 | in through the paternal lineage, through the fathers,

01:01:42.740 | we talk about two generations

01:01:45.940 | and when you go through the mother, it's three generations

01:01:48.560 | to talk about when you need to invoke

01:01:52.300 | some real epigenetic mechanism.

01:01:53.980 | And there, the evidence becomes much more scarce in mammals.

01:01:58.460 | There are examples, more or less convincing,

01:02:02.420 | the field is evolving and improving a lot.

01:02:05.020 | So for example, now, many people use,

01:02:09.380 | the cutting edge is to use IVF in vitro fertilization

01:02:13.580 | or transfer of embryos to make sure that you actually,

01:02:16.540 | it's the heritable information and not the environment

01:02:19.500 | that it goes through the germline.

01:02:23.140 | So this is something that is being done now.

01:02:24.820 | There are studies--

01:02:25.660 | - You're talking about the three-parent IVF

01:02:26.940 | where they take the DNA from mom, the sperm from dad,

01:02:29.740 | and they take the DNA from mom

01:02:31.020 | and put it into a novel cytoplasm or--

01:02:33.860 | - No, not at all, you just take the sperm

01:02:37.140 | and transfer it and fertilize it, an egg.

01:02:41.340 | - So standard IVF.

01:02:42.420 | - Yes, standard IVF, yeah.

01:02:43.700 | You can do it in many different ways,

01:02:45.340 | but this idea that you separate the environment

01:02:48.780 | of the mother from the inheritance

01:02:50.540 | or the environment of the father

01:02:52.080 | and to control and separate nature from nature.

01:02:55.460 | - The environment becomes the culture dish.

01:02:57.500 | - Yes, so the field is improving.

01:03:01.780 | People do experiments that have a higher end,

01:03:04.340 | so more replicates and better controlled.

01:03:07.820 | And there are some examples for effects that transfer,

01:03:10.820 | and it depends who you ask,

01:03:12.220 | whether people believe it or not.

01:03:13.820 | Many geneticists do not believe it,

01:03:17.060 | and many people do believe it,

01:03:18.700 | and it depends on the community.

01:03:20.220 | There are strong resistance for many reasons.

01:03:23.780 | Some of them are justified, some less justified

01:03:26.380 | and are part of the scientific process and how things work,

01:03:31.540 | because it's a new, it's challenging the dogma.

01:03:34.740 | So this is very interesting on its own.

01:03:37.300 | If you ask psychologists, many psychologists believe

01:03:39.800 | that there's heritable trauma and things like this.

01:03:42.820 | Population geneticists, less so.

01:03:45.540 | So this really depends.

01:03:47.180 | And I think that we are just at a point in time

01:03:51.340 | where we don't really know whether it happens

01:03:54.140 | and to what extent, and we need bigger studies.

01:03:57.080 | Even if you think about normal, just genetic studies,

01:03:59.620 | where people are trying to understand the genetic underpinning

01:04:02.500 | of complex traits,

01:04:05.200 | like anything that involves the brain, pretty much.

01:04:10.060 | We now know that you need to study many, many, many people.

01:04:13.860 | So now these big genome-wide association studies,

01:04:17.000 | big genetic studies involve hundreds of thousands of people.

01:04:20.580 | No one did an experiment like this for epigenetics.

01:04:23.300 | It's much more complicated because you need to also

01:04:25.500 | take into account the environment.

01:04:28.580 | I'm not even sure we know how to design such an experiment.

01:04:31.860 | It's very, very challenging.

01:04:33.860 | So part of the resistance to the idea

01:04:38.140 | is based on theoretical grounds because of these barriers

01:04:42.380 | and because of the controversies.

01:04:45.560 | On the other hand, people really want to believe it.

01:04:51.860 | People really want to believe it.

01:04:54.140 | Because it sort of gives your life meaning

01:04:58.780 | if you can change your biology through changing,

01:05:03.460 | of your kids through changing your biology.

01:05:05.780 | Psychologically, I can understand

01:05:07.300 | why many people want this to happen.

01:05:09.120 | Even Schrodinger, the famous physicist,

01:05:11.420 | so he wrote a very important book in '44.

01:05:14.900 | So this was before the double helix.

01:05:17.180 | It's called What is Life?

01:05:21.440 | This is actually a book that drove many physicists

01:05:24.660 | to establish molecular biology.

01:05:26.120 | It's very, very important.

01:05:27.160 | And he talks about the heritable material.

01:05:28.760 | He also talks about evolution and he said,

01:05:30.800 | "Unfortunately, Lamarckism or inheritance of acquired traits

01:05:33.820 | "is untenable, it doesn't happen."

01:05:36.200 | And he writes, "This is very, very sad or unfortunate

01:05:39.720 | "because unlike Darwinism or natural selection,

01:05:42.600 | "which is gloomy, it doesn't matter what you do,

01:05:46.160 | "the next generation will be born based on the instruction

01:05:48.840 | "in the sperm and the egg."

01:05:51.120 | You can't influence it.

01:05:52.080 | Of course, you can give your kids money and education,

01:05:54.180 | but you can't biologically influence it.

01:05:56.140 | - You can also, one thing I'm fascinated by

01:06:00.040 | for a number of reasons is partner selection.

01:06:02.520 | I mean, in some ways, we think,

01:06:04.060 | oh, we want to find someone who is kind.

01:06:06.960 | That does seem to be, by the way, the primary feature,

01:06:09.320 | at least in the data, tell us.

01:06:11.360 | We had David Boss on the podcast

01:06:12.560 | of how women select men, that people are kind.

01:06:14.880 | There's also resource potential.

01:06:16.080 | There's also beauty or aesthetic attractiveness

01:06:19.260 | in males and females, et cetera, male, male, female, female,

01:06:22.980 | as the case may be, but in terms of reproduction,

01:06:24.720 | sperm, egg, male, female, obviously.

01:06:27.680 | So we're selecting for a number of traits,

01:06:30.940 | but presumably subconsciously,

01:06:32.800 | we are also selecting for a number of traits

01:06:34.860 | related to vigor and in the idea

01:06:37.200 | that if we were to have offspring with somebody,

01:06:40.020 | that those traits would be selected for.

01:06:42.060 | - Right, and we actually have work on that in nematodes

01:06:45.560 | that I'll be happy to tell you about in a second

01:06:47.160 | after we-

01:06:48.000 | - The dating behavior?

01:06:49.680 | - The dating and worms, and where we understand

01:06:53.140 | the mechanism, and we'll go into that in a second,

01:06:56.300 | or in a few minutes after we dive into the worms.

01:06:59.180 | But yes, the original calculations

01:07:03.800 | of how population genetics work,

01:07:06.380 | to simplify things, and to do the math,

01:07:08.240 | so it would be as if it was random mating.

01:07:09.960 | Of course, it doesn't work like that.

01:07:11.520 | So it complicates things, because we know.

01:07:13.560 | And there's research about potential capacity

01:07:17.640 | to somehow sense immune compatibility

01:07:20.960 | and things like this, which is, I don't know,

01:07:22.540 | I'm not an expert on that, but yeah.

01:07:24.640 | - Neither am I, but my understanding is that of course,

01:07:26.600 | we're familiar with the other traits we select for,

01:07:28.960 | like potential nurturing ability,

01:07:31.260 | whether or not someone is reliable,

01:07:32.640 | predicts something about their nurturing ability,

01:07:34.620 | and for offspring potentially.

01:07:36.000 | I mean, you can draw lines between these things

01:07:37.920 | without any direct evidence,

01:07:39.640 | but they seem so logical, right?

01:07:42.200 | That somebody kind who might also stick around

01:07:44.240 | or be honest in these kinds of things that it makes sense.

01:07:47.040 | But that one would be selecting

01:07:48.220 | for certain biological traits like immune function

01:07:50.680 | or some other form of robustness that we're not aware of

01:07:54.440 | is I think a fascinating, fascinating area of biology.

01:07:57.640 | Yeah.

01:07:58.480 | - Yeah, so this is where the work in mammals stands.

01:08:03.440 | However, there's also one additional thing to mention,

01:08:06.720 | which is that on top of chemical modifications to the DNA

01:08:11.720 | and the proteins that condense the DNA,

01:08:16.760 | which are called histones,

01:08:18.160 | there are also other mechanisms

01:08:19.360 | that might transmit information,

01:08:21.160 | including transmission between generations of RNA.

01:08:24.200 | And there are different types of RNA,

01:08:27.480 | not just the RNA that we mentioned before,

01:08:29.440 | the messenger RNA, which encodes for the information

01:08:34.440 | for making protein,

01:08:35.440 | but also other RNAs that regulate gene expression.

01:08:39.080 | And this is, and I think that in recent years,

01:08:42.400 | also in the mammalian field,

01:08:44.640 | RNA as the molecule that has the potential

01:08:47.820 | to transmit information between generation took center stage.

01:08:51.440 | So I think this is the cutting edge,

01:08:53.240 | a lot more to understand than no,

01:08:56.760 | but RNA has a lot of potential for doing that,

01:08:59.660 | as we'll explain soon, but we have to go to worms first.

01:09:03.120 | - I'd like to just take a brief moment

01:09:04.680 | and thank one of our podcast sponsors,

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01:09:18.780 | for the simple reason that blood work is the only way

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01:09:24.080 | lipids, metabolic factors, et cetera,

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01:09:28.940 | One major challenge with blood work, however,

01:09:31.060 | is that most of the time it does not come back

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01:10:16.600 | Again, that's insidetracker.com/huberman to get 20% off.

01:10:20.780 | - Thank you for that incredible overview of genetics,

01:10:24.820 | and RNA, and epigenetics,

01:10:27.220 | and was essentially a survey of this very interesting,

01:10:31.240 | and on the face of it, a complex field,

01:10:33.880 | but you've simplified it a great deal for us.

01:10:37.700 | In our transition to talking about worms,

01:10:40.640 | I would like to plant a flag in the Huberman Lab podcast,

01:10:45.640 | and say that what we are about to discuss

01:10:47.880 | is the first time that anyone on this podcast

01:10:51.080 | has discussed so-called model organisms.

01:10:53.600 | I may have mentioned a fly paper here or there,

01:10:56.120 | or a study on honeybees, and caffeine,

01:10:58.160 | and flower preference at one point,

01:11:00.640 | but typically that's done in passing,

01:11:02.060 | and we quickly rotate to humans.

01:11:04.280 | I know that many, if not most of our listeners,

01:11:06.620 | are focused on humans, and human biology,

01:11:08.540 | and health, et cetera,

01:11:09.820 | but I cannot emphasize enough

01:11:12.400 | the importance of model organisms,

01:11:14.700 | and the incredible degree to which they've informed us

01:11:17.720 | about human health, especially when it comes

01:11:19.620 | to very basic functions in cells, right?

01:11:22.740 | I mean, one could argue, okay,

01:11:24.140 | and there's been some debate, telomeres in mice,

01:11:26.020 | did that really lead to the same sort of data in humans?

01:11:28.160 | Okay, there are those cases, certainly,

01:11:30.920 | but model organisms are absolutely critical,

01:11:33.900 | and have been, and basically inform

01:11:35.280 | most of what we understand about human health.

01:11:37.100 | So before we start to go into the description

01:11:40.760 | about worms, per se, could you just explain

01:11:43.200 | to a general audience what a model organism is, right?

01:11:46.820 | They're not modeling, they're not posing

01:11:48.300 | for photographs, obviously, what that means,

01:11:52.000 | and what some of the general model organisms are,

01:11:54.560 | and why you've selected or elected

01:11:57.960 | to work on a particular type of worm

01:12:01.160 | to study these fascinating topics

01:12:04.060 | that there's zero question,

01:12:06.880 | also take place in humans at some level.

01:12:10.380 | - So it's a real pleasure and an honor

01:12:13.300 | to represent the model organisms here.

01:12:15.020 | I'm really happy just for that, it was worth it,

01:12:18.800 | because as you said, model organisms

01:12:21.840 | are extremely important, and we learned so much

01:12:24.260 | about biology through them.

01:12:26.500 | The model organisms mean that it's an organism

01:12:30.660 | that many people work on, so there's a community

01:12:33.220 | of people that work on it.

01:12:34.060 | People study many types of organisms,

01:12:36.380 | but not around every organism, there's a huge community

01:12:39.700 | of researchers that combine sources

01:12:43.380 | to create all the resources and the tools

01:12:46.100 | and the understanding that accumulates.

01:12:48.880 | There is just a handful of model organisms

01:12:51.580 | in the short history of the field of biology,

01:12:55.100 | it's not so long.

01:12:56.300 | We learned about every aspect of biology through them,

01:12:58.860 | including many important diseases, human diseases,

01:13:03.380 | and these are E. coli bacteria, phage,

01:13:07.700 | which is a virus of bacteria, flies,

01:13:10.580 | worms that are called C. elegans nematodes,

01:13:18.220 | this is what we study in the lab,

01:13:20.500 | fish which are called zebrafish.

01:13:23.120 | It's a particular-- - It's Danyo danyo.

01:13:24.980 | - Right, and of course there are also model organisms,

01:13:28.780 | other, and mouse, and also plants, important plants,

01:13:33.780 | the most in studies, one is the Arabidopsis.

01:13:37.540 | - Yeah, and perhaps less so nowadays,

01:13:39.180 | but non-human primates, macaque monkeys,

01:13:41.900 | marmosets, squirrel monkeys, mainly.

01:13:43.780 | - These, I don't know exactly how the definition is,

01:13:45.900 | but emerging model organisms, there are many model organisms

01:13:48.700 | that are emerging and there are communities that are formed,

01:13:51.620 | including also around the planaria that we mentioned before,

01:13:54.320 | this flatworm that regenerates,

01:13:56.020 | this is a great model for studying regenerations.

01:13:58.220 | If we could develop new heads, it would be incredible.

01:14:00.900 | And we can learn from these organisms.

01:14:02.420 | And the reason that we can learn a lot also about humans

01:14:05.380 | by studying these animals is that we all evolve

01:14:08.420 | from the same ancestor.

