WEBVTT 00:00:00.000 --> 00:00:04.519 Welcome to Huberman Lab Essentials, where we revisit past episodes for the most 00:00:04.602 --> 00:00:09.005 potent and actionable science-based tools for mental health, physical health, 00:00:09.088 --> 00:00:10.020 and performance. 00:00:11.540 --> 00:00:15.945 I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology 00:00:16.028 --> 00:00:20.820 at Stanford School of Medicine. And now for my discussion with Dr. Oded Rehavi. 00:00:20.970 --> 00:00:24.522 Odette, thank you so much for being here. - Totally, my pleasure. 00:00:24.605 --> 00:00:27.010 - Today what I mainly want to talk about is 00:00:27.630 --> 00:00:30.281 the incredible questions that you probe in your lab, 00:00:30.365 --> 00:00:33.595 which are incredibly significant for each and all of our lives. 00:00:33.678 --> 00:00:37.118 I think most people have a general understanding of what genes are, 00:00:37.201 --> 00:00:41.062 what RNA is, and so on. But maybe you could explain to people in very basic 00:00:41.146 --> 00:00:42.187 terms. And I'll just, 00:00:42.270 --> 00:00:45.846 preface all this by saying that I think most people understand that if they have 00:00:45.929 --> 00:00:47.880 two blue-eyed parents that there's a 00:00:48.420 --> 00:00:53.454 higher probability that their offspring will have blue eyes than brown eyes. 00:00:53.538 --> 00:00:58.437 But most people generally understand and accept that if they spend part of 00:00:58.520 --> 00:01:01.467 their life, let's say, studying architecture, 00:01:01.551 --> 00:01:05.797 that if they have children, that there's no real genetic reason. 00:01:05.880 --> 00:01:10.300 we assume, that their children would somehow be... 00:01:10.710 --> 00:01:13.927 better at architecture because they contain the knowledge 00:01:14.010 --> 00:01:17.352 through the DNA of their parents. They might be exposed to it in the home, 00:01:17.435 --> 00:01:19.759 so-called nature nurture, also nurture in that case, 00:01:19.842 --> 00:01:21.980 but that they wouldn't inherit knowledge. Today, 00:01:22.064 --> 00:01:23.707 I'm hoping you can explain to us why 00:01:23.790 --> 00:01:28.502 eye color but not knowledge is thought to be inherited and the huge landscape 00:01:28.586 --> 00:01:33.070 of interesting questions that this opens up including some evidence that 00:01:33.210 --> 00:01:38.259 Contrary to what we might think, certain types of knowledge at the level of cells 00:01:38.342 --> 00:01:41.617 and systems can be inherited. So DNA is the material, 00:01:41.700 --> 00:01:45.989 the genetic instructions that is contained in every one of our cells. 00:01:46.072 --> 00:01:50.551 We have the set of genes containing the entire set is called the genome. 00:01:50.635 --> 00:01:55.450 And this is present in every cell of our body, the same set of instructions. 00:01:55.890 --> 00:01:59.701 Genes are made of DNA and chromosomes that are contained in chromosomes. 00:01:59.784 --> 00:02:03.865 Chromosomes is the DNA and the proteins that condense the DNA because we have 00:02:03.948 --> 00:02:07.488 a huge amount of DNA in every cell that you need to condense it to. 00:02:07.572 --> 00:02:11.790 Sort of like thread on a spool. Right. Huge amounts that you have to condense. 00:02:12.420 --> 00:02:15.680 And we have the same genome, the same DNA in every... 00:02:15.900 --> 00:02:19.990 sell in our body. It's good to have an analogy to understand how it works. 00:02:20.074 --> 00:02:21.487 This is like the IKEA book 00:02:21.570 --> 00:02:25.355 that you have in every cell in your body the instructions to make everything 00:02:25.439 --> 00:02:28.766 that you need in your house, the chairs, the kitchen, the pictures. 00:02:28.849 --> 00:02:31.922 But in every room, you want something else. So in the kitchen, 00:02:32.005 --> 00:02:34.772 you want things that fit the kitchen. And in the toilet, 00:02:34.856 --> 00:02:38.590 you want things that fit the toilet. So you only remove one particular page 00:02:38.673 --> 00:02:42.001 of instructions, which is the instructions of how to build a chair. 00:02:42.084 --> 00:02:45.207 And this you place in the living room, okay? And in the toilet, 00:02:45.291 --> 00:02:49.178 you put it in the toilet. So the genome is the instruction to make everything. 00:02:49.261 --> 00:02:51.450 This is the IKEA book. And in every cell... 00:02:51.570 --> 00:02:52.207 we 00:02:52.290 --> 00:02:56.287 We take just the instructions for make one particular furniture, and this is the RNA. 00:02:56.370 --> 00:03:00.030 And then the end you'll build the chair, the chair is the protein. 00:03:00.113 --> 00:03:03.970 This is true for one particular type of RNA, which is messenger RNA. 00:03:04.140 --> 00:03:07.500 In fact, this is just a small percent of our 00:03:07.680 --> 00:03:13.132 of the RNA in the cell. So we have a very big genome and less than 2% of it encodes 00:03:13.216 --> 00:03:18.401 for this messenger RNA. However, a lot of the genome is transcribed to make RNA 00:03:18.484 --> 00:03:24.020 that does other things. Some of these RNAs we understand and many of them we don't. 00:03:24.360 --> 00:03:28.709 I think it's a beautiful description, and IKEA is not a sponsor of the podcast, 00:03:28.792 --> 00:03:32.804 so it's totally fair game to use the IKEA catalog as the analogy for DNA. 00:03:32.888 --> 00:03:36.732 The specific instructions for specific pieces of furniture is the RNA, 00:03:36.815 --> 00:03:40.603 and the furniture pieces being the proteins that are essentially made 00:03:40.686 --> 00:03:43.071 from RNA using messenger RNA. Correct. Okay. 00:03:43.155 --> 00:03:47.560 Despite the fact that the same genes are contained in all the cells of the body, 00:03:47.643 --> 00:03:50.280 is it fair to say that there's basically one... 00:03:50.400 --> 00:03:54.174 very important exception, which is somatic cells versus germ cells. 