01:14:11.060 | So we share a lot of our functions with them,

01:14:16.060 | and also a lot of our genes.

01:14:18.780 | C. elegans, and they have, the different model organisms

01:14:23.060 | have different advantages that serve us.

01:14:25.940 | They sometimes have some things

01:14:29.540 | that are much more apparent in them that we can study.

01:14:31.820 | For example, learning and memory was largely studied

01:14:34.660 | in the beginning in a snail, a plesia,

01:14:37.640 | where many of the discoveries were made

01:14:39.820 | because it has big noir ones

01:14:41.820 | that you can easily study and examine.

01:14:46.020 | - And yes, snails learn.

01:14:47.860 | - Yes, they learn.

01:14:48.820 | Even C. elegans, these nematodes that we study, learn,

01:14:52.620 | and they are much simpler than,

01:14:54.900 | another important reason to study them, of course,

01:14:56.860 | is you can actually experiment on them.

01:14:59.300 | We can't do this to humans,

01:15:00.900 | the things that we do to these animals,

01:15:02.700 | and we can change their genes,

01:15:05.720 | do all kinds of things for them.

01:15:08.060 | - And in some, sorry to interrupt, but in some cases,

01:15:10.540 | I think you're going to tell us, for instance,

01:15:11.780 | in C. elegans in particular,

01:15:13.300 | the presence of particular cell types is so stereotyped

01:15:18.300 | that you can look at several different worms and you can,

01:15:21.740 | the community of people that study C. elegans

01:15:24.100 | has literally numbered and named each neuron

01:15:26.860 | so that two laboratories on opposite sides of the world

01:15:29.660 | can publish papers on the same neuron,

01:15:31.620 | knowing that it's the same neuron

01:15:33.780 | in the two different laboratories,

01:15:35.340 | something that is extremely hard to do

01:15:37.720 | in any mammalian model, mouse or certainly in humans,

01:15:42.260 | and has posed huge challenges that give great advantages

01:15:46.080 | to studies of things like C. elegans.

01:15:48.180 | - Yeah, so C. elegans, this is the star now of what,

01:15:51.820 | and this is what we study.

01:15:53.740 | These are nematodes, small worms, round worms,

01:15:57.540 | that are just one millimeter long,

01:15:59.980 | so you can't see them with a naked eye.

01:16:01.500 | You have to look under the scope.

01:16:02.940 | - Where do they live in the natural world?

01:16:05.140 | - So they used to call them soil nematodes,

01:16:09.020 | but this is not really true.

01:16:10.600 | They are in many places,

01:16:12.160 | but they're mostly in rotten fruits and leaves,

01:16:15.300 | and you can find them in the ground as well,

01:16:18.320 | but you can also find them, and there are free living,

01:16:20.420 | so they're not parasites,

01:16:21.680 | but you can sometimes also find them in snails, okay?

01:16:25.160 | But the best way to isolate them is from rotten fruits.

01:16:28.060 | - Okay, I like the idea that they're not parasites.

01:16:30.420 | I'm one of these people that gets a little squeamish

01:16:32.000 | about the notion of parasites.

01:16:33.320 | - Yeah, so they're not parasites.

01:16:34.840 | They're really fun to handle

01:16:36.040 | because they're so small and easy.

01:16:37.200 | You just grow them on plates with agar and E. coli bacteria.

01:16:40.300 | This is what they eat in the lab.

01:16:41.860 | You can just pick them with a small wire pick,

01:16:47.740 | and move them around, and change their genes,

01:16:51.740 | and do many things for them,

01:16:52.580 | but they have many advantages for neuroscience

01:16:55.700 | and for studying inheritance.

01:16:57.920 | As you mentioned, they have always

01:17:00.740 | a certain number of cells in the body,

01:17:02.860 | so a C. elegans nematode always has 959 cells in its body.

01:17:07.440 | That's it, okay?

01:17:08.280 | - Not 960, not 958.

01:17:10.420 | - 959, okay, and out of which 302 are neurons.

01:17:16.420 | Always 302.

01:17:18.940 | There's a huge debate now over Twitter

01:17:21.720 | on whether it's 302 or 300.

01:17:24.220 | I mean, I don't want to get into trouble, okay,

01:17:26.400 | but people take this very, very hard.

01:17:29.740 | I think it's 302, but let's not get into it

01:17:31.700 | because I'll get into trouble.

01:17:32.700 | - Well, we can equilibrate all things here by you say 302.

01:17:36.300 | Granted, you're far more informed in this model organism

01:17:38.640 | than I am or ever will be.

01:17:40.840 | I'll say 300, and then we're balanced

01:17:43.260 | in terms of partisan politics and the C. elegans community.

01:17:45.900 | - Perfect.

01:17:46.740 | - And it's always the same, and each neuron has a name,

01:17:50.820 | like you said, and not only does every neuron has a name,

01:17:55.020 | many of them, we know what they do.

01:17:57.940 | So there's a few cells that are sensory neurons

01:18:01.820 | that sense particular chemicals.

01:18:03.900 | In certain situations, we know that a chemical

01:18:06.420 | will be sensed just by one neuron.

01:18:08.620 | There are the motor neurons and internal neurons

01:18:10.340 | and all of that.

01:18:11.220 | We know how many dopamine neurons they are

01:18:13.760 | and serotonin neurons, and we know them all by their name.

01:18:16.700 | Not only that, we know how they are connected

01:18:18.620 | to one another.

01:18:19.820 | We have a map, a connectome, since the '80s,

01:18:22.980 | like a subway map that tells us which neuron

01:18:26.740 | talks with which other neurons, and it is the same, okay?

01:18:30.200 | It was used to, people thought that it was exactly

01:18:33.260 | the same between genetically identical worms.

01:18:35.780 | Now we know that there are slight differences,

01:18:37.180 | but by and large, it is the same, and we have a map,

01:18:40.260 | a roadmap that we can use to study.

01:18:42.100 | - The so-called connectome.

01:18:43.260 | - The connectome.

01:18:44.100 | Not only that, the worms are transparent,

01:18:46.740 | so we can actually see the neurons fire

01:18:50.420 | using particular tools.

01:18:52.980 | And we can activate genes and silent genes

01:18:55.780 | using optogenetics, like I was discussing on the podcast.

01:18:59.380 | We can make the worms go forward or backward

01:19:02.740 | or lay an egg by shining different waves of light on them.

01:19:07.900 | And so we have very powerful tools

01:19:11.420 | for manipulating the brain.

01:19:13.460 | On top of that, we have great understanding

01:19:17.580 | of the genetics of the worm, of the genome.

01:19:20.860 | This is, coelacans is the first animal

01:19:23.260 | to have its genome sequenced before humans.

01:19:27.340 | Before that, of course, there were bacteria, but.

01:19:29.700 | And we know that in each worm produced,

01:19:33.420 | each mother produces about 250 babies,

01:19:37.020 | which are almost genetically identical.

01:19:39.020 | So we can, and we know where we grow them.

01:19:44.140 | The environment is very controlled.

01:19:45.860 | So we grow them in the plate with just bacteria.

01:19:48.940 | So we can easily separate between nature and nurture.

01:19:52.380 | - And one thing that I wonder about often

01:19:55.340 | is generation time.

01:19:56.900 | Even though mice are not humans,

01:19:59.140 | mice have certain advantages

01:20:00.460 | because they're mammalian species.

01:20:01.780 | You can't do all the magnificent things

01:20:03.420 | that you can do in coelacans in mice,

01:20:04.980 | but one major issue with mice

01:20:07.940 | is that the generation time is somewhat long.

01:20:10.340 | You pair two mice, they mate,

01:20:12.060 | you get a mouse or litter of mice 21 days later.

01:20:14.660 | It might seem like, okay, that's only 21 days or so.

01:20:17.940 | But if you are a graduate student or postdoc

01:20:21.460 | trying to do a project, I mean,

01:20:22.980 | that can extend the time to do experiments

01:20:25.420 | out three or four years

01:20:27.220 | compared to what you could do in coelacans.

01:20:28.660 | - You're absolutely right.

01:20:29.540 | This is one of the major advantages.

01:20:31.420 | The generation time in coelacans is three days, three days.

01:20:35.100 | So you can do hundreds of worm generations in one PhD.

01:20:38.980 | This is very important.

01:20:40.260 | Not only that, every worm will produce

01:20:42.300 | hundreds of progenies that are genetically identical,

01:20:45.340 | so you will have great statistics for your experiment.

01:20:47.700 | - And the worms probably don't mind

01:20:49.140 | living on these agar plates, you know,

01:20:50.740 | munching away on E. coli, where--

01:20:53.140 | - It's the good life.

01:20:53.980 | - You know, it's questionable whether or not mice are,

01:20:56.020 | certainly, listen, I'm a proponent of well-controlled

01:21:00.820 | and as long as there's oversight animal research,

01:21:03.700 | it's necessary for the development of treatments

01:21:05.780 | of diseases that hinder humans.

01:21:08.420 | But it is always a little bit of a kind of a cringe and go

01:21:12.780 | kind of thing when you're dealing with mammals

01:21:15.300 | that are living so far outside their natural environment.

01:21:18.260 | I'd be lying if I didn't say

01:21:19.300 | that it gets to you after a while,

01:21:20.780 | and if it doesn't get to you,

01:21:21.620 | you kind of have to wonder about your own psyche a bit.

01:21:23.860 | - Right, I also think that this is important,

01:21:26.060 | but for me, it's much easier to work on worms.

01:21:28.660 | I don't have to, you know, feel bad about it.

01:21:32.420 | - Yeah, they're happy.

01:21:33.740 | - They're happy, and you also, I mean, if a worm dies,

01:21:38.180 | it's less painful to the human

01:21:39.860 | than if other more sensitive animals.

01:21:43.540 | - Yeah, I would argue yes, I agree, yeah.

01:21:46.820 | - So yes, so there are many advantages

01:21:48.700 | for studying C. elegans.

01:21:50.580 | And in the worm, we now have very obvious

01:21:56.220 | and clear cut proof that there is inheritance

01:21:59.980 | of acquired traits, so much so that I don't think

01:22:03.180 | that anyone pretty much in the epigenetic field

01:22:06.540 | argues against it.

01:22:07.940 | - Well, and in large part, thanks to you

01:22:10.380 | and the work you've done.

01:22:11.340 | So could you tell us what was the first experiment

01:22:14.060 | that you did on C. elegans that confirmed for you

01:22:18.180 | that there is inheritance of acquired traits?

01:22:21.260 | Because of course, the best experiments

01:22:23.180 | and experimenters always set out to disprove

01:22:27.060 | their hypothesis, and when the hypothesis survives,

01:22:30.340 | despite all the control experiments and poking

01:22:33.260 | and prodding and attempts to contradict oneself,

01:22:37.660 | then it's considered a victory.

01:22:39.420 | But it's one that we all have to be very cautious

01:22:41.860 | about enjoying because of the tendency

01:22:44.620 | to want our hypotheses to be true.

01:22:46.780 | So what was the first experiment where you were convinced

01:22:49.700 | that inheritance of acquired traits is real?

01:22:52.540 | - The first experiment I did was when I, in my postdoc,

01:22:57.220 | which I did with Oliver Hobart in University of Columbia,

01:23:00.620 | we set to test whether worms can produce

01:23:07.060 | transgenerational for multiple generation resistance

01:23:11.140 | to viruses.

01:23:12.660 | - Oh wow, this is a very pertinent topic.

01:23:14.580 | - Which is relevant to you.

01:23:16.460 | And worms, these worms don't have dedicated immune cells

01:23:20.700 | like we do, they don't have T-cells or B-cells.

01:23:23.900 | They defend themselves from viruses

01:23:26.460 | very efficiently using RNA.

01:23:29.620 | So in fact, when we started these experiments,

01:23:31.620 | there wasn't any natural virus that was known

01:23:34.460 | to infect C. elegans, which is amazing.

01:23:36.580 | 'Cause viruses are very good,

01:23:37.700 | as we all experience now in infecting.

01:23:40.940 | And the worms are resistant to viruses

01:23:44.060 | because of RNA molecules, short RNA molecules

01:23:48.620 | that destroy viruses.

01:23:50.020 | And these are called small RNAs.

01:23:54.180 | Now we need to discuss them before I explain my experiment.

01:23:57.060 | In 2006, two researchers that were studying C. elegans,

01:24:03.700 | Andrew Fire and Craig Mello, got the Nobel Prize

01:24:08.460 | for showing that there is a mechanism that regulates genes

01:24:12.220 | that happens through small RNAs.

01:24:16.220 | What they've shown is that if you inject the worms

01:24:20.900 | with RNA molecules, which are double-stranded,

01:24:25.140 | they lead to the site, they shut off the genes

01:24:30.020 | that correspond, that match in sequence to this RNA.

01:24:33.180 | - So it's sort of like taking the specific instructions

01:24:36.900 | for the coffee table from your IKEA handbook,

01:24:40.580 | and you insert a copy of that into the book.

01:24:45.100 | And in doing so, you prevent the expression of,

01:24:49.100 | sort of erase the original page.

01:24:50.620 | - Perfect explanation, perfect explanation.

01:24:53.100 | And they found that double-stranded RNA,

01:24:56.420 | RNA that has two strands, is what starts the response,

01:25:00.620 | leading to the production of small RNA molecules,

01:25:03.180 | which are the ones that actually find the messenger RNA

01:25:06.220 | and leads to destruction.

01:25:07.980 | Silence it so you don't get proteins in the end.

01:25:10.660 | For that, they got the Nobel Prize

01:25:11.940 | after people found that this is conserved

01:25:14.580 | in many organisms, including humans.

01:25:16.620 | And now there are now drugs.

01:25:18.220 | This was only in 2006 that the Nobel Prize paper

01:25:21.260 | was published in '98.

01:25:22.660 | There are now drugs that use this mechanism also in humans.

01:25:27.340 | - And I'll just interject and say that not only

01:25:29.260 | is it a recent discovery and an incredibly important one,

01:25:32.740 | but Andy Fire and Craig Miller are also really nice people.