00:03:54.258 --> 00:03:58.090 And would you mind sharing with us what that distinction is? So yes, 00:03:58.173 --> 00:04:01.314 every cell type is different. We have cells in the legs, 00:04:01.397 --> 00:04:04.999 we have cells in the brain, we have cells that produce dopamine, 00:04:05.082 --> 00:04:09.317 cells that produce serotonin, and so on. But we can make one very important 00:04:09.400 --> 00:04:12.599 distinction between the somatic cells and the germ cells. 00:04:12.682 --> 00:04:16.540 The germ cells are supposed to be the only cells that contribute in 00:04:16.890 --> 00:04:21.342 to the next generation, out of which the next generation will be made. 00:04:21.425 --> 00:04:25.748 So each of us is made just from a combination of a sperm and an egg. 00:04:25.831 --> 00:04:30.690 These are two types of germ cells. And then they fuse, and you get one egg. 00:04:30.900 --> 00:04:35.554 fertilized egg. And out of this one cell, all the rest of the body will develop. 00:04:35.638 --> 00:04:39.625 And what happens in the soma, which are all the cells that are not the germ cells, 00:04:39.709 --> 00:04:43.796 should stay in the soma. It should not be able to contribute to the next generation. 00:04:43.879 --> 00:04:47.718 This is very important, and it's thought to be one of the main barriers that we 00:04:47.801 --> 00:04:52.087 have for the inheritance of acquired traits, the inheritance of memory, 00:04:52.170 --> 00:04:56.707 and so on. Because, for example, like the example that you gave with learning 00:04:56.790 --> 00:04:58.230 architecture, if I learn 00:04:58.440 --> 00:05:02.360 about architecture. The information is encoded in my brain. 00:05:02.640 --> 00:05:08.820 and since migraine cells can't transfer information to the sperm and the egg, 00:05:09.180 --> 00:05:13.748 because the information is supposed to reside in synaptic connections between 00:05:13.831 --> 00:05:17.191 different neurons, in particular circuits that developed. 00:05:17.275 --> 00:05:22.145 So what happens is the brain shouldn't be able to transfer to the next generation. 00:05:22.228 --> 00:05:27.000 Even simpler, a simpler example, if you go to the gym and you build up muscles, 00:05:27.390 --> 00:05:30.693 you know that your kids will have to work out on their own. 00:05:30.776 --> 00:05:34.767 This shortout won't happen. This is something that we know intuitively, 00:05:34.851 --> 00:05:37.522 even if we don't have any background in biology. 00:05:37.605 --> 00:05:41.195 This is connected to the fact that, as we said at the beginning, 00:05:41.278 --> 00:05:43.605 every cell in the body has its own genome, 00:05:43.688 --> 00:05:48.024 and the next generation will only form from the combination of the genomes in 00:05:48.107 --> 00:05:49.370 the sperm and the egg. 00:05:50.160 --> 00:05:55.537 even if you somehow acquire the mutation or change in your DNA. 00:05:55.620 --> 00:05:59.278 in one of particular brain cells, it wouldn't matter because this mutation, 00:05:59.361 --> 00:06:03.169 there's no way to transfer it to the DNA of the germ cell that will contribute 00:06:03.253 --> 00:06:04.403 to the next generation. 00:06:05.130 --> 00:06:07.942 I'd like to take a quick break and acknowledge our sponsor, 00:06:08.025 --> 00:06:11.622 Eight Sleep. 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Again, that's 8sleep.com slash Huberman to save 00:07:21.346 --> 00:07:22.179 up to $350. 00:07:23.520 --> 00:07:28.530 There is this idea, and I'll say it so that you don't have to, that dates back to 00:07:28.620 --> 00:07:31.613 Lamarck and Lamarckian evolution, very controversial, right? 00:07:31.696 --> 00:07:35.560 And maybe not even controversial. I think it's very offensive even to certain 00:07:35.644 --> 00:07:39.540 people. This idea of inheritance of acquired traits, the idea that one could 00:07:39.840 --> 00:07:43.333 change themselves through some activity. Use the example of going to the gym. 00:07:43.417 --> 00:07:46.771 We could also use the example of somebody who becomes an endurance runner, 00:07:46.854 --> 00:07:50.154 then decides to have children within another endurance runner. And 00:07:50.370 --> 00:07:53.508 has in mind the idea that because they did all this running, 00:07:53.591 --> 00:07:57.427 and not just because they were biased towards running in the first place, 00:07:57.510 --> 00:07:58.507 but because they... 00:07:58.590 --> 00:08:03.126 of the distance they actually ran that their offspring somehow would be fabulous 00:08:03.209 --> 00:08:05.230 runners. This Lamarckian concept is 00:08:05.430 --> 00:08:09.979 We believe wrong. So how do we talk about inheritance of acquired traits? 00:08:10.062 --> 00:08:14.294 What's the proper language for us to frame this discussion? Lamarck, 00:08:14.378 --> 00:08:18.990 this is what he believed. And he thought this is how evolution progressed. 00:08:19.073 --> 00:08:22.798 And later, Darwin showed that it's really natural selection. 00:08:22.881 --> 00:08:27.620 The selecting of the organisms that already contain the particular qualities 00:08:27.704 --> 00:08:32.590 are selected based on whether they survive or not in particular environments. 00:08:35.430 --> 00:08:38.839 they become more common and take over. This is very different. 