01:25:35.780 | - Yeah.

01:25:36.620 | - They just happen to be very nice people.

01:25:37.780 | And Craig Miller is an excellent,

01:25:39.700 | I think he's a kite surfer.

01:25:41.380 | When I, the only time I met him in person was at a meeting

01:25:43.940 | and he had a black eye and I thought, okay, wow,

01:25:46.260 | I guess he's also a pugilist or something,

01:25:48.220 | but turns out he had done that kite surfing.

01:25:50.580 | So scientists actually do things other than

01:25:54.220 | go to the laboratory, Nobel Prize winning scientist that is.

01:25:58.620 | Okay, I'll let you continue.

01:25:59.980 | Thanks for allowing me that.

01:26:00.820 | - Yeah, incredible scientists.

01:26:02.020 | And there were also studies in many organisms

01:26:05.900 | on the mechanisms of how this happens.

01:26:08.220 | It is called RNA interference.

01:26:11.220 | RNA interferes in the expression of a gene

01:26:14.300 | in the function of a gene.

01:26:15.780 | And it's also called gene silencing

01:26:18.020 | because these RNAs enforce the silencing of genes

01:26:20.900 | instead of the genes being expressed,

01:26:22.940 | they are silenced and you don't manifest the function.

01:26:26.140 | Already in the first paper that they published about this,

01:26:30.980 | where they've shown the double-strand RNA

01:26:32.980 | is what leads to the silencing of the control,

01:26:35.660 | they've shown two very important things.

01:26:38.540 | One of them is that if you inject the worms

01:26:41.460 | with double-strand RNA,

01:26:42.660 | you don't only see the action in the cell that you injected

01:26:48.740 | or in the tissue that you injected,

01:26:50.340 | but you see it all over the worm's body, it spreads.

01:26:53.420 | It wasn't exactly clear what spreads,

01:26:56.700 | but it was clear that it spreads.

01:26:58.260 | You see the silencing all over the body.

01:27:01.020 | This includes also the germ cells.

01:27:04.260 | So if you inject the double-strand RNA

01:27:06.140 | just to somatic cells, even to the head,

01:27:09.940 | you will get also the effect in the germ cells

01:27:13.100 | and in the next generation, okay,

01:27:16.140 | in the immediate progeny, the F1 generation, the kids.

01:27:19.940 | So this was really clear proof that this is inherited.

01:27:24.380 | However, this is just one generation, okay,

01:27:28.820 | in these original studies.

01:27:30.180 | Later they've shown something

01:27:33.020 | which will immediately remind you

01:27:34.980 | what I told you about with planaria,

01:27:36.900 | that you can just take worms

01:27:39.060 | and feed them on bacteria

01:27:42.060 | that produce this double-strand RNA,

01:27:44.780 | and that the silencing would move

01:27:46.980 | from the site of ingestion from the gut

01:27:49.220 | where the bacteria are eaten to the rest of the body

01:27:52.980 | and also to the next generation, okay?

01:27:55.500 | So before we left,

01:27:56.860 | when I mentioned these cannibalistic experiments

01:27:59.100 | of McConnell with the planaria,

01:28:01.100 | and now you see that it can happen,

01:28:03.100 | and this is not controversial at all.

01:28:05.220 | This is being done routinely every day

01:28:07.820 | by any C. elegans biologist in the world.

01:28:10.820 | This has been replicated a million times.

01:28:13.780 | Not only that, you can also feed planaria,

01:28:16.100 | these other worms, with RNA.

01:28:18.660 | You can just put it in chopped liver and let them eat it,

01:28:21.500 | and again, this will sign genes throughout the body, okay?

01:28:24.900 | - Wild.

01:28:25.740 | - Okay, and this is what we do routinely.

01:28:28.460 | We always, when we use this technique

01:28:32.220 | to see what genes do.

01:28:34.100 | If we want to see whether a particular gene is important

01:28:36.340 | for a certain behavior or a certain something,

01:28:39.860 | the way to study is to neutralize the gene activity,

01:28:44.340 | and we do it by just introducing the worms

01:28:46.380 | with double-strand RNA that correspond in sequence,

01:28:49.620 | that match in sequence this gene.

01:28:51.540 | This will lead to the silencing.

01:28:53.180 | This activate the gene's activity,

01:28:55.780 | and if then the effect stops,

01:28:58.460 | we know this gene is involved in the function,

01:29:00.900 | and we never want to just examine one worm,

01:29:04.220 | so we feed the mother with double-strand RNA,

01:29:06.780 | and then we examine all of its children

01:29:09.020 | so we can have the statistics over hundreds of worms

01:29:11.460 | or thousands of worms.

01:29:13.300 | So this is validated and not controversial at all

01:29:15.580 | and totally routine.

01:29:18.140 | - Is it fair to say that McConnell's experiments

01:29:20.460 | of chop blending up these worms,

01:29:23.180 | the graphic image, blending up these worms

01:29:25.540 | and then feeding them to other worms, planaria,

01:29:28.700 | that those experiments can, yes,

01:29:31.620 | be explained by double-stranded RNA

01:29:35.500 | and through RNA interference?

01:29:36.940 | - Potentially.

01:29:37.780 | It hasn't been done yet.

01:29:38.940 | We are working on it in my lab now

01:29:41.100 | in collaboration with other labs,

01:29:42.660 | but it wasn't published.

01:29:43.700 | But yes, this could be the explanation, okay?

01:29:46.860 | So Fire and Mellow did these experiments.

01:29:52.140 | Some other people did these experiments.

01:29:54.460 | When I started my work, I wanted to see

01:29:57.220 | whether in addition to artificial double-stranded RNA,

01:30:00.500 | some natural traits can also transmit across generations

01:30:04.980 | because of RNA, because of small RNAs.

01:30:07.100 | - Right, because injecting RNAi,

01:30:09.140 | or shorter interfering RNAs, that is,

01:30:12.860 | or putting worms into an environment

01:30:17.860 | with an abundance of inhibitory RNAs as an experiment

01:30:20.740 | is very different than worms experiencing something

01:30:23.300 | and then passing on that acquired trait to their offspring.

01:30:26.860 | And it's a world apart, in my opinion,

01:30:29.660 | because one is an extreme manipulation

01:30:31.180 | that illustrates an underlying principle.

01:30:33.180 | The other is something that in theory occurs

01:30:35.660 | in the passage of generations just naturally.

01:30:39.060 | - We're going from the less artificial

01:30:40.540 | to the more artificial.

01:30:42.060 | The advantages, just like with model organisms,

01:30:44.900 | that the more artificial it is,

01:30:46.340 | the easier it is to, you know exactly what you did.

01:30:49.180 | Just now introduce one factor

01:30:51.180 | and you can follow the result.

01:30:52.580 | So this is always the trait.

01:30:54.540 | What I did was, in Oliver's lab,

01:30:56.860 | is to see whether the magic, part of the magic

01:31:00.420 | for the worms' resistance to viruses

01:31:03.100 | is the capacity to transmit information

01:31:05.820 | in the form of RNA molecules, inhibitory RNA molecules,

01:31:09.260 | to the next generations.

01:31:10.820 | And it has been shown before in C. elegans

01:31:13.660 | that the worms resist viruses using this mechanism,

01:31:17.860 | these small RNAs, okay?

01:31:20.140 | In fact, this is probably the reason

01:31:21.700 | that these small RNAs evolved in the first place,

01:31:24.620 | to get rid of viruses and other parasitic genomic elements.

01:31:29.620 | And this is a mechanism to fight them.

01:31:35.460 | And what I did is a very simple experiment.

01:31:38.740 | I took worms and I infected them with a virus.

01:31:41.180 | When you do this, this also has been shown in the past,

01:31:44.860 | the worms destroy the virus, okay?

01:31:48.500 | We demonstrated this very clearly using a fluorescent virus.

01:31:53.500 | So if the virus replicates successfully,

01:31:59.580 | the worms just turns green.

01:32:02.060 | And if the virus is destroyed, the worm stays black.

01:32:05.100 | This is very simple.

01:32:05.940 | It's a clear cut off.

01:32:06.980 | It's not, you don't examine the worm

01:32:09.660 | and ask whether it feels good.

01:32:11.460 | You just see this green light.

01:32:13.020 | - Binary response.

01:32:14.100 | - Yes. - Yeah.

01:32:15.660 | - And so we took worms,

01:32:17.740 | we infect them with the fluorescent virus, they destroyed.

01:32:20.940 | This also has been done in the past.

01:32:22.620 | But then what we did is we neutralized the machinery

01:32:27.620 | that makes small RNAs in the descendants of the worms.

01:32:32.740 | So they cannot make small RNAs from the start on their own

01:32:37.300 | because they just don't have the genes

01:32:38.660 | that you need to make these small RNAs, okay?

01:32:41.780 | And then we ask, what will happen

01:32:45.300 | when we'll infect these worms with a virus?

01:32:47.580 | Will they be green or black?

01:32:50.300 | They can't make their own small RNAs.

01:32:52.620 | So they can't protect themselves on their own.

01:32:54.820 | The only way for them to stay black

01:32:56.940 | for them not having the virus replicate

01:32:59.380 | is if they inherit the small RNAs from their parents.

01:33:01.540 | And this is exactly what happens.

01:33:03.740 | All the worms progeny, although they don't have the gene

01:33:07.260 | that is needed for making the small RNAs are black.

01:33:09.980 | They signed the virus.

01:33:11.020 | And this also continues for additional generations, okay?

01:33:13.740 | - So the parent worms effectively put something

01:33:18.100 | into the genetic instructions of the offspring

01:33:20.740 | that would afford them this,

01:33:22.760 | let's call it an advantage in this case,

01:33:24.660 | but afford them an advantage if they were to be confronted

01:33:28.300 | with the same thing that the parents were.

01:33:29.660 | - Right, and we know exactly what these advantages.

01:33:32.740 | The advantages are small RNAs that match the viral genome

01:33:37.740 | and just chop up the virus in the next generation.

01:33:41.460 | And we can identify these small RNAs in the inhibitory RNAs

01:33:46.460 | in the descendants, although they don't have the machinery

01:33:49.280 | to make it, just because they inherit it.

01:33:51.220 | We can identify them by sequencing,

01:33:53.620 | by RNA sequencing, which is like DNA sequencing.

01:33:56.180 | You actually get the actual sequence of the RNA molecules.

01:33:59.700 | And we can see that they correspond to the virus

01:34:01.660 | and they inherit these small RNAs

01:34:04.500 | only if their parents were infected with them.

01:34:06.820 | - So there's specificity there.

01:34:08.400 | - There's specificity.

01:34:09.440 | Yeah, it's not some just general resilience passage.

01:34:13.300 | I have to be careful in drawing an analogy

01:34:15.280 | that isn't correct.

01:34:16.960 | And I want to acknowledge that what I'm about to say

01:34:19.400 | with certainty cannot be entirely correct.

01:34:21.440 | But the analogy that comes to mind in mammals is this idea

01:34:25.220 | that if one generation is stressed,

01:34:27.120 | that their offspring may, in some cases,

01:34:29.600 | have a higher stress threshold, the resilience to stress.

01:34:33.380 | I could imagine why that would be advantageous, right?

01:34:35.960 | Your parents have a hard life, they have offspring,

01:34:38.640 | and they want their children

01:34:40.400 | to have a higher threshold to stress

01:34:41.860 | because stress can inhibit reproduction, et cetera.

01:34:43.880 | And I always say, you know, at the end of the day

01:34:46.520 | and at the end of life, evolution is about the offspring,

01:34:49.320 | not about the parents.

01:34:50.680 | And every species pretty much seems to want

01:34:52.840 | to make more of itself and protect its young,

01:34:54.920 | one way or another, either through nature or through nurture.

01:34:58.000 | This is a nature-based protection of young.

01:35:00.460 | Is it fair to say that in the mammalian experiment

01:35:03.260 | with a passage of stress resilience,

01:35:05.840 | that it could be RNA-based,

01:35:10.380 | that that would be, perhaps, set some new threshold

01:35:13.280 | on glucocorticoid production?

01:35:14.600 | Here, I'm speculating,

01:35:15.880 | and I want to highlight that I'm speculating,

01:35:17.600 | but I'm speculating with a reason,

01:35:19.120 | which is, I think, for people

01:35:20.060 | that are hearing about this in worms,

01:35:21.880 | you've done a beautiful job of splaying out

01:35:24.200 | why model organisms are really important,

01:35:26.640 | but to think about how this may operate

01:35:28.200 | in the passage of human generations,

01:35:30.600 | I think is a reasonable thing to entertain.

01:35:32.600 | - Right, and it is true that also in mammals,

01:35:37.480 | now RNAs and small RNAs are a leading candidate

01:35:41.920 | for something that could mediate the transmission

01:35:44.120 | of stress protection or also harmful effects

01:35:48.440 | that transmit between generations.

01:35:49.920 | Perhaps, RNA do it.

01:35:51.400 | However, in worms, the RNAs have one more trick

01:35:55.640 | that we don't know the equivalent in mammals yet.

01:35:59.560 | This is something very crucial

01:36:00.800 | that we showed in that particular paper, in the first paper.

01:36:03.360 | - Which is?

01:36:04.400 | - So the effect that I described,

01:36:06.480 | this transmission of resistance to viruses

01:36:09.000 | through these RNAs, doesn't only affect the next generation.

01:36:12.840 | It also affects multiple additional generations.

01:36:15.340 | - So it gets passed.

01:36:16.440 | - It gets passed, and you have to ask yourself,

01:36:18.800 | how doesn't it get diluted?

01:36:20.360 | Why isn't it diluted, right?

01:36:23.840 | Because, I mean, everyone produces 250 babies,

01:36:27.520 | so you dilute by 250,

01:36:29.240 | and if something is diluted for four generations,

01:36:31.800 | so it's 250 times 250, after four generations,

01:36:34.520 | it's a dilution of four billions,

01:36:36.820 | completely homeopathic would never work.

01:36:39.520 | It's just there's nothing left.

01:36:41.840 | The secret of these worms is that they have a machinery

01:36:45.000 | for amplifying the small RNAs in every generation.

01:36:47.640 | This is called RNA-dependent RNA polymerase.

01:36:52.520 | It's a complex which uses the RNA

01:36:57.880 | to find, and once it finds the messenger RNA,

01:37:00.840 | it just creates many, many, many, many small RNAs,

01:37:03.320 | so they don't get diluted,

01:37:04.480 | and they pass on for additional generations.

01:37:06.680 | And this is the trick.

01:37:10.060 | We later also identify genes that regulate

01:37:13.000 | for how long an effect would last.

01:37:14.960 | Otherwise, if in the beginning we ask,

01:37:19.220 | how doesn't it stop after one generation,

01:37:21.540 | now we have to ask, why doesn't it last forever?

01:37:24.000 | And it doesn't.

01:37:25.680 | Typically we see that the responses last

01:37:27.960 | not only with the viral resistance,

01:37:29.200 | but also with other traits for a few generations,

01:37:32.280 | three to five generations.

01:37:33.680 | We found genes that function as a sort of a clock

01:37:38.540 | that times the duration of the inheritance.

01:37:40.820 | - What sorts of genes are those?

01:37:43.220 | - So we call these genes MOTEC genes.

01:37:45.280 | MOTEC, I don't know how is your Hebrew,

01:37:47.720 | but MOTEC, it means sweetheart in Hebrew,

01:37:50.540 | but the acronym is modified transgenerational

01:37:52.720 | epigenetic kinetics.

01:37:55.120 | There are different types of genes like that.

01:37:57.460 | And some of them, if you mutate,

01:38:01.080 | if you disrupt their function,

01:38:03.000 | now the effect would transmit stably

01:38:05.620 | for hundreds of generations.

01:38:06.960 | It would never stop.

01:38:08.680 | Because their role is to stop the inheritance

01:38:11.640 | from just, you don't wanna carry over something forever,

01:38:15.680 | otherwise it will no longer fit the environment

01:38:18.440 | of the parents, and you'll be prepared

01:38:19.920 | for the wrong things.

01:38:21.280 | So this is important.

01:38:23.640 | What type of genes are they?

01:38:25.040 | One gene that we studied, it's called MET2.

01:38:28.360 | It's actually a gene that functions in methylation

01:38:32.000 | of the proteins that condense the DNA.

01:38:35.040 | So this is, but then there are other genes

01:38:38.040 | that affect also production of small RNAs.

01:38:40.280 | - Is there some mechanism that controls

01:38:43.620 | the duration of passage in a way that logically links up

01:38:48.620 | with the lifespan of the organism?

01:38:52.320 | So for instance, I knew my grandparents,

01:38:54.920 | met them, I did not ever meet my great-grandparents,

01:38:58.760 | and I certainly didn't meet my great-great-grandparents.

01:39:01.280 | I could imagine that my great-great-grandparents

01:39:03.720 | or my great-grandparents experienced certain things

01:39:06.020 | that were passed into their children

01:39:08.520 | and perhaps into their children.

01:39:11.160 | But it seems reasonable, given that humans live

01:39:13.880 | somewhere between zero and 100 years,

01:39:17.960 | typically what now, 80 years,

01:39:20.080 | is that the typical lifespan, more or less, okay?

01:39:22.680 | That if I were going to design the system,

01:39:26.440 | and again, I was not consulted at the design phase,

01:39:28.920 | I would want an adaptive trait

01:39:32.160 | to be passed for two generations,

01:39:34.200 | because given the way that our,

01:39:36.480 | given how long our species lives,

01:39:37.860 | and certainly given the way the world looks now,

01:39:39.640 | as opposed to the turn of the previous century

01:39:41.920 | or the turn of the previous century,

01:39:43.580 | different stressors, different life environments,

01:39:48.120 | and what I would want to pass on to my offspring,

01:39:51.600 | I can basically hedge pretty well.

01:39:53.880 | I can place a good bet on the next 100 years,

01:39:56.160 | maybe the next 200, but I don't have the foggiest clue

01:39:59.640 | what the world is going to look like in 300 years.

01:40:02.100 | Does what I'm saying make any sense whatsoever?

01:40:03.800 | - It makes a lot of sense.

01:40:05.040 | And really, we need to talk about two things

01:40:08.200 | in response to this question.

01:40:09.120 | First of all, yes, you can imagine that the reason

01:40:13.000 | that the worms inherit, typically,

01:40:15.520 | for three to five generations is that this is relevant

01:40:18.280 | to something that happened in their environment.

01:40:20.220 | For example, we also showed that when you starve the worms,

01:40:24.880 | it affects the next generations,

01:40:26.320 | again, for a few generations.

01:40:28.820 | - Which in itself is amazing, right?

01:40:30.480 | I just want to highlight that.

01:40:32.040 | I mean, you can imagine next generation,

01:40:33.420 | it's sort of like a genetic version of be careful, kids,

01:40:36.840 | but I'm going to give you this extra lunch pack

01:40:38.800 | in your genome that protects you

01:40:40.440 | against the possibility of starvation.

01:40:42.440 | But it's also saying, and were you to have kids?

01:40:44.780 | - Right. - They have it also.

01:40:46.000 | - Yeah, so I have to just make a disclaimer

01:40:49.140 | that we don't know that necessarily it's adaptive.

01:40:52.040 | It could also be damaged.

01:40:53.200 | As I said, when you starve them,

01:40:54.400 | the next generations live longer,

01:40:55.800 | but this could be a trade-off for fertility or something.

01:40:59.840 | So other labs have also shown, following our work,

01:41:03.600 | that if you starve the worms, the next generations

01:41:05.200 | are also more resistant to harsher starvation.

01:41:08.360 | This sounds, this is not our work,

01:41:10.720 | but this sounds adaptive, okay?

01:41:13.040 | But whenever you're talking about adaptation,

01:41:14.880 | you have to see it in the context of evolution.

01:41:16.960 | There's also this famous saying, nothing in biology

01:41:19.140 | makes sense except in the light of evolution.

01:41:21.260 | And so it's very hard to say,

01:41:23.380 | without doing the lab evolution experiments,

01:41:25.820 | we actually see who wins, the ones that inherit

01:41:28.380 | or the ones that don't inherit, who takes over.

01:41:30.840 | Otherwise, it's hard to talk about

01:41:32.340 | whether it's adaptive or not.

01:41:33.540 | But when it comes to the duration of the response,

01:41:35.620 | yes, it could be programmed to fit something.

01:41:39.500 | For example, if you're talking about starvation,

01:41:41.780 | worms transition between periods of starvation

01:41:44.860 | and periods where they have a lot of food.

01:41:46.820 | So let's say they find an apple.

01:41:48.640 | For a few generations, they will consume the apple

01:41:50.540 | and then they will be starved for a while.

01:41:52.920 | Perhaps this is the number of generations

01:41:55.200 | that takes them to finish an apple.

01:41:57.200 | Or perhaps there are other responses

01:41:59.420 | also to higher temperatures.

01:42:01.580 | If you grow worms in higher temperatures,

01:42:03.360 | their offerings are different.

01:42:05.200 | They change how they mate.

01:42:08.060 | It's what I alluded to before.

01:42:09.940 | - We're gonna get back to this

01:42:10.780 | because it relates to cold exposure,

01:42:12.480 | which many listeners are interested in.

01:42:13.540 | - And perhaps it is somehow correlated with

01:42:18.100 | the cycle of the year.

01:42:20.140 | But to tell you the truth, I don't know.

01:42:22.000 | As I said, we go from the more artificial

01:42:25.680 | to the less artificial.

01:42:27.700 | If double-strand RNA, just synthetic RNA,

01:42:30.380 | is the most artificial, starvation is more natural,

01:42:34.700 | but it's not starvation in the real context of the world,

01:42:38.060 | in a real apple.

01:42:39.500 | It's a plate with or without E. coli bacteria.

01:42:42.260 | It's not an apple on a tree exposed to the elements

01:42:46.860 | with other worms, with bacteria,

01:42:49.140 | with all kinds of complications.

01:42:50.860 | And it could be that we will see

01:42:52.580 | different durations of heritable effects.

01:42:54.660 | The more natural we go,

01:42:56.020 | it's just much less controllable and hard to do.

01:42:58.680 | And again, when we're talking about humans,

01:43:01.780 | part of the argument why people, why the disbelievers,

01:43:04.860 | it's not about faith.

01:43:07.420 | The critics say that this wouldn't happen in humans

01:43:10.100 | is they say the worms' generation time is just three days.

01:43:14.940 | The chances that the parent's environment will match

01:43:17.640 | the children's environment is very high

01:43:19.840 | because there's not a lot of time

01:43:23.260 | for the environment to change it,

01:43:24.500 | plus they can't go very far, they're small.

01:43:27.160 | There are many examples of epigenetic inheritance in plants.

01:43:31.940 | This is a big field where the very established proof

01:43:35.980 | for inheritance of acquired traits,

01:43:37.540 | for epigenetic inheritance.

01:43:38.820 | Be more careful, epigenetic inheritance of acquired traits

01:43:42.220 | is more low than 10, but in plants it also happens.

01:43:45.060 | And then you also say these are sessile organisms,

01:43:47.620 | they can't run away, so the environment is more constant.

01:43:50.700 | - Well, ideas, maybe just a quick example

01:43:52.780 | that I've heard before.

01:43:53.740 | Tell me if I'm wrong, I very well may be.

01:43:56.560 | For instance, a particular species of plant

01:43:59.020 | that grows a straight, maybe slightly bended stalk

01:44:02.340 | might be exposed to some environment

01:44:03.860 | where in order to capture enough sunlight

01:44:07.160 | and other nutrients might need to grow in a corkscrew form.

01:44:10.380 | The corkscrew form can be inherited

01:44:12.220 | several generations from.

01:44:13.460 | - This is an example that I don't know,

01:44:14.920 | but perhaps it-- - Something like that.

01:44:16.560 | I seem to, someone will tell, trust me,

01:44:18.520 | the one thing we know about podcasting and YouTube

01:44:20.580 | is someone will tell us in the comments.

01:44:22.080 | So, and please do, we invite that.

01:44:24.380 | - Right, but there's a long history

01:44:25.860 | of epigenetic inheritance studies in plants

01:44:28.380 | with excellent studies, well-controlled,

01:44:30.820 | showing that it happens also there.

01:44:32.680 | So this is very clear.

01:44:34.120 | When it comes to humans, you could say maybe my kids

01:44:36.520 | will go off to live in a different continent

01:44:40.720 | and they will be on the computer every day.

01:44:43.500 | Everything will be different, so it makes less sense

01:44:45.700 | to prepare them for the same hardships that I experienced.

01:44:48.760 | However, this, in my opinion, this argument comes a lot.

01:44:53.380 | It's not the best argument because it depends on the scale

01:44:58.380 | of how you look at things.

01:45:00.340 | We experience, we meet, for example,

01:45:02.180 | I'm not saying that this is inherited in humans,

01:45:04.000 | but we experience the same pathogens

01:45:05.900 | and the same viruses all the time,

01:45:08.040 | so perhaps it is worth preparing for that.

01:45:10.060 | Again, I'm not saying that it happens,

01:45:12.340 | but it depends on the scale.

01:45:15.020 | - Well, what you're describing makes perfect sense,

01:45:17.320 | and I do want to acknowledge these critics,

01:45:19.320 | whoever they may be.

01:45:20.160 | I do have the advantage that I don't work

01:45:21.420 | in this exact field, and so I'm happy to stand

01:45:23.980 | toe-to-toe with those critics now and say that,

01:45:27.700 | at least in terms of an inheritance of reactions

01:45:31.920 | or adaptive or maladaptive traits to stress

01:45:35.640 | or to reward, you talked about nicotine before,

01:45:38.220 | passage of response to drugs of different kinds,

01:45:40.400 | not being specific to nicotine.

01:45:41.960 | It was sort of a more general passage

01:45:44.240 | of some sort of information related to reactions

01:45:48.660 | to chemicals present in nicotine but other drugs.

01:45:51.900 | I have long been irritated and a little bit tickled

01:45:58.440 | by the fact that people say, oh, you know,

01:45:59.900 | we have this system for stress that was really designed

01:46:02.180 | to keep us safe from lions and saber-toothed tigers.

01:46:05.940 | Sure, but the hallmark of the stress system

01:46:08.580 | is that it generalizes.

01:46:09.900 | I mean, if I get a troubling text message

01:46:12.000 | or if I suddenly see a dark figure in the hallway

01:46:14.440 | when I go to the bathroom at night that I don't recognize,

01:46:18.080 | both of those have the same generic response,

01:46:20.420 | which is the deployment of adrenaline

01:46:23.140 | in both brain and body, changes in the optics of the eyes,

01:46:26.240 | quickening of the heart rate.

01:46:27.400 | Stress is, by design, generic, and so one could imagine

01:46:30.980 | that a passage of some sort of stress resilience

01:46:33.840 | or a maladaptive passage to stress

01:46:36.820 | would be also somewhat generic,

01:46:38.320 | and that's actually advantageous overall.

01:46:40.960 | Same thing with the reward system.

01:46:43.300 | We essentially have one or two chemical systems of reward.

01:46:46.880 | I mean, there's the opioid system

01:46:48.160 | and there's the cannabinoid system,

01:46:49.560 | but in large part, anticipation and reward

01:46:51.920 | is governed by the dopamine circuits,

01:46:54.080 | and anticipation and reward of an ice cream cone for a kid

01:46:57.320 | is the same neural circuitry that's going to be repurposed

01:47:01.320 | when they get to reproductive age

01:47:03.180 | and they are anticipating creating children with their mate

01:47:05.740 | and assuming they want to do that,

01:47:06.960 | the dopaminergic system is going to be engaged.

01:47:08.680 | So ice cream, sex, you know, stress to weather,

01:47:13.680 | stress to famine, the biology of these more modal systems,

01:47:18.880 | especially in the nervous system are,

01:47:20.940 | again, I have to be careful with the words, by design,

01:47:23.180 | are certainly generic, and so I don't see the need

01:47:27.240 | for immense specificity.