00:08:38.923 --> 00:08:43.234 Two different explanations. The most common way this is contrasted is the neck 00:08:43.317 --> 00:08:46.896 of the giraffes. This is a classic example. According to Lamarck, 00:08:46.979 --> 00:08:50.190 the giraffes had to stretch their necks towards the trees 00:08:50.460 --> 00:08:54.013 to eat when the trees were high. And because of that, 00:08:54.097 --> 00:08:58.837 they transmitted these traits long next to their children who also had 00:08:58.920 --> 00:09:02.967 And according to Darwin, just that a giraffe that happened to be born with 00:09:03.051 --> 00:09:07.433 a long neck survived because it ate. So it's genetic heritable materials in know 00:09:07.516 --> 00:09:11.898 about genetics, but I take over and the rest of the giraffes that have different 00:09:11.981 --> 00:09:16.196 heritable materials just die. So this is natural selection versus inheritance 00:09:16.279 --> 00:09:17.340 of acquired traits. 00:09:28.920 --> 00:09:33.132 to be breached for this to happen. And you can narrow it down to two main barriers. 00:09:33.216 --> 00:09:37.014 The first barrier, we mentioned it, this is the separation of the soma from 00:09:37.097 --> 00:09:41.258 the germline. Right, the somatic cells, they can change in response to experience. 00:09:41.341 --> 00:09:45.773 The sperm and the egg, the so-called germ cells, cannot. That's the idea. 00:09:45.856 --> 00:09:48.941 Or they are isolated from what happens in the soma. 00:09:49.025 --> 00:09:52.917 The man who first thought about this barrier is called Weizmann. 00:09:53.001 --> 00:09:55.775 August Weizmann, this was in the 19th century. 00:09:55.859 --> 00:09:58.530 So it is called today the Weizmann Barrier. 00:09:58.830 --> 00:09:59.927 Separation of the sum 00:10:00.010 --> 00:10:03.416 From the germline, only the germline transmit information to the next 00:10:03.499 --> 00:10:06.551 generation. And this is also called the second law of biology. 00:10:06.634 --> 00:10:10.242 So this is very, very fundamental. So natural selection is the first one. 00:10:10.325 --> 00:10:13.882 This is the second one because it's so important to how our bodies work. 00:10:13.966 --> 00:10:17.050 The other main barrier, it's called epigenetic reprogramming. 00:10:17.380 --> 00:10:24.122 which is that we acquired our cells, the genetic material in our cells acquires all 00:10:24.206 --> 00:10:29.880 kinds of chemical changes, but these modifications are largely erased 00:10:30.610 --> 00:10:36.250 in the transition between generations. So in the germline, in the sperm and the egg, 00:10:36.430 --> 00:10:41.390 and also in the early embryo, most of the modifications are removed 00:10:41.500 --> 00:10:45.510 So we can start a blank slate based on the genetic instructions 00:10:45.760 --> 00:10:48.300 and this is cool shot, otherwise 00:10:48.760 --> 00:10:51.170 According to the theory, it's not clear that it's actually true, 00:10:51.253 --> 00:10:53.687 because in some organisms it doesn't really happen. 00:10:53.770 --> 00:10:59.254 we will not develop according to the species' typical genetic instructions. 00:10:59.337 --> 00:11:04.375 So to preserve this, we erase all these modifications and start anew. 00:11:04.459 --> 00:11:08.829 And this is in mammoths and in humans. This is largely true. 00:11:08.912 --> 00:11:13.728 Most of the modifications in the sperm and in the egg are removed, 00:11:13.811 --> 00:11:18.280 so about 90% of them. So the idea, if I understand correctly, is that 00:11:18.730 --> 00:11:25.007 there's some advantage to wiping the slate clean and returning to the original plan. 00:11:25.090 --> 00:11:28.414 In the context of the IKEA furniture analogy, 00:11:28.497 --> 00:11:34.607 the instruction book is the one that's issued to everybody, or every cell, right? 00:11:34.690 --> 00:11:37.156 Only certain instructions are used for certain cells, 00:11:37.239 --> 00:11:41.139 say a skin cell or a neuron or a liver cell or any other cell for that matter. 00:11:41.470 --> 00:11:43.849 through the course of the lifespan of the organism, 00:11:43.932 --> 00:11:46.552 those specific instructions are adjusted somewhat. Okay, 00:11:46.635 --> 00:11:48.724 so maybe the idea is to take the instruction, 00:11:48.807 --> 00:11:51.331 but go through and erase all the pen and pencil marks, 00:11:51.414 --> 00:11:54.565 erase all those additional little modifications that the owner used 00:11:54.648 --> 00:11:57.799 or introduced to it, and return to the original instruction. Right, 00:11:57.882 --> 00:12:00.454 because if you want to bring back the instruction book, 00:12:00.537 --> 00:12:03.592 you want it to have all the potential to make all the furnitures. 00:12:03.675 --> 00:12:06.425 You don't want it to be restricted to the ones that you 00:12:11.470 --> 00:12:16.030 is based on theoretical grounds because of these barriers 00:12:16.810 --> 00:12:20.740 and because of the controversies. On the other hand, 00:12:20.823 --> 00:12:26.650 people really want to believe it because It sort of gives your life meaning. 00:12:27.190 --> 00:12:30.270 If you can change your biology, 00:12:30.760 --> 00:12:34.786 of your kids through changing your biological disorder. Psychologically, 00:12:34.869 --> 00:12:38.838 I can understand why many people want this to happen. Even Schrodinger, 00:12:38.921 --> 00:12:40.097 the famous physicist, 00:12:40.180 --> 00:12:44.286 So he wrote a very important book in 44. And he talks about the heritable material. 00:12:44.370 --> 00:12:46.457 It also talks about evolution. And he said, 00:12:46.540 --> 00:12:49.697 inheritance of acquired traits is untenable. It doesn't happen. 00:12:49.780 --> 00:12:51.860 And you're right. 00:12:51.970 --> 00:12:56.281 This is very, very sad or unfortunate because unlike Darwinism or natural 00:12:56.365 --> 00:12:59.950 selection, which is gloomy, It doesn't matter what you do. 00:13:00.460 --> 00:13:04.771 The next generation will be born based on the instruction in the sperm and the egg. 00:13:04.854 --> 00:13:08.900 You can't influence it. Of course, you can give your kids money and education, 00:13:08.984 --> 00:13:11.494 but you can't biologically influence it. However, 00:13:11.578 --> 00:13:15.783 there's one additional thing to mention, which is there are also other mechanisms 00:13:15.866 --> 00:13:20.260 that might transmit information, including transmission between generations of RNA. 00:13:20.830 --> 00:13:24.914 And there are different types of RNA, not just messenger RNA, 00:13:24.998 --> 00:13:28.331 which encodes the information for making proteins, 00:13:28.414 --> 00:13:31.830 but also other RNAs that regulate gene expression. 00:13:32.230 --> 00:13:37.487 And I think that in recent years, also in the mammalian field, RNA... 00:13:37.570 --> 00:13:42.059 as the molecule that has the potential to transmit information between generations 00:13:42.142 --> 00:13:43.090 took center stage 00:13:43.360 --> 00:13:47.537 So I think this is the cutting edge. A lot more to understand and know, 00:13:47.620 --> 00:13:51.677 but RNA has a lot of potential for doing that, as we'll explain soon, 00:13:51.760 --> 00:13:53.740 but we have to go to worms first. 00:13:54.010 --> 00:13:58.363 Many, if not most of our listeners are focused on humans and human biology 00:13:58.446 --> 00:14:02.919 and health, et cetera. But I cannot emphasize enough the importance of model 00:14:03.002 --> 00:14:07.475 organisms and the incredible degree to which they've informed us about human 00:14:07.558 --> 00:14:11.431 health, especially when it comes to very basic functions in cells. 00:14:11.515 --> 00:14:15.148 Before we start to go into the description about worms per se, 00:14:15.232 --> 00:14:16.937 could you just explain to the 00:14:17.020 --> 00:14:23.700 a general audience, what a model organism is and why you've selected or elected 00:14:23.784 --> 00:14:24.640 to work on 00:14:24.760 --> 00:14:29.490 a particular type of worm to study these fascinating topics that there's zero 00:14:29.574 --> 00:14:32.554 question also take place in humans at some level. 00:14:32.637 --> 00:14:35.242 Model organisms mean that it's an organism. 00:14:35.325 --> 00:14:39.868 There's a huge community of researchers that combine sources to create all 00:14:39.952 --> 00:14:43.807 the resources and the tools and understanding that accumulates. 00:14:43.890 --> 00:14:47.183 We learned about every aspect of biology through them, 00:14:47.266 --> 00:14:52.434 including many important diseases. And the reason that we can learn a lot also about 00:14:52.517 --> 00:14:53.351 humans by 00:14:54.760 --> 00:14:57.860 that we all evolved from The same end system. 00:14:58.180 --> 00:15:01.609 We share a lot of our functions with them, and also a lot of our genes. 00:15:01.692 --> 00:15:04.726 They sometimes have things that are much more apparent in them, 00:15:04.809 --> 00:15:08.139 that we can study. Another important reason to study them, of course, 00:15:08.223 --> 00:15:11.454 is you can actually experiment on them. We can't do this to humans, 00:15:11.537 --> 00:15:15.037 the things that we do to these animals. And we can change their genes. 00:15:15.640 --> 00:15:19.354 Do all kinds of things for them. The community of people that study C. 00:15:19.438 --> 00:15:23.532 elegans has literally numbered and named each neuron so that two laboratories 00:15:23.615 --> 00:15:27.275 on opposite sides of the world can publish papers on the same neuron, 00:15:27.358 --> 00:15:30.964 knowing that it's the same neuron in the two different laboratories. 00:15:31.047 --> 00:15:33.760 Something that is extremely hard to do in any way. 00:15:33.880 --> 00:15:37.526 mammalian model, a mouse or certainly in humans, 00:15:37.609 --> 00:15:43.897 and has posed huge challenges that give great advantages to studies of things like 00:15:43.980 --> 00:15:48.014 C. elegans. C. elegans nematode always has 959 cells, 00:15:48.098 --> 00:15:53.450 out of which 302 are neurons. We have a connectome, Since the 80s, 00:15:53.590 --> 00:15:58.208 like a subway map that tells us which neuron talks with which other neurons 00:15:58.291 --> 00:16:01.990 and it is the same not only that, the worms are transparent 00:16:02.080 --> 00:16:07.487 So we can actually see the neurons fire using particular tools. 00:16:07.570 --> 00:16:12.178 And we can activate genes and silage genes using optogenetics. On top of that, 00:16:12.262 --> 00:16:15.630 we have great understanding of the genetics of the worm. 00:16:16.450 --> 00:16:22.138 of the genome. Silicone is the first animal to have its genome sequenced before 00:16:22.221 --> 00:16:26.970 humans. And we know that each worm produces, each mother produces 00:16:27.220 --> 00:16:31.300 about 250 babies which are almost genetically identical 00:16:31.540 --> 00:16:35.057 And we know where we grow them. The environment is very controlled. 00:16:35.141 --> 00:16:37.720 So we grow them in the plate with just bacteria. 00:16:37.810 --> 00:16:40.779 So we can easily separate between nature and nurture. 00:16:40.863 --> 00:16:43.570 The generation time in C elegans is three days. 00:16:43.780 --> 00:16:47.635 Three days. So you can do hundreds of worm generations in one PhD. 00:16:47.719 --> 00:16:51.872 This is very important. Not only that, every worm will produce hundreds 00:16:51.955 --> 00:16:54.378 of progeny that are genetically identical, 00:16:54.462 --> 00:16:58.460 so you will have great statistics for your experiment. In the worm. 00:16:58.810 --> 00:17:03.257 We now have very... Obviously, and clear-cut 00:17:03.340 --> 00:17:06.640 proof that there is inheritance of acquired trades. 00:17:06.730 --> 00:17:11.770 So much so that I don't think that anyone pretty much in the epigenetic field 00:17:12.100 --> 00:17:13.400 argues against it. 00:17:13.540 --> 00:17:17.182 I'd like to take a quick break and acknowledge our sponsor, AG1. 00:17:17.266 --> 00:17:20.559 AG1 just launched their newest formulation called AG1 Pro. 00:17:20.642 --> 00:17:24.459 And right now you can get an extra 20% off your first subscription. 