01:47:29.320 | I mean, it's not like we're, well, COVID just happened,

01:47:32.040 | so could you imagine that there's the passage

01:47:33.640 | of a COVID-19 specific resilience?

01:47:36.620 | No, I think what would probably be passed along

01:47:38.920 | would be some sort of, if it does occur,

01:47:40.600 | would be some sort of resilience to viruses more generally,

01:47:44.220 | and that would be advantageous.

01:47:46.000 | - Right, so I agree, and this opens the question

01:47:50.120 | of what is the bandwidth of inheritance?

01:47:52.320 | How specific can it be that it makes sense

01:47:54.920 | for it to be specific?

01:47:56.480 | And in the case of C. elegans,

01:47:59.360 | the response can be very specific

01:48:01.360 | through this inheritance of RNAs,

01:48:02.800 | which are just sequence specific,

01:48:04.680 | they control one particular gene, okay?

01:48:09.160 | In other cases, it could be a very general response,

01:48:13.800 | and it's very interesting to think about it

01:48:16.800 | when we talk about inheritance of memories,

01:48:19.160 | which is the most interesting thing we could imagine.

01:48:21.880 | Can brain activity of some sort transmit,

01:48:25.720 | at least in these worms?

01:48:26.640 | I said, no, I said this disclaimer multiple times,

01:48:30.000 | in members we don't know, times we'll tell,

01:48:32.720 | in worms we know a lot,

01:48:34.640 | so can worms transmit brain activity,

01:48:37.560 | do they have the specificity to do it, okay?

01:48:40.240 | Before I'll say that, I'll just say that we,

01:48:42.320 | over the years, learned a lot about the mechanisms

01:48:45.080 | that shuttle the RNAs between generations.

01:48:47.980 | We know about genes that are needed just for that.

01:48:50.580 | About worms, it would be perfectly okay,

01:48:54.040 | but just don't have the capacity to transfer the RNAs

01:48:56.480 | to the next generations.

01:48:57.940 | We know about genes that will make the responses

01:49:00.560 | longer or shorter.

01:49:02.360 | We know about genes that prevent the transfer of RNA

01:49:05.300 | between different tissues.

01:49:06.680 | About genes that make certain small RNAs.

01:49:10.000 | So we know a lot about that.

01:49:11.360 | And then the question arises, we can finally ask,

01:49:14.840 | can memory transfer between generation?

01:49:16.800 | I think that, first of all,

01:49:19.500 | we need to define memory for this,

01:49:21.300 | and the broadest definition would be,

01:49:23.520 | any change in your behavior

01:49:25.820 | because of what happened in the past,

01:49:27.760 | or in your response because what happened in the past,

01:49:30.680 | or because of your history.

01:49:32.840 | The more interesting part, of course,

01:49:34.120 | is to talk about memories that are encoded in the brain.

01:49:37.080 | And the reason is that the brain is capable

01:49:39.280 | of holding much more specific and elaborate memories.

01:49:42.160 | I think that any tissues that transmit RNA

01:49:46.720 | to the next generation and affect the next generation,

01:49:48.720 | is interesting.

01:49:49.640 | The gut, muscles, everything.

01:49:51.600 | But the brain can synthesize information

01:49:55.880 | about the environment and about internal state,

01:49:58.780 | and can also think ahead.

01:50:00.540 | And the most provocative thing you can say

01:50:02.440 | is that you could plan how, somehow,

01:50:05.480 | the fate of your nation using your brain

01:50:08.760 | after taking many things into the code.

01:50:10.640 | - Without talking to them.

01:50:11.920 | - Right, without talking.

01:50:12.840 | - Right, and instruction.

01:50:14.040 | So it's, again, we go back to this instruction manual.

01:50:16.280 | It's like writing something into the instruction manual

01:50:18.560 | based on your own experience.

01:50:20.160 | - Right, and can it happen?

01:50:21.880 | And what is the bandwidth?

01:50:22.840 | Can we transfer specific things?

01:50:24.440 | And then I have to agree with you

01:50:28.000 | that I would imagine that what can transfer,

01:50:30.720 | and I could be wrong,

01:50:32.320 | is a general something, sensitivity.

01:50:37.320 | We can make the analogy to being inflamed or not,

01:50:43.080 | hypersensitive to pathogens, hypervigil, something like that.

01:50:48.360 | But it can also be something very specific.

01:50:50.480 | Now we have to understand that the brain

01:50:55.080 | uses a different language than the language of inheritance.

01:50:59.900 | The brain, the way we normally think about the brain,

01:51:02.440 | is that it keeps information in synapses,

01:51:07.440 | in the connections between different neurons.

01:51:09.600 | When you learn something,

01:51:11.080 | you make some connections stronger

01:51:12.660 | and other connections weaker,

01:51:14.840 | and you wire the nervous system in a different way.

01:51:18.600 | The information in the brain is synaptic,

01:51:20.920 | and it is in the connections.

01:51:22.720 | On the other hand, heritable information of any sort

01:51:26.520 | has to go through a bottleneck of one cell,

01:51:29.660 | the fertilized egg, because we all start from just one cell.

01:51:34.420 | So it cannot be in the connections,

01:51:36.200 | because this cell doesn't have any connections

01:51:37.900 | without the cell, they're alone.

01:51:39.800 | So heritable information has to be molecular,

01:51:42.640 | it has to be inside this one cell.

01:51:44.720 | So the question is, can you or do you

01:51:46.920 | translate information, this 3D structure information

01:51:50.520 | of synapses and the connection between brains

01:51:52.800 | in the architecture of the brain,

01:51:54.360 | can you somehow translate it to heritable information

01:51:57.200 | to a molecular form?

01:51:58.880 | - It's an incredibly important and deep question.

01:52:02.360 | It brings to mind something that was once told to me,

01:52:04.360 | which as soon as I heard it was obvious,

01:52:06.400 | but was very important in formulating

01:52:08.720 | my understanding of biology,

01:52:10.780 | which is that a map is just the transformation

01:52:15.440 | of one set of points into another set of points, right?

01:52:18.280 | So a map of the world essentially is just,

01:52:21.320 | you take what's been drawn out

01:52:23.560 | in terms of the architecture and the coastlines, et cetera,

01:52:26.520 | and divisions between states,

01:52:28.040 | and you transfer that to an electronic map

01:52:29.960 | or a piece of paper.

01:52:30.800 | Seems so obvious, it's sort of a duh,

01:52:32.440 | why are we talking about this?

01:52:33.920 | But just to make sure that people understand

01:52:35.580 | what you're really talking about is,

01:52:37.320 | let's say the memory, and I have a very distinct memory

01:52:40.080 | for my childhood phone number.

01:52:42.120 | Phone number doesn't exist anymore.

01:52:44.760 | And I won't give it out because then some other person

01:52:46.560 | might get you with repeated calls.

01:52:48.400 | But in any case, I remember it,

01:52:50.040 | it's totally useless information,

01:52:51.360 | but it lives in my neocortex or my hippocampus

01:52:54.120 | or somewhere as a series of connections between neurons

01:52:56.960 | at the locations as you call synapses.

01:52:59.080 | Would my grandchildren know that phone number?

01:53:02.640 | There's no reason for them. - Absolutely no.

01:53:04.160 | - No, right?

01:53:05.000 | Would my children know that,

01:53:06.040 | unless there was some adaptive reason

01:53:08.240 | or some other reason for them to know

01:53:09.880 | and this passage of acquired traits.

01:53:13.760 | And what you're saying is, in order for that to happen,

01:53:17.160 | there has to be a transformation of the neural circuit,

01:53:20.520 | literally the wiring of neuron A, B, C, D

01:53:22.560 | that relates and carries the information of that number,

01:53:25.520 | into the kind of nucleotide sequences

01:53:28.280 | that are contained in DNA or patterns of methylation

01:53:30.920 | or RNA more likely.

01:53:33.040 | So it's the transformation of one set of points

01:53:35.060 | in physical space to a translation of points

01:53:37.640 | in genetic space, is that right?

01:53:40.120 | - Right, and then we have many problems.

01:53:42.400 | First of all, we don't know a mechanism to translate

01:53:45.400 | between the two different languages,

01:53:47.160 | the language of the brain and the language of inheritance.

01:53:49.640 | We are not familiar with a mechanism like that.

01:53:51.600 | Second, the next generation, if it's not a worm,

01:53:56.000 | if it's a mammal, would have a different brain.

01:53:58.780 | Even if it was genetically identical to the parrot,

01:54:03.780 | the wiring of the brain

01:54:05.840 | and the particular neuronal circuits will be different.

01:54:09.940 | This is true for twins.

01:54:11.540 | It will always be true because it depends,

01:54:13.900 | because it's partially random

01:54:15.360 | and it depends on the environment,

01:54:16.700 | even if you have the same genetic instructions.

01:54:18.840 | So let's say you somehow had a mechanism,

01:54:22.280 | miracle mechanism, to take the 3D information

01:54:25.600 | and translate it to the language of inheritance.

01:54:28.460 | You would then in the next generation

01:54:29.800 | have to translate it again to the brain,

01:54:32.760 | although it is different.

01:54:34.240 | This sounds very unlikely.

01:54:35.760 | I'm playing a trick on you now, okay?

01:54:40.920 | - I believe it, I'm easy to trick, so that's good.

01:54:44.580 | - But if this is how it happened,

01:54:46.800 | or if this was required,

01:54:48.340 | it could never happen in my opinion.

01:54:50.560 | Which means, and I still think,

01:54:52.020 | that there are certain memories

01:54:53.180 | that cannot transfer transgenerationalities complex,

01:54:56.480 | and things that you learn about the environment

01:54:58.600 | that are arbitrary.

01:54:59.600 | None of our listeners' kids will remember this conversation.

01:55:05.180 | No way, this is impossible.

01:55:06.780 | - Unless they're listening with them.

01:55:08.620 | There are some families or parents

01:55:09.820 | that tell me they're listening.

01:55:11.480 | - But it cannot transmit because it's random,

01:55:14.520 | and these are connections that are arbitrary.

01:55:16.960 | So this seems to be a limitation of what can transfer.

01:55:21.200 | On the other hand, so perhaps more general things

01:55:25.680 | could pass, these type of things, I doubt they could pass.

01:55:29.220 | However, you can nevertheless imagine

01:55:32.480 | that some things that are very specific,

01:55:34.940 | some memories that are very, very specific,

01:55:37.160 | could nevertheless transmit from the brain

01:55:39.440 | after learning to the next generation.

01:55:41.320 | I'll give you an example.

01:55:42.960 | You can teach worms, even though they have just 302 neurons,

01:55:45.900 | you can teach them simple things about the world.

01:55:48.020 | For example, you can take an odor that the worms like.

01:55:50.480 | The worms have thousands of odorant receptors,

01:55:53.880 | and they can recognize many, many, many molecules.

01:55:56.700 | They can smell them so they can find food or avoid enemies.

01:56:00.300 | You can take an odor that the worms like,

01:56:03.680 | and pair it to something bad, like starvation.

01:56:06.920 | And then the worms will learn to dislike this odor.

01:56:09.480 | We don't know that this learning involves necessarily

01:56:14.840 | changing in the strength of synapses.

01:56:17.360 | It's a possibility, but it doesn't have to be the case.

01:56:19.920 | It could be that just the receptor for this particular odor

01:56:23.400 | is being removed, and this is how they live.

01:56:27.920 | Now they won't have the receptor, they won't smell,

01:56:29.680 | they won't like the odor.

01:56:30.880 | This is a possibility.

01:56:31.980 | This type of thing, you can perhaps,

01:56:36.080 | not that anyone has showed it convincingly,

01:56:38.600 | transmit to the next generation,

01:56:40.000 | because all it would take is an RNA

01:56:42.600 | that will control this particular receptor, okay?

01:56:46.680 | So this is a possibility.

01:56:48.320 | People have shown things like that, not in C. elegans,

01:56:51.320 | but people have shown things like this in mammals.

01:56:53.820 | They said that you learn certain thing,

01:56:56.840 | and then just in the next generation,

01:56:59.680 | that a particular receptor would be methylated

01:57:02.840 | or would change, and this would transmit the response.

01:57:06.100 | And on the one hand, it could be true.

01:57:10.100 | On the other hand, you need to understand,

01:57:12.680 | they'll need to prove,

01:57:13.580 | and this wasn't done convincingly enough yet,

01:57:16.460 | how exactly does the information transfer

01:57:18.540 | from the brain to the germ cells,

01:57:20.380 | and then in the next generation,

01:57:21.540 | from the germ cells back to the brain

01:57:23.260 | to where the receptor need to operate.

01:57:26.620 | And this is a challenge.

01:57:27.900 | This is the current state of the field

01:57:30.380 | that this is something that needs to be proven.

01:57:32.700 | What we didn't see, elegans,

01:57:34.380 | is we showed that the brain can communicate

01:57:38.860 | with the next generations using small RNAs,

01:57:41.340 | and that this can change behavior.

01:57:44.720 | And it doesn't require any translating between any language.

01:57:48.160 | It is very simple.

01:57:49.500 | What we've shown is that if you take a worm

01:57:52.300 | and you change the production of small RNAs

01:57:54.680 | just in its brain, in the next generations,

01:57:58.480 | their behavior will be different,

01:57:59.940 | even though you don't mess with their brains.

01:58:02.240 | This is a paper that we published in 2019 in Cell.

01:58:06.880 | We showed that you just manipulate the production

01:58:09.960 | of endogenous natural RNAs in the worm's brain

01:58:13.280 | that are always made, but you change their amount,

01:58:16.200 | and this changes the capacity of the worms

01:58:18.560 | in the next generation to find food,

01:58:20.680 | to find, not only in one generation,

01:58:23.640 | but three generations down the road.

01:58:25.920 | And the way that it works is that

01:58:28.600 | perturbing the production of these small RNAs in the brain

01:58:32.120 | affects in the end the expression of a gene in the germline.