00:17:24.542 --> 00:17:27.021 AG1 takes the clinically backed AG1 formula, 00:17:27.104 --> 00:17:30.921 which is a blend of vitamins, minerals, probiotics, and adaptogens, 00:17:31.004 --> 00:17:35.345 and adds three important new ingredients, creatine monohydrate, calcium HMB, 00:17:35.429 --> 00:17:39.944 and zinc carnosine. 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For a limited time, you can get an extra 20% off your first 00:18:18.703 --> 00:18:23.332 subscription to AG1 Pro by going to drinkag1.com slash Huberman and using 00:18:23.415 --> 00:18:26.881 the code back to routine. So that's with a numeral two, 00:18:26.965 --> 00:18:31.160 back numeral two routine. Just go to drinkag1.com slash Huberman. 00:18:31.840 --> 00:18:35.219 What was the first experiment that you did on C. 00:18:35.302 --> 00:18:40.629 elegans that confirmed for you that inheritance of acquired traits is real? 00:18:40.712 --> 00:18:46.472 We set to test whether worms can produce transgenerational resistance to viruses. 00:18:46.555 --> 00:18:50.583 These worms don't have dedicated immune cells like we do. 00:18:50.666 --> 00:18:55.847 They don't have T cells or B cells. They defend themselves from viruses. 00:18:55.930 --> 00:18:58.450 using RNA that destroy viruses. 00:18:58.660 --> 00:19:00.420 And these are called small RNAs. 00:19:00.580 --> 00:19:04.520 2006, two researchers that were studying C. elegance, 00:19:04.810 --> 00:19:07.810 Andrew Feier and Craig Mello got the Nobel Prize. 00:19:08.050 --> 00:19:12.310 for showing that there is a mechanism that regulates genes 00:19:13.060 --> 00:19:18.100 that happens for small RNAs. What they've shown is that if you... 00:19:18.490 --> 00:19:20.160 inject The warmth. 00:19:20.800 --> 00:19:26.560 with RNA molecules, which are double-stranded. They shut off the genes, 00:19:26.680 --> 00:19:28.900 that match in sequence to this RNA. 00:19:29.020 --> 00:19:34.122 So sort of like taking the specific instructions for the coffee table 00:19:34.205 --> 00:19:36.760 from your IKEA handbook and you... 00:19:36.880 --> 00:19:40.370 insert a copy of that into the book. And in doing so, 00:19:40.453 --> 00:19:44.887 you prevent the expression of, you sort of erase the original page. 00:19:44.971 --> 00:19:49.960 Perfect explanation. They found that double-strand RNA RNA is two strands. 00:19:50.050 --> 00:19:54.502 is what starts the response, leading to the production of small RNA molecules, 00:19:54.586 --> 00:19:58.689 which are the ones that actually find the messenger RNA and leads to its 00:19:58.772 --> 00:20:02.030 destruction. Silence it so you don't get proteins in the end. 00:20:02.600 --> 00:20:06.997 For that, they got the Nobel Prize after people found that this is conserved 00:20:07.080 --> 00:20:10.829 in many organisms, including humans. And now there are now drugs. 00:20:10.912 --> 00:20:14.955 This was only in 2006, the Nobel Prize. The paper was published in 98. 00:20:15.039 --> 00:20:19.460 There are now drugs that use this mechanism. It is called RNA interference. 00:20:19.760 --> 00:20:23.856 RNA interferes in the expression of a gene in the function of a gene. 00:20:23.939 --> 00:20:28.459 And it's also called gene silencing because these RNAs enforce the silencing 00:20:28.542 --> 00:20:32.540 of genes. Instead of the genes being expressed, they are silenced. 00:20:32.660 --> 00:20:37.137 and you don't manifest the function. They've shown Two very important things. 00:20:37.220 --> 00:20:39.440 You don't only see the... 00:20:39.830 --> 00:20:43.649 action in the cell that you injected or in the tissue that you injected, 00:20:43.732 --> 00:20:46.497 but you see it all over the worm's body. It spreads. 00:20:46.580 --> 00:20:49.590 This includes also The Joneses. 00:20:50.150 --> 00:20:53.870 So if you inject the davenant RNA just to somatic cells, 00:20:54.650 --> 00:20:57.530 even to the head, you will get also 00:20:57.650 --> 00:21:00.597 the effect in the germ cells and in the next generation. 00:21:00.680 --> 00:21:05.730 Later they've shown that you can just take worms and feed them. 00:21:05.900 --> 00:21:09.620 on bacteria that produce this double-strand RNA. 00:21:09.740 --> 00:21:13.288 And that the double stand and the silencing would move from the site 00:21:13.371 --> 00:21:16.220 of ingestion from the gut where the Bacteria are eaten. 00:21:16.640 --> 00:21:19.487 to the rest of the body and also to the next generation. 00:21:19.571 --> 00:21:23.600 And this is not controversial at all. This is being done routinely every day, 00:21:23.870 --> 00:21:26.170 by any C. elegans biologist. in the world. 00:21:26.630 --> 00:21:29.127 This has been replicated a million times. 00:21:29.210 --> 00:21:33.648 When I started my work, I wanted to see whether in addition to artificial 00:21:33.731 --> 00:21:36.790 double-stranded RNA, some natural traits 00:21:36.920 --> 00:21:41.038 can also transmit across generations because of RNA, 00:21:41.122 --> 00:21:47.341 because of small RNAs. Right, because injecting RNAi or short-term interfering 00:21:47.424 --> 00:21:51.250 RNAs, that is, or... you know, putting Thank you. 00:21:51.650 --> 00:21:54.820 worms into an environment with an abundance of inhibitory RNAs as 00:21:54.903 --> 00:21:58.924 an experiment is very different than worms experiencing something and then passing 00:21:59.008 --> 00:22:01.110 on that acquired trait to their offspring. 00:22:02.450 --> 00:22:05.811 It's a world apart, in my opinion, because one is extreme manipulation 00:22:05.895 --> 00:22:09.237 that illustrates an underlying principle. The other is something that 00:22:09.320 --> 00:22:12.665 in theory, occurs in the passage of generations just naturally. 