01:58:37.000 | One gene is called SAGE2, don't know how it works,

01:58:40.840 | but we can do all kinds of controls

01:58:42.840 | where we manipulate the activity of the gene

01:58:44.380 | and see that this also affects behavior.

01:58:46.960 | And this gene works in the germ cells.

01:58:50.700 | The information needs to go from the brain to the germ cells.

01:58:53.120 | It doesn't need to go back from the germ cells

01:58:54.960 | to the brain to affect behavior.

01:58:57.040 | And this depends, we know that this is

01:58:59.200 | a true epigenetic effect because it goes on

01:59:01.440 | for multiple generations,

01:59:02.800 | and also because it requires the machinery

01:59:05.440 | that transfers RNAs between generations.

01:59:08.440 | If you don't have the protein that physically carries

01:59:10.720 | the RNA between generations, it doesn't happen.

01:59:12.620 | - So it has to be RNA.

01:59:14.460 | - It has to be RNA.

01:59:15.560 | And we can actually, we can also find the RNAs

01:59:18.720 | in the next generation that change.

01:59:20.400 | We sequence the actual RNAs that change

01:59:22.960 | in the next generation.

01:59:24.360 | - You mentioned that you don't know what SAGE,

01:59:26.960 | this gene SAGE does, but is it reasonable to assume

01:59:29.800 | that it does something in the context of the nervous system

01:59:32.240 | or that's unclear as well?

01:59:33.480 | - It is possible, it is possible,

01:59:35.120 | but we have reasons to believe or experiments to show,

01:59:40.120 | although there could be alternative explanations,

01:59:42.920 | that it functions for the germ line.

01:59:45.000 | Now you may ask, how can you affect behavior

01:59:48.100 | just by changing the germ cells, right?

01:59:50.140 | - Well, it would have to change the germ cells

01:59:51.960 | in very specific ways because as people probably recall,

01:59:55.400 | the germ line, the germ cells are where

01:59:58.280 | the inheritable information is contained,

02:00:00.680 | but you can imagine it, for instance,

02:00:02.560 | adjusting the gain or sensitivity rather

02:00:07.560 | on some sort of sensory foraging system, right?

02:00:12.560 | - Right, and the interesting thing is

02:00:16.000 | it again can be quite unspecific.

02:00:18.960 | So it sounds weird that you change germ cells

02:00:22.560 | and it changes behavior, sperm and egg,

02:00:24.440 | but if you think about it, it's trivial.

02:00:26.440 | If you castrate a dog, it behaves differently, right?

02:00:30.180 | - Sadly, yeah, I did that to my dog

02:00:31.920 | and I ended up putting him on testosterone therapy later

02:00:34.080 | and it brought him back, just as an aside.

02:00:37.720 | - Yes, this is because the germ cells affect the soma,

02:00:41.140 | including the brain, in many ways

02:00:43.320 | by secreting certain chemicals.

02:00:45.880 | And also because the other cells develop

02:00:49.540 | from the germ cells, so some information

02:00:52.120 | could be transmitted over development

02:00:54.480 | or the course of development could be altered

02:00:56.920 | because of changes that occur in the germ cells.

02:01:00.100 | For example, in mammals, one of the explanations

02:01:03.360 | for how inheritable information transmits

02:01:05.880 | is that it just affects something very own in development.

02:01:10.120 | I told you that the secret to worm's inheritance

02:01:13.700 | is that they have the capacity to amplify

02:01:15.500 | these small RNAs all the time.

02:01:16.980 | This is what keeps it going, prevents the dilution.

02:01:20.720 | In mammals, we don't know of such an amplification mechanism

02:01:23.280 | so you ask, how can a little bit of RNA or something

02:01:26.840 | without amplifying affect the entire organism?

02:01:29.920 | And it could be that you just perturb something

02:01:32.900 | in the very beginning, when you just have a few cells

02:01:36.160 | or even in the placenta that develops in pregnancy

02:01:39.720 | and this later throws everything off

02:01:42.240 | and because of that, you have many problems

02:01:44.440 | in metabolism and so on.

02:01:46.320 | And this is called, it's an idea

02:01:48.200 | of the developmental origin of health and disease.

02:01:51.640 | Many of the functions occur early on in development.

02:01:55.520 | - So you raised a number

02:01:56.360 | of incredibly fascinating aspects to this.

02:01:58.680 | I do have a question about one particular aspect

02:02:01.000 | and feel free to pass on this for a future episode

02:02:03.200 | if it's going to take us too far off track.

02:02:05.080 | But something you said, it really captured my attention,

02:02:09.860 | although I was listening to all of it,

02:02:11.020 | which is that the germ cells,

02:02:12.680 | so in the case of males, it's going to be sperm

02:02:15.560 | and in the case of females, it can be eggs.

02:02:18.240 | Something perhaps not coincidental about those cells

02:02:21.740 | and the environment that they live in is that yes,

02:02:25.240 | they contain the genetic information

02:02:26.920 | that passed to offspring, right?

02:02:28.200 | Of course you explained how that works,

02:02:30.480 | but also those cells live in a region

02:02:35.480 | that is rich with hormones that can be secreted

02:02:39.000 | and in fact are secreted

02:02:40.300 | and through so-called endocrine signaling,

02:02:42.780 | communicate with other cells,

02:02:44.980 | not just at the level of receptors on their surface,

02:02:47.120 | but also can enter the genomes of those cells

02:02:49.040 | and modify those cells.

02:02:50.480 | In other words, it seems to me that the microenvironment

02:02:52.960 | of the germ cells, the testes and the ovaries

02:02:55.960 | are rich with information,

02:02:58.260 | not just for the passage to next generations,

02:03:00.220 | but also for all the, as you said,

02:03:02.240 | all the somatic cells of the body,

02:03:03.880 | they're telling the somatic cells of the body

02:03:05.640 | what to do and what to become.

02:03:06.480 | And the best example I can think about this

02:03:08.340 | would be puberty, right?

02:03:09.560 | I mean, I would argue that one of the greatest rates

02:03:13.880 | of aging and transitions we go through in life

02:03:16.720 | is from puberty.

02:03:17.560 | I mean, a child becomes a very different person

02:03:19.440 | after puberty.

02:03:20.280 | They look at the world differently.

02:03:21.400 | They think about it differently.

02:03:23.160 | It's not just about the growth of the hair and the jaw

02:03:24.840 | and the atoms, apple and breasts and so on.

02:03:27.100 | It's a transformation of the somatic cells

02:03:30.640 | from the same microenvironment

02:03:32.400 | that the DNA containing cells reside.

02:03:36.400 | - Right, so once you think about it like this,

02:03:38.520 | it becomes obvious that just by affecting the germ cells,

02:03:41.520 | you can affect the rest of the body.

02:03:43.360 | And in C. elegans, there are experiments

02:03:44.920 | that show it very clearly.

02:03:45.980 | So for example, if you just take worms

02:03:49.000 | and prevent sperm production,

02:03:51.980 | it changes the capacity to smell.

02:03:54.100 | These are experiments done by others,

02:03:57.180 | which is obviously a brain function.

02:04:00.480 | - And in a castrated dog,

02:04:01.640 | you're not just eliminating the possibility

02:04:03.600 | of transfer of DNA information to subsequent generations.

02:04:07.200 | You're also limiting communication of, yeah.

02:04:09.560 | Oh, without question, my bulldog, Costello,

02:04:11.520 | changed after castration and was a wonderful dog,

02:04:14.640 | but at some point developed some health issues.

02:04:16.420 | The introduction of a small amount of testosterone

02:04:18.800 | every other day changed him fundamentally,

02:04:22.040 | in that case for the better,

02:04:23.940 | back to a version of himself

02:04:25.580 | that I had only observed earlier,

02:04:26.800 | but also a different version of the same dog.

02:04:28.660 | And no, he wasn't humping everything,

02:04:30.220 | maybe the occasional knee,

02:04:32.120 | particular people whose names I won't mention.

02:04:34.360 | But it was absolutely clear that the hormone

02:04:37.680 | was not just taking a system and amplifying it.

02:04:40.660 | It was actually modifying the system.

02:04:42.840 | So anyway, I just wanted to highlight that.

02:04:44.920 | And then now, thank you for indulging me.

02:04:47.340 | Let's, if you will,

02:04:49.120 | let's continue down this path that we were going on,

02:04:52.400 | because I want to make sure

02:04:53.220 | that we absolutely get to this issue

02:04:54.960 | of transmission of information

02:04:56.760 | about sex choice of offspring.

02:04:59.040 | - So the worms are hermaphrodites,

02:05:01.560 | which means that they make both sperm and eggs.

02:05:04.520 | But there are also males, which are much more rare,

02:05:07.000 | and they can choose to mate with the males or not.

02:05:11.200 | And when they mate with the male, it's a huge decision,

02:05:14.720 | because it's very costly, energetically,

02:05:17.840 | and they also risk predation and all kinds of troubles.

02:05:22.060 | The males hurt them and reduce their lifespan

02:05:24.400 | when they mate with them.

02:05:25.540 | - People are gonna draw all sorts of analogies here,

02:05:27.700 | but it's inevitable, but hey, here we go.

02:05:29.560 | - Yes, and most importantly for evolution,

02:05:33.680 | when you mate with another animal,

02:05:36.520 | you dilute your genome in half,

02:05:39.200 | 'cause the worms can just self-fertilize

02:05:41.280 | and transmit the exact same genome to the next generation,

02:05:43.760 | but when they mate, they dilute it in half.

02:05:45.800 | So this is a big price to pay.

02:05:48.560 | On the other hand, when you mate, you diversify your genome.

02:05:51.560 | So maybe some combination of gene will be good.

02:05:54.280 | - And we know that in humans, I mean,

02:05:56.160 | it's kind of interesting that the brain circuits

02:05:57.920 | that are associated with aversion and with approach

02:06:02.000 | are fairly hardwired for a number of things,

02:06:05.040 | like puddle of vomit, almost everybody kind of cringes,

02:06:07.440 | a plate of cookies, if you like cookies, you move towards it.

02:06:10.400 | But there's one particular word in the English

02:06:13.160 | and presenting the Israeli language

02:06:14.280 | that ought to evoke disgust, and that's incest,

02:06:17.920 | because incest is actually not just disgusting

02:06:20.280 | as a practice, but it's dangerous genetically, right,

02:06:22.920 | because inbreeding creates a deleterious mutation.

02:06:25.600 | - Right, so there are studies of how people

02:06:27.200 | in Israeli kibbutz, for example,

02:06:29.120 | where they all grow together, the children live together,

02:06:31.560 | it used to be like that, don't date each other,

02:06:34.600 | 'cause this is their classic thing.

02:06:36.080 | I talked to some of them, the kibbutz told me

02:06:37.560 | that's not true, but yes, there are studies like this

02:06:39.760 | that say, but it makes sense.

02:06:41.280 | - And in some countries, Scandinavian countries,

02:06:43.080 | or in Lapland and Iceland where populations are small,

02:06:45.920 | they keep exquisite records of lineage

02:06:48.320 | in order to avoid inbreeding.

02:06:50.040 | - Right, right, so you're absolutely right.

02:06:52.040 | But the worms, it's the safe choice for them

02:06:54.880 | is to self mate, and if they mate with a male,

02:06:58.520 | they take a risk, but they diversify, okay?

02:07:02.560 | What we found is that if you take the hermaphrodites,

02:07:07.120 | we can call it the female for just one second,

02:07:10.240 | and you stress it with high temperatures,

02:07:12.680 | then the next generations of worms, for three generations,

02:07:18.220 | mate much more with males, and they do it

02:07:21.280 | because the female starts secreting a pheromone

02:07:23.760 | that attracts the males.

02:07:25.520 | - Ah, that's a very cryptic mechanism.

02:07:28.600 | It's not that she somehow changes and then goes seeking males

02:07:31.360 | it's that it draws males in.

02:07:32.760 | - It draws males, and we know how it works.

02:07:34.440 | We think we know how it works.

02:07:35.480 | What happens is that the stress, the high temperatures,

02:07:38.720 | compromise the production of sperm in the hermaphrodites.

02:07:42.360 | So the hermaphrodite don't, they make sperm enough

02:07:44.720 | to make generations, but the sperm,

02:07:47.280 | because of defective small RNA inherited,

02:07:50.160 | 'cause RNAs are not inherited, okay?

02:07:52.400 | The sperm is not made optimally, so they make less sperm.

02:07:56.240 | And when they don't make a lot of sperm,

02:07:58.920 | they feel that they don't self-fertilize correctly,

02:08:01.580 | so they call the males by secreting the pheromones

02:08:04.340 | so that it would provide its own sperm

02:08:06.840 | and they can continue to make babies, okay?

02:08:09.560 | And we know this also from experiments,

02:08:11.080 | you just take hermaphrodites and you kill its sperm,

02:08:13.480 | starts secreting the pheromone, and the males come.

02:08:15.640 | - It's a need-based system. - Exactly, exactly.

02:08:18.600 | - Incredible.

02:08:19.440 | And I hope people can appreciate as they're hearing this

02:08:21.480 | that none of this, we assume,

02:08:24.480 | I don't know how to speak worm,

02:08:26.520 | none of this, we assume, is a conscious decision

02:08:29.460 | in these animals, much like human mating behavior,

02:08:32.200 | which to us always seems so conscious,

02:08:34.140 | but is being governed by both conscious

02:08:35.920 | and subconscious decision-making.

02:08:37.980 | None of this is an active decision

02:08:40.960 | to secrete the hormone to draw in more males.

02:08:44.240 | It's simply a biasing of probabilities, right?

02:08:46.920 | The hormone is now secreted in greater quantities

02:08:49.640 | or greater frequency, the males therefore approach more,

02:08:52.800 | so it's just increasing probability of interactions.

02:08:55.160 | Is that right?

02:08:56.000 | - What happens, naturally, normally,

02:08:57.760 | if you don't stress the ancestors,

02:09:00.080 | is that the worm starts secreting the pheromone

02:09:02.360 | only when they are old.

02:09:03.880 | It's also, you know, people will-

02:09:05.720 | - When they're running out of their own fertility.

02:09:08.840 | - Exactly, because they only make the sperm

02:09:10.880 | at a particular time, and then they run out of stem,

02:09:14.560 | they can self-fertilize, so they have to call the males

02:09:16.800 | if they want to continue to mate.

02:09:18.520 | - Well, this is sort of the plastic surgery approach.

02:09:21.720 | Okay, I'll take the heat for that one.

02:09:23.120 | But, you know, but it's true, I think as certain people age

02:09:26.240 | to a certain point and they feel

02:09:27.320 | that their fertility is waning, if they want offspring,

02:09:30.400 | they need to take any number of different approaches.

02:09:32.460 | They could get a, here we're talking about a female,

02:09:34.360 | but we could also do the reverse, right?

02:09:37.200 | Sperm donor, right?

02:09:38.520 | But if they want to attract a lifelong mate

02:09:40.200 | or co-parent with somebody, oftentimes they will do things

02:09:44.120 | to adjust their attractiveness

02:09:46.120 | in any number of different ways,

02:09:47.080 | psychological attractiveness or physical attractiveness.

02:09:49.960 | I'm not afraid to bring this up

02:09:51.000 | because I think that the parallels are very important

02:09:53.260 | because I do think that every species

02:09:56.240 | and individuals within a species, of course,

02:09:58.180 | decides whether or not they want to reproduce or not,

02:10:00.240 | but has an inherent understanding, conscious or subconscious,

02:10:04.400 | about where they reside in the arc of their lifespan.

02:10:06.740 | I do believe that, not just based on experience.

02:10:09.480 | Some people are very attuned to the passage of time

02:10:12.760 | being very fast, others very slow.

02:10:15.000 | I think that knowing how long your parents

02:10:17.040 | and their parents lived makes a big difference.

02:10:19.340 | I have friends whose fathers in particular

02:10:21.660 | died fairly young, and all these guys basically got married

02:10:24.680 | and had kids really young.

02:10:26.200 | - Right, so here, luckily for me,

02:10:28.540 | I don't have to get into psychology of the worms.

02:10:31.020 | The explanation is just like an instinct.

02:10:33.660 | When they run out of sperm,

02:10:34.820 | they start secreting the pheromones and attract the males.

02:10:37.240 | There are studies also in humans about older fathers,

02:10:41.200 | that children of older fathers have more,

02:10:44.120 | has a higher chance of becoming autistic.

02:10:47.700 | - 40 and up, basically.

02:10:49.760 | - However, in this case, it's not clear

02:10:51.540 | that this is not, that this is something epigenetics

02:10:53.880 | could be just because of DNA damage,

02:10:56.040 | because it accumulates.

02:10:58.520 | - And actually nowadays there,

02:10:59.920 | we have an episode on fertility coming up,

02:11:01.560 | both male and female fertility.

02:11:02.780 | And there are actually DNA fragmentation kits for,

02:11:06.960 | at home DNA fragmentation kits are sperm analysis.

02:11:09.280 | You send the sperm back in, you don't get the DNA.

02:11:11.400 | People pipetting semen at home would be an odd picture.

02:11:14.680 | Let's not go there.

02:11:15.760 | But there are clinics that do this for a nominal charge.

02:11:20.340 | But it's, I did want to ask about autism

02:11:24.160 | and human disease in particular.

02:11:25.680 | Another thing that you hear sometimes,

02:11:27.340 | and here I want to acknowledge autism is on a spectrum.

02:11:29.560 | Some people get upset if you call it a disorder.

02:11:31.520 | There are some adaptive autistic traits and et cetera.

02:11:34.060 | But one thing that often comes up is this idea

02:11:37.700 | that two people who are more of the kind of engineering,

02:11:42.280 | hard science, if you will, of phenotype,

02:11:44.900 | mate and have children,

02:11:46.280 | higher probability of the offspring being on the spectrum.

02:11:50.480 | Some people would argue, ah,

02:11:51.660 | but that's already selecting for people

02:11:53.120 | that might've already been partially on the spectrum.

02:11:55.060 | So maybe it's a gene copy issue.

02:11:56.680 | I'm not asking you to comment on autism in particular,

02:11:59.380 | but when you hear things like that,

02:12:01.560 | that the children of older fathers,

02:12:03.920 | born from older fathers,

02:12:06.000 | tend the higher probability of autism,

02:12:08.500 | what does that, at the level of intuition,

02:12:11.540 | does that strike you as an epigenetic phenomenon,

02:12:14.020 | as a nurture mishmash,

02:12:16.800 | or the possibility that it's RNA passage or anything?

02:12:20.080 | Does anything sort of trigger the whiskers,

02:12:23.400 | your spidey sense?

02:12:24.880 | - So in that case,

02:12:25.800 | I would go with the most parsimonious explanation,

02:12:28.480 | which is just less fidelity of DNA,

02:12:33.360 | less DNA maintenance and some damage that passes on.

02:12:36.680 | It doesn't have to be an epigenetic thing.

02:12:39.420 | - But the sperm are generated at once every 60 days.

02:12:42.240 | So the damage must be at the level of the germ cells

02:12:45.080 | not having the proper machinery?

02:12:46.960 | - Right.

02:12:47.800 | - Mitochondria or something like that?

02:12:48.640 | - Or the DNA repair machinery.

02:12:50.780 | The DNA repair machinery could be defective

02:12:53.560 | or could work less well in older people,

02:12:57.020 | leading to the constant production of germ cells

02:13:00.100 | with more mutation.

02:13:00.940 | This is a possibility.

02:13:01.900 | - Do we know exactly what the DNA repair machinery is?

02:13:04.680 | - Yes.

02:13:05.520 | There are many types of DNA repair.

02:13:07.680 | There's one that use other copies of the DNA

02:13:11.880 | to correct.

02:13:15.240 | There are ones that just recognize all kinds of lesions

02:13:17.880 | on the DNA and remove it.

02:13:20.880 | It's a very elaborate and complicated system.

02:13:23.720 | - And is it a system that is now tractable

02:13:25.600 | that can be modified through pharmacology

02:13:28.520 | or through anything like that?

02:13:29.880 | - So I don't know about drugs that improve it.

02:13:33.480 | Maybe they exist and I'm not aware,

02:13:35.800 | but it's very well understood

02:13:37.680 | and many people have studied these directions.

02:13:40.440 | - Yeah, one thing that came across

02:13:42.380 | in the exploration of the fertility work

02:13:45.560 | is that what I'm about to describe is not legal in the US.

02:13:49.980 | It is illegal, but is legal in the UK

02:13:52.080 | and in other countries is this notion of three parent IVF,

02:13:55.560 | where it does seem that some of the eggs

02:13:58.060 | that persist in older females don't,

02:14:01.000 | even if fertilized, don't produce healthy embryos,

02:14:04.860 | they have chromosomal abnormalities or replications

02:14:07.540 | and deletions that are problematic for the development

02:14:10.940 | of the embryo, such as trisomy 21, AKA Down syndrome,

02:14:15.940 | in part or in large part because of deficits

02:14:18.460 | in the mitochondrial genome.

02:14:19.780 | So what they now do is they take the,

02:14:21.820 | because the mitochondrial genome resides mainly

02:14:23.940 | in the cytoplasm, they'll take an egg from the mother,

02:14:27.500 | the sperm from the father,

02:14:28.620 | but they'll take the nucleus from the mother

02:14:32.020 | and put that into a cytoplasm of a younger woman

02:14:36.500 | whose mitochondrial DNA is healthy,

02:14:38.260 | then use the sperm to fertilize that egg,

02:14:41.960 | and that's why it's called three parent IVF,

02:14:43.620 | then implant that into the mother.

02:14:45.220 | And this has been done several times

02:14:46.980 | for in cases of mitochondrial damage

02:14:49.220 | or mutations in the mother.

02:14:52.300 | It works, the question is whether or not

02:14:54.180 | those offspring will grow up to be healthy.

02:14:56.160 | So this, of course, is not just a pure divergence.

02:14:59.060 | It raises a bigger question that I have for you,

02:15:00.940 | which is in terms of the work in either C. elegans

02:15:05.480 | or in other model organisms,

02:15:06.860 | but in particular in C. elegans,

02:15:09.040 | where do you see this going next?

02:15:10.820 | And if you would indulge us,

02:15:12.580 | I would love for you to tell us a little bit

02:15:13.920 | about the admittedly unpublished work that you're doing

02:15:16.680 | on temperature exposure and environments.

02:15:20.020 | I mean, how malleable is this system?

02:15:22.020 | Because to me, it just seems incredibly malleable,

02:15:25.820 | and yet a lot of it's still cloaked off to us.

02:15:28.500 | There's still a ton to learn.

02:15:29.780 | - So assuming that we will discover similar things

02:15:34.300 | in humans, which we don't know that this is the case,

02:15:36.900 | but let's say we find it.

02:15:38.600 | I think there are many things you can do

02:15:39.960 | before you change it.

02:15:42.120 | For example, you could also change aberrant inheritance

02:15:47.120 | by having the parent exercise, for example.

02:15:52.200 | And some things like this have been done.

02:15:54.140 | For example, there are experiments in rodents

02:15:57.080 | where they show that overfeeding the rodents

02:16:01.600 | creates problems for the next generations,

02:16:03.340 | for the children.

02:16:05.300 | However, if you let the rodent exercise,

02:16:09.700 | then it corrects the aberrant inheritance.

02:16:11.740 | So this is one possibility.

02:16:13.180 | And you can also manipulate it at the source.

02:16:16.940 | You can change if it's RNAs.

02:16:18.900 | Let's say you could, in the future,

02:16:20.380 | perhaps if we understand how it works,

02:16:22.300 | actually change the composition of the heritable RNAs.

02:16:24.960 | - By eating RNAs just like the worms?

02:16:26.700 | A RNA sandwich?

02:16:27.700 | - No, so the RNA sandwich will be difficult

02:16:29.820 | because it's not, I don't know,

02:16:32.220 | but if you do IVF, if you're doing vitro fertilization,

02:16:35.500 | you could perhaps change the composition of the RNAs

02:16:38.740 | in the stuff that you introduce.

02:16:40.860 | But way before that, what you could do,

02:16:44.340 | perhaps even in the not so far future,

02:16:46.820 | is use this for diagnostics.

02:16:49.860 | DNA-based diagnostics for every couple

02:16:53.260 | that wants to have a kid.

02:16:54.500 | In Israel, this is done for most couples.

02:16:58.340 | You can look at the DNA and look for genetic disease.

02:17:01.980 | But no one is looking at the RNA at the moment.

02:17:04.580 | If we understand how it works better,

02:17:06.220 | we'll have another level, a whole new world to look at.

02:17:09.380 | And perhaps there will be some RNAs

02:17:11.200 | that correlate with disease that will say,

02:17:14.340 | okay, the beauty is that this, unlike DNA, it's plastic.

02:17:18.580 | So with DNA, this is your DNA,

02:17:19.980 | perhaps we can choose another embryo.

02:17:22.340 | But here you could say, perhaps,

02:17:24.940 | or again, in the future, this is science fiction,

02:17:26.640 | doesn't happen now, but if we understand this and it's true,

02:17:29.100 | we can say, maybe you should run on the treadmill

02:17:32.460 | a little bit, this will change the profile of your RNAs,

02:17:34.760 | and then we will use it for IVF.

02:17:37.360 | This seems more, because just it correlates

02:17:40.000 | with healthy profiles of RNAs.

02:17:42.380 | This is a level that no one looks at now

02:17:44.220 | and holds great potential.

02:17:46.700 | Again, with a disclaimer that we don't know

02:17:48.740 | how it works in humans at all.

02:17:50.380 | - Yeah.

02:17:51.220 | - Yes.

02:17:52.060 | But of course, this is why it's so interesting.

02:17:54.540 | - Yeah, it's super interesting, incredibly promising.

02:17:57.980 | So along the lines of things that one can do

02:17:59.940 | in the short term, and your experiments on C. elegans,

02:18:04.780 | I'd love for you to share with us what you're observing

02:18:07.460 | about cold exposure and how that impacts

02:18:10.620 | subsequent generations of C. elegans.

02:18:12.960 | And if you would indulge us with the story

02:18:16.060 | of this discovery, like some of the earlier stories

02:18:19.340 | you told us, it is a surprising and fascinating one.

02:18:22.220 | - I'll gladly tell you about it.

02:18:23.460 | This is not a story about transgenerational inherent.

02:18:25.820 | It's a story about memory within one generation.

02:18:28.220 | - Ah, excuse me, okay.

02:18:29.060 | - Within one generation, okay?

02:18:30.740 | And as you said, the story of how it happens

02:18:33.300 | is totally by accident, it's a funny story.

02:18:36.500 | And I'm bringing this up because I know Donna Landshaft

02:18:39.660 | who is a huge fan of your postdocs will really be happy.

02:18:43.220 | - This is her work.

02:18:45.020 | - This is her work and this is unpublished work.

02:18:47.180 | We didn't even finish it, so we're working on it.

02:18:50.180 | - Okay, well, when it's published, we will feature the paper

02:18:52.420 | 'cause I love this story.

02:18:53.980 | - Oh, thanks a lot, thanks a lot.

02:18:55.420 | Great, so what happened is that when you,

02:18:58.900 | we talked about transgenerational memories

02:19:00.660 | and I said that in worms,

02:19:02.700 | there are very long transgenerational memories.

02:19:04.780 | If a generation time for C. elegans is three days,

02:19:08.300 | some memories last for many generations,

02:19:11.380 | so way beyond the lifespan of the worm.

02:19:13.980 | The lifespan of the worm is three weeks, okay?

02:19:16.980 | You have a new generation every three days,

02:19:18.700 | but every worm lives for three weeks.

02:19:20.540 | But there's a lot of research that shows

02:19:22.980 | that unlike heritable memory, which can be very long,

02:19:26.220 | the memories that the worms acquire during the lifetime

02:19:29.380 | is very short-lived.