00:22:12.749 --> 00:22:15.931 We're going from the less artificial to the more artificial. 00:22:16.014 --> 00:22:18.816 There are advantages, just like with model organisms, 00:22:18.899 --> 00:22:21.646 that the more artificial it is, the easier it is to, 00:22:21.729 --> 00:22:26.000 you know exactly what you did. Just now, introduce one factor and you can follow 00:22:26.083 --> 00:22:28.260 the result. So this is always the trade. 00:22:28.610 --> 00:22:32.161 In fact, this is probably the reason that these small organes evolved in the first 00:22:32.244 --> 00:22:33.077 place. 00:22:33.320 --> 00:22:36.810 to get rid of viruses and other 00:22:36.950 --> 00:22:41.550 parasitic genomic elements, and this is a mechanism to fight them. 00:22:41.750 --> 00:22:44.830 We demonstrated this very clearly, 00:22:45.950 --> 00:22:49.974 using a fluorescent virus. If the virus replicates successfully, 00:22:50.057 --> 00:22:54.600 the virus just turns green. And if the virus is destroyed, The warm stays black. 00:22:54.950 --> 00:22:57.770 This is very simple. It's a clear cutoff. We took worms. 00:22:58.190 --> 00:23:01.140 We infect them with the fluorescent virus. They destroy it. 00:23:01.310 --> 00:23:06.170 This also has been done in the past. But then what we did is we neutralized... 00:23:06.590 --> 00:23:11.120 the machinery that makes small RNAs in the 00:23:11.660 --> 00:23:15.620 descendants of the worms. So they cannot make small RNAs 00:23:15.920 --> 00:23:19.975 from the start on their own, because they just don't have the genes that you need 00:23:20.058 --> 00:23:24.061 to make this model. And then we ask, what will happen when we affect these worms 00:23:24.145 --> 00:23:26.490 with the vows? Will they be green? 00:23:26.960 --> 00:23:29.840 or black. They can't make their own small RNAs. 00:23:30.140 --> 00:23:34.300 So they can't protect themselves on their own. The only way for them to stay black 00:23:34.490 --> 00:23:38.103 for them not having the virus replicate is if they inherit a small amount from 00:23:38.187 --> 00:23:42.179 their parents. And this is exactly what happens. All the worms' progeny, 00:23:42.262 --> 00:23:44.250 although they don't have the gene, 00:23:44.570 --> 00:23:48.070 that is needed for making the small RNAs are black. They silence the virus. 00:23:48.153 --> 00:23:50.703 And this also continues for additional generations. 00:23:51.290 --> 00:23:54.590 So the parent worms effectively... 00:23:54.860 --> 00:23:58.871 put something into the genetic instructions of the offspring that would 00:23:58.955 --> 00:24:01.928 afford them, let's call it an advantage in this case, 00:24:02.011 --> 00:24:06.426 but afford them an advantage if they were to be confronted with the same thing 00:24:06.510 --> 00:24:10.636 that the parents were. Right. And we know exactly what this advantage is. 00:24:10.720 --> 00:24:16.090 The advantage is. are small RNAs that match the viral genome. 00:24:16.190 --> 00:24:19.132 Then just chop up the virus in the next generation. 00:24:19.215 --> 00:24:21.410 And we can identify these small RNAs. 00:24:22.460 --> 00:24:24.740 in the inhibitory RNAs in the descendants, 00:24:24.823 --> 00:24:29.241 although they don't have the machinery to make it, just because they inherit it. 00:24:29.324 --> 00:24:32.110 We can identify them by sequencing. RNA sequencing, 00:24:32.194 --> 00:24:36.443 which is like DNA sequencing, you actually get the actual sequence of the RNA 00:24:36.526 --> 00:24:39.819 molecules. And we can see that they correspond to the virus, 00:24:39.902 --> 00:24:44.320 and they inherit these small RNAs only if their parents were infected with them. 00:24:44.403 --> 00:24:48.220 It is true that also in mammoths, RNAs and small RNAs. 00:24:48.350 --> 00:24:53.150 are a leading candidate for something that could mediate the transmission of virus. 00:24:53.510 --> 00:24:58.205 stress protection or also of harmful effects that transmit between generations. 00:24:58.289 --> 00:25:02.742 Perhaps RNA do it. And it's very interesting to think about it when we talk 00:25:02.825 --> 00:25:07.097 about inheritance of memories. Can brain activity of some sort transmit, 00:25:07.181 --> 00:25:11.694 at least in these words? I said, Noah, I said this disclaimer multiple times 00:25:11.778 --> 00:25:13.257 in members we don't know. 00:25:13.340 --> 00:25:17.997 Times will tell. In worms, we know a lot. So can worms transmit brain activity? 00:25:18.080 --> 00:25:22.677 Do they have the specificity to do? I think that any tissues that transmit RNA 00:25:22.760 --> 00:25:26.900 to the next generation and affect the next generation is interesting. 00:25:27.230 --> 00:25:30.117 the guts Muscles, everything, but the brain. 00:25:30.200 --> 00:25:35.097 can synthesize information about the environment and about 00:25:35.180 --> 00:25:40.687 internal state and can also think ahead. And the most provocative thing you can say 00:25:40.770 --> 00:25:43.017 is that you could plan how somehow 00:25:43.100 --> 00:25:45.624 the fate of your nation using your brain. You know, 00:25:45.707 --> 00:25:49.458 after taking many things into the code. - Without talking to them. - Right, 00:25:49.542 --> 00:25:52.730 without talking. - Again, we go back to this instruction manual. 00:25:52.814 --> 00:25:56.463 It's like writing something into the instruction manual based on your own 00:25:56.546 --> 00:25:59.460 experience. - Right. We have to understand that the brain 00:26:00.170 --> 00:26:03.657 uses a different language. than the language of inheritance. 00:26:03.740 --> 00:26:09.038 It keeps information... In... synapses in the connections between different neurons. 00:26:09.122 --> 00:26:13.201 When you learn something, you make some connections stronger and other connections 00:26:13.285 --> 00:26:17.030 weaker. And you wire the nervous system in a different way. 00:26:17.113 --> 00:26:22.488 On the other hand, heritable information of any sort has to go through a bottleneck 00:26:22.571 --> 00:26:27.210 of one cell. the fertilized egg, because we all start from just one cell. 00:26:27.410 --> 00:26:30.969 So the question is, can you or do you translate the information, 00:26:31.052 --> 00:26:35.408 this 3D structure information of synapses and the connection between brains in 00:26:35.491 --> 00:26:39.506 the architecture of the brain? Can you somehow translate it to heritable 00:26:39.589 --> 00:26:41.367 information to a molecular form? 00:26:41.450 --> 00:26:44.171 You can teach worms, even though they have just 302 neurons, 00:26:44.254 --> 00:26:47.069 you can teach them simple things about the world. For example, 00:26:47.152 --> 00:26:50.007 you can take an odor that the worms like. The worms have... 00:26:50.090 --> 00:26:53.827 thousands of odorant receptors, and they can recognize many, many, 00:26:53.910 --> 00:26:58.169 many molecules. They can smell them so they can find food or avoid enemies. 00:26:58.252 --> 00:27:02.220 You can take an odor that the worms like and pair it to something bad, 00:27:02.304 --> 00:27:03.230 like starvation. 00:27:04.190 --> 00:27:06.830 And then the worms will learn to dislike this auto. 00:27:08.390 --> 00:27:13.342 We don't know that this learning involves necessarily changing in the strengths 00:27:13.425 --> 00:27:17.486 of synapses. It's a possibility, but it doesn't have to be the case. 00:27:17.570 --> 00:27:20.820 It could be that just the receptor for this particular odor 00:27:21.710 --> 00:27:23.250 is being removed. 00:27:23.930 --> 00:27:26.800 And this is how they live. Now they won't have the receptor, they won't smell, 00:27:26.883 --> 00:27:29.247 they won't like the odor. This is a possibility. 00:27:29.330 --> 00:27:31.610 This type of thing you can perhaps... 00:27:31.790 --> 00:27:34.073 not that anyone has showed it convincingly, 00:27:34.156 --> 00:27:38.311 transmit to the next generation because all it would take is an RNA that will 00:27:38.394 --> 00:27:40.210 control this particular receptor. 00:27:40.700 --> 00:27:43.566 People have shown things like that, not in C. elegans, 00:27:43.649 --> 00:27:46.380 but people have shown things like this in members. 00:27:47.570 --> 00:27:50.970 They said that you learn certain things and then Thank you. 00:27:51.260 --> 00:27:54.800 Just in the next generation, that's a particular receptor would be... 00:27:54.950 --> 00:27:58.490 Methylated or would change and this would transmit the response. 00:27:58.730 --> 00:28:01.620 And On the one hand, it could be 00:28:02.360 --> 00:28:05.420 True. On the other hand, you need to understand 00:28:05.510 --> 00:28:09.006 They'll need to prove, and this wasn't done convincingly enough yet, 00:28:09.090 --> 00:28:13.375 how exactly does the information transfer from the brain to the germ cells and then 00:28:13.459 --> 00:28:17.692 in the next generation from the germ cells back to the brain to where the receptor 00:28:17.775 --> 00:28:18.670 needs to operate. 00:28:19.250 --> 00:28:22.365 And this is a challenge. This is the current state of the field that this 00:28:22.449 --> 00:28:24.299 is something that needs to be proven. 00:28:24.470 --> 00:28:28.257 What we did in C.E.L.A.G.A.N.S., is we showed that the brain 00:28:28.340 --> 00:28:31.812 can communicate with the next generations using small RNAs. 00:28:31.895 --> 00:28:36.693 And that this can change behavior. And it doesn't require any translating between 00:28:36.777 --> 00:28:41.470 any language. It is very simple. What we've shown is that if you take a worm, 00:28:41.630 --> 00:28:45.650 and you change the production of small RNAs just in its brain, 00:28:46.220 --> 00:28:49.578 In the next generations, their behavior will be different, 00:28:49.661 --> 00:28:52.247 even though you don't mess with their brains. 00:28:52.331 --> 00:28:56.757 This is a paper that we published in 2019 in Cell. We show that you just... 00:28:56.840 --> 00:29:01.712 manipulates the production of endogenous, natural RNAs in the worm's brain that are 00:29:01.795 --> 00:29:06.727 always made, but you change their amount. And this changes the capacity of the worms 00:29:06.811 --> 00:29:08.960 in the next generation to find food. 00:29:09.260 --> 00:29:12.500 Not only in one generation, but three generations down the road. 00:29:12.800 --> 00:29:15.297 And the way that it works is that 00:29:15.380 --> 00:29:20.560 perturbing the production of these small RNAs in the brain, affects in the end 00:29:20.720 --> 00:29:23.240 the expression of a gene in the germline. 00:29:23.840 --> 00:29:27.685 one gene, it's called SAGE2, we can do all kinds of controls where we manipulate 00:29:27.768 --> 00:29:31.018 the activity of the gene and see that this also affects behavior. 00:29:31.460 --> 00:29:35.570 And this gene It works in the jumpsuits. 00:29:35.780 --> 00:29:38.213 The information needs to go from the brain to the germ-sys. 00:29:38.296 --> 00:29:41.877 It doesn't need to go back from the germ-sys to the brain to affect behavior. 00:29:41.960 --> 00:29:46.261 And this depends, we know that this is a true epigenetic effect because it goes 00:29:46.344 --> 00:29:50.340 on for multiple generations, and also because it requires the machinery. 00:29:51.470 --> 00:29:55.163 that transfers RNA between generations. If you don't have the protein that physically 00:29:55.246 --> 00:29:57.627 carries the RNA between generations, it doesn't happen. 00:29:57.710 --> 00:29:59.110 So it has to be RNA. 00:30:00.000 --> 00:30:03.000 We can also find alienating the next generation to change. 00:30:03.180 --> 00:30:07.460 We sequence the actual RNAs the change in the next generation. 