02:19:30.940 | So if you teach something, after two hours, it forgets.

02:19:34.000 | So for example, you can teach the worm,

02:19:38.060 | you can take an order that it likes

02:19:40.620 | and pair it with starvation

02:19:42.380 | and then it would dislike the order.

02:19:44.500 | And then there's a simple test, you just put it in a plate,

02:19:47.220 | you put the order in one side

02:19:49.200 | and the control order in the other side

02:19:50.500 | and you see whether it prefers this order or not

02:19:52.300 | and it stops preferring it, okay?

02:19:54.280 | There is 30 years or more of research,

02:19:57.620 | 40 years of research on this,

02:19:59.380 | showing that the worms forget after two hours.

02:20:02.540 | The reason I went to study C. elegans

02:20:04.380 | is that I wanted to understand memory

02:20:06.220 | because such a simple nervous system,

02:20:07.980 | you say maybe I have the potential

02:20:09.020 | to actually understand how it works.

02:20:10.580 | But this is slightly disappointing

02:20:11.900 | because they forget after two hours.

02:20:13.060 | So what is it exactly, okay?

02:20:14.460 | My idea was, and I tried to convince students

02:20:18.340 | to do it for 10 years, is to take the worms,

02:20:21.460 | teach them this association to dislike the order

02:20:24.220 | that they innately like,

02:20:25.340 | and then just put the worms in minus 80 and freeze them,

02:20:29.620 | freeze them completely,

02:20:31.140 | thaw them and see whether they still remember

02:20:33.180 | after their thought.

02:20:34.220 | - The Han Solo experiment.

02:20:35.980 | - And I didn't want to do it

02:20:37.180 | because of cryopreservation or something like this.

02:20:39.900 | I wanted to do it because, as you know better than me,

02:20:42.620 | many theories about memory

02:20:44.420 | say that you need electrical activity

02:20:46.180 | to maintain the memory,

02:20:47.380 | need to reverberate it in the brain.

02:20:48.900 | During dreams or replay of the thing or whatever.

02:20:52.580 | - And if the memories will nevertheless be kept,

02:20:54.980 | even though the worms were frozen in minus 80,

02:20:58.940 | it would mean that it was kept in the absence of electricity

02:21:03.660 | because there was no electricity in minus 80 degrees.

02:21:06.340 | This was the idea.

02:21:07.620 | I asked many students, no one wanted to do it

02:21:09.900 | because it's not so easy and also a little crazy.

02:21:12.820 | - Well, and when the PI, the principal investigator

02:21:15.260 | or lab has a pet experiment,

02:21:16.540 | no one wants to do that experiment.

02:21:17.380 | - That is true, that is the university tool.

02:21:19.620 | So, and then I agreed to do it, Dana Landshaft.

02:21:23.180 | I was very happy only later to find out

02:21:25.820 | that she ignored me completely

02:21:27.260 | and did a different experiment.

02:21:29.420 | The experiment that Dana did instead

02:21:32.660 | is to just take the worms, teach them the association

02:21:35.620 | and place them on ice.

02:21:37.300 | She wanted to see how the kinetics of memory

02:21:39.980 | and forgetting change in low temperature

02:21:43.140 | because maybe whatever memory is,

02:21:48.140 | the breakdown of the memory is affected by the temperature.

02:21:51.740 | A very simple idea.

02:21:54.500 | - Different experiment.

02:21:55.660 | - A different experiment, but a cool experiment.

02:21:58.540 | - Very cool.

02:21:59.580 | - And what she found is that when you place the worms on ice

02:22:03.060 | after you teach them, they just don't forget.

02:22:05.220 | If they're even 10 times longer than control worms.

02:22:08.940 | At that point, after 24 hours,

02:22:10.660 | if no one wants to forget after two hours,

02:22:12.740 | after 24 hours, the worms will become sick.

02:22:14.500 | So normally we do shorter experiments, okay?

02:22:16.940 | But for two hours, the worms don't forget.

02:22:19.380 | This is cool, but it was only the beginning

02:22:21.380 | because the boring explanation is just what I just said,

02:22:26.980 | that everything slows down in low temperatures.

02:22:29.020 | So the breakdown of memory, again, we don't know what it is,

02:22:31.300 | but whatever it is, happens slower in low temperatures.

02:22:35.060 | But this is not the case.

02:22:36.060 | It's not merely the physical, it's the response,

02:22:38.300 | it's the changing of the internal state of the worms

02:22:40.900 | which affects the memory kinetics.

02:22:42.380 | How do we know this?

02:22:43.660 | There's a beautiful work over the last one years

02:22:46.020 | on cold tolerance in C. elegans nematodes.

02:22:49.780 | If you take the worms and you place them on ice,

02:22:52.820 | like she did, but longer, for 48 hours, they all die.

02:22:55.820 | However, if you take the worms,

02:22:58.940 | acclimate them to lower temperatures for a few hours,

02:23:03.100 | five hours is the minimum,

02:23:04.420 | and then place them on ice, they all survive.

02:23:07.020 | They become cold tolerant and people who study this show

02:23:09.260 | that this involves changes in lipid metabolism

02:23:12.100 | and many things.

02:23:12.940 | So Dana took the worms, acclimated them

02:23:16.620 | to slightly lower temperatures, made them cold resistant,

02:23:20.740 | and then taught them their association

02:23:22.740 | and placed them on ice, and now they forgot immediately,

02:23:26.900 | which means that when they change their internal state

02:23:29.300 | to become cold tolerant,

02:23:31.100 | they no longer extend memories on ice,

02:23:32.980 | which means it's not only the temperature

02:23:34.300 | because the temperature was in any way low.

02:23:36.100 | Now they know the memory.

02:23:37.580 | We took this as a starting point to understand

02:23:39.940 | which genes change when the worms are becoming

02:23:43.020 | cold tolerant on and off ice.

02:23:44.700 | And we found genes that when you mutate them,

02:23:47.540 | the worms just remember longer always,

02:23:50.220 | even when they're off ice,

02:23:51.420 | because these are the genes that normally change

02:23:53.100 | when they are surprised on the ice.

02:23:55.580 | And these genes are expressed just in one pair of neurons,

02:23:59.860 | just two out of the 302.

02:24:02.180 | - Notice he said 302, not 300.

02:24:04.140 | - And we can manipulate the activities of these genes

02:24:08.060 | in these neurons to extend memory.

02:24:10.740 | And then the punchline of everything that happened

02:24:16.380 | is that we found out that this neuron,

02:24:19.380 | where these genes function, this one pair of neuron,

02:24:22.500 | is the only neuron in C. elegans

02:24:24.380 | which is sensitive to lithium.

02:24:26.700 | Lithium is a drug that is being given

02:24:31.180 | to bipolar disorder patients for decades,

02:24:35.580 | although it's not entirely clear how it works.

02:24:37.260 | It's very, very interesting.

02:24:39.060 | It's also interesting.

02:24:39.900 | There's an episode, of course, in your podcast about this.

02:24:42.100 | You know more about this than me a lot,

02:24:43.860 | but it's also interesting because it's just an atom

02:24:45.860 | created in the big bang,

02:24:47.020 | yet it works on our brains in such a fundamental way.

02:24:50.340 | And we wanted to see whether it works also on the worm

02:24:52.700 | because this neuron was tied

02:24:54.500 | to this memory extension phenotype that we found.

02:24:57.100 | So Dana grew the worms on lithium,

02:24:59.780 | removed them from lithium,

02:25:01.180 | got them the association and found out

02:25:04.660 | that they remember a lot longer than control worms.

02:25:09.460 | Not only that, if you first make the worms cold tolerant,

02:25:12.700 | and then lithium doesn't work on them.

02:25:15.460 | So lithium switches this forgetfulness mechanism on and off.

02:25:19.980 | - Amazing.

02:25:20.820 | - And it's all connected to cold tolerance.

02:25:23.620 | - Amazing and amazing for a number of reasons.

02:25:28.300 | And so at risk of being long-winded in my response,

02:25:30.900 | I just wanted to highlight something

02:25:33.120 | that I think will be of relevance to most people,

02:25:35.360 | which is when at some point

02:25:37.480 | we did a few episodes on memory

02:25:39.400 | and I highlighted a review

02:25:42.020 | that was written by the great James McGaugh,

02:25:43.560 | one of the great mammalian memory researchers

02:25:45.440 | who's worked a lot on humans and mice.

02:25:47.580 | And I was shocked, pun intended,

02:25:50.920 | and amused to learn that in medieval times,

02:25:53.980 | if people wanted children to remember lessons,

02:25:56.760 | they could be religious lessons or school doctrine

02:25:58.680 | or whatever it was, mathematics,

02:26:00.320 | they would take children, teach them,

02:26:03.040 | and then throw them into cold water

02:26:05.000 | to introduce a memory instilling event.

02:26:09.000 | And we now know that the memory instilling event

02:26:11.720 | is the release of adrenaline in the body,

02:26:13.360 | which makes perfect sense

02:26:14.400 | if you think about traumatic events,

02:26:16.180 | but it also, this whole general mechanism

02:26:18.340 | also applies to the learning of other types of information.

02:26:20.940 | And so if I understand correctly about the role of lithium

02:26:24.500 | and the role of cold in the experiments

02:26:25.800 | that you just described,

02:26:27.320 | there's some general state switch,

02:26:30.080 | some internal state switch that says,

02:26:31.960 | what happened in the minutes or hours preceding this

02:26:35.620 | was important.

02:26:36.460 | It acts as sort of like a highlighter pen

02:26:38.600 | in the book of experiences.

02:26:41.040 | And I'm absolutely curious to know

02:26:44.960 | whether or not this is an RNA dependent mechanism

02:26:47.640 | in some way.

02:26:48.480 | So is this literally like the highlighter

02:26:50.180 | in the IKEA instruction book?

02:26:51.960 | - This we don't know.

02:26:52.800 | This we don't know.

02:26:53.880 | And as I said, this is not even a finished work.

02:26:57.120 | It's not peer reviewed.

02:26:58.400 | It's just the state that I told you about,

02:27:00.840 | but it's very exciting for me to go into this new field.

02:27:05.440 | And once it's out, I'd be happy to talk more about it

02:27:09.520 | and think about the implications and the connection

02:27:11.480 | to other things and more about the mechanisms.

02:27:13.440 | - Yeah, well, thank you for sharing with us

02:27:15.680 | despite the fact that it's not finished.

02:27:18.200 | People now know that it's also not finished

02:27:20.280 | and I love a good cliffhanger.

02:27:21.880 | So we await the full conclusion and interpretation

02:27:25.960 | of these results.

02:27:27.640 | Today, you've taken us on an amazing journey

02:27:30.000 | through the genome, RNA, short interfering RNAs,

02:27:35.000 | a ton of history of prior experiments,

02:27:37.520 | some of which ended tragically,

02:27:38.760 | many of which unfortunately did not.

02:27:41.080 | And they were true triumphs.

02:27:42.280 | And in particular, the work in your laboratory,

02:27:45.240 | which is just incredible.

02:27:46.800 | And also this introduction of model organisms.

02:27:48.760 | So, and I only mentioned a short handful of the things

02:27:52.400 | that you've taught us about today.

02:27:54.560 | So first I want to extend thanks for the incredible teaching.

02:27:57.680 | I also want to say thank you

02:28:00.160 | for something equally important,

02:28:03.640 | which is that absolutely came through,

02:28:06.120 | but is what initially brought me to explore you

02:28:09.240 | and your work more, although I had certainly heard of you,

02:28:11.600 | which is that your spirit and kind of approach to biology

02:28:16.040 | is an extremely unique and intoxicating one.

02:28:19.880 | It's even, I venture to call it seductive.

02:28:22.800 | It's, you know, there's a,

02:28:24.240 | I do believe that whether or not it's music or poetry

02:28:26.800 | or science or mathematics,

02:28:29.040 | that the spirit behind something

02:28:32.520 | dictates the amount of intelligence and precision

02:28:35.200 | with which that thing is carried out.

02:28:37.520 | And it absolutely comes through.

02:28:40.160 | So if I'm making you feel on the spot about this,

02:28:42.920 | I've succeeded.

02:28:43.760 | - Thank you, thank you very much.

02:28:45.000 | - But I know that the listeners can feel it.

02:28:47.680 | It's a felt thing.

02:28:49.360 | So thank you.

02:28:50.200 | There are many scientists out there,

02:28:53.080 | fewer with this phenotype and even fewer that,

02:28:56.520 | you know, I think that can communicate

02:28:57.760 | with such a articulate precision.

02:29:00.040 | So thank you so much.

02:29:01.840 | - Thank you.

02:29:02.680 | - It's been a real pleasure.

02:29:03.760 | - Pleasure was all mine.

02:29:05.320 | Thanks a lot.

02:29:06.160 | - Great, well, we'll do it again.

02:29:07.120 | And we'll learn about all the incredible things

02:29:08.640 | you're doing trying to transform science as it were

02:29:11.400 | at the level of publishing,

02:29:12.600 | at the level of social media,

02:29:13.840 | because there's a whole other discussion there.

02:29:15.720 | Meanwhile, we will of course,

02:29:16.720 | point people in the direction of you

02:29:18.360 | and to learn more about your work.

02:29:20.200 | And I look forward to hearing the conclusion

02:29:22.440 | of Dana's studies.

02:29:24.160 | - Thanks a lot.

02:29:25.000 | It's been a real pleasure.

02:29:26.800 | - Thank you for joining me today

02:29:27.940 | for my discussion with Dr. Oded Rahavi

02:29:30.320 | about genetics, inheritance,

02:29:32.280 | the epigenome and transgenerational passage of traits.

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02:31:47.680 | Thank you once again for joining me for today's discussion

02:31:50.260 | with Dr. Oded Rahavi.

02:31:51.940 | And last, but certainly not least,

02:31:54.300 | thank you for your interest in science.

02:31:56.100 | [upbeat music]

02:31:58.680 | (upbeat music)

Dr. Oded Rechavi: Genes & the Inheritance of Memories Across Generations | Huberman Lab Podcast

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