00:30:07.770 --> 00:30:08.670 It sounds weird. 00:30:09.030 --> 00:30:12.311 that you change germ cells and it changes behavior, sperm and egg. 00:30:12.394 --> 00:30:15.350 But if you think about it, the germ cells affect the soma, 00:30:15.630 --> 00:30:19.110 including the brain, in many ways by secreting 00:30:19.200 --> 00:30:24.412 certain chemicals. And also because the other cells develop from the germ cells, 00:30:24.495 --> 00:30:29.111 so some information could be transmitted over development or the course 00:30:29.194 --> 00:30:34.406 of development could be altered because of changes that occur in the germ cells. 00:30:34.489 --> 00:30:39.436 For example, in MEMES, one of the explanations for how heritable information 00:30:39.520 --> 00:30:43.117 transmits is that it just affects something very own in 00:30:43.200 --> 00:30:47.857 I told you that the secret to worms' inheritance is that they have the capacity 00:30:47.940 --> 00:30:52.777 to amplify these small RNAs all the time. This is what keeps it going and prevents 00:30:52.860 --> 00:30:57.277 the dilution. In mammals, we don't know of such an amplification mechanism. 00:30:57.360 --> 00:30:58.627 So you ask, how can... 00:30:58.710 --> 00:31:03.651 A little bit of RNA or something without amplifying affect the entire organism. 00:31:03.734 --> 00:31:08.103 And it could be that you just perturb something in the very beginning, 00:31:08.186 --> 00:31:13.381 when you just have a few cells, or even in the placenta that develops in pregnancy. 00:31:13.465 --> 00:31:17.070 And this later throws everything off. And because of that, 00:31:17.153 --> 00:31:20.059 you have many problems in metabolism and so on. 00:31:20.142 --> 00:31:24.193 And this is called the idea of the developmental origin of health 00:31:24.276 --> 00:31:28.410 and disease. Many of the functions occur early on in development. 00:31:28.980 --> 00:31:32.223 I'd like to take a quick break and acknowledge one of our sponsors, 00:31:32.306 --> 00:31:36.245 Element. 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Again, that's drink element.com slash Huberman to claim a free sample 00:33:00.301 --> 00:33:01.135 pack. 00:33:01.230 --> 00:33:06.128 In terms of the work in either C. elegans or in other model organisms, 00:33:06.211 --> 00:33:10.825 but in particular in C. elegans, where do you see this going next? 00:33:10.908 --> 00:33:13.447 So assuming that we will discover... 00:33:13.530 --> 00:33:17.713 similar things in humans, which we don't know that this is the case, 00:33:17.796 --> 00:33:22.544 but let's say we find it. I think there are many things you can do before you 00:33:22.627 --> 00:33:27.814 change it. You could also change a parent inheritance by having the parent exercise, 00:33:27.897 --> 00:33:32.202 for example. And some things like this have been done. For example, 00:33:32.285 --> 00:33:37.300 there are experiments in rodents where they show that overfeeding the rodents 00:33:37.384 --> 00:33:41.290 creates problems for the next generation, for the children. 00:33:42.780 --> 00:33:47.513 If you let the rodent exercise, then it corrects the aberrant inheritance. 00:33:47.597 --> 00:33:52.265 So this is one possibility. And you can also manipulate it at the source. 00:33:52.348 --> 00:33:56.025 You can change it. If it's RNAs, let's say you could, in the future, 00:33:56.108 --> 00:33:59.791 perhaps if we understand how it works, actually change the composition of 00:33:59.874 --> 00:34:01.657 the heritable RNAs. If you do IVFs, 00:34:01.740 --> 00:34:06.664 if you need vitro fertilization you can perhaps change the composition of the RNAs 00:34:06.747 --> 00:34:09.370 in the stuff that you introduce Thank you. 00:34:09.480 --> 00:34:14.622 But way before that, what you could do, perhaps even in the not so far future, 00:34:14.705 --> 00:34:16.837 is... use this for diagnostics. 00:34:16.920 --> 00:34:21.417 DNA-based diagnostics for every couple that wants to have a kid. In Israel, 00:34:21.500 --> 00:34:25.997 this is done for most couples. You can look at the DNA and look for genetic 00:34:26.080 --> 00:34:29.500 disease. But no one is looking at the RNA at the moment. 00:34:29.880 --> 00:34:33.247 If we understand how it works better, we'll have another level, 00:34:33.330 --> 00:34:37.628 a whole new world to look at. And perhaps there will be some RNAs that correlate 00:34:37.711 --> 00:34:41.133 with disease. The beauty is that this, unlike DNA, it's plastic. 00:34:41.216 --> 00:34:44.857 So with DNA, this is your DNA. Perhaps we can choose another embryo. 00:34:44.940 --> 00:34:48.515 But here you could say, Perhaps, again, in the future, this is science fiction, 00:34:48.598 --> 00:34:51.227 it doesn't happen now, but if we understand this and it's true, 00:34:51.310 --> 00:34:54.702 we can say... Maybe you should run on the treadmill a little bit. 00:34:54.786 --> 00:34:58.536 This will change the profile of your RNAs, and then we will use it for IVF. 00:34:58.770 --> 00:35:01.670 This seems more because just it correlates 00:35:01.770 --> 00:35:06.461 with healthy profiles of RNAs. This is a level that no one looks at now and holds 00:35:06.545 --> 00:35:11.354 great potential. Again, with a disclaimer that we don't know how it works in humans 00:35:11.437 --> 00:35:15.880 at all. Yes. But of course, this is why it's so interesting. Today, 00:35:15.963 --> 00:35:19.884 you've taken us on an amazing journey through the genome RNA, 00:35:19.967 --> 00:35:24.347 in particular the work in your laboratory, which is just incredible, 00:35:24.431 --> 00:35:28.811 and also this introduction of model organisms. So thank you so much. 00:35:28.895 --> 00:35:33.030 It's been a real pleasure. Pleasure was all mine. Thanks a lot.