1 00:00:00,000 --> 00:00:04,519 Welcome to Huberman Lab Essentials, where we revisit past episodes for the most 2 00:00:04,602 --> 00:00:09,005 potent and actionable science-based tools for mental health, physical health, 3 00:00:09,088 --> 00:00:10,020 and performance. 4 00:00:11,540 --> 00:00:15,945 I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology 5 00:00:16,028 --> 00:00:20,820 at Stanford School of Medicine. And now for my discussion with Dr. Oded Rehavi. 6 00:00:20,970 --> 00:00:24,522 Odette, thank you so much for being here. - Totally, my pleasure. 7 00:00:24,605 --> 00:00:27,010 - Today what I mainly want to talk about is 8 00:00:27,630 --> 00:00:30,281 the incredible questions that you probe in your lab, 9 00:00:30,365 --> 00:00:33,595 which are incredibly significant for each and all of our lives. 10 00:00:33,678 --> 00:00:37,118 I think most people have a general understanding of what genes are, 11 00:00:37,201 --> 00:00:41,062 what RNA is, and so on. But maybe you could explain to people in very basic 12 00:00:41,146 --> 00:00:42,187 terms. And I'll just, 13 00:00:42,270 --> 00:00:45,846 preface all this by saying that I think most people understand that if they have 14 00:00:45,929 --> 00:00:47,880 two blue-eyed parents that there's a 15 00:00:48,420 --> 00:00:53,454 higher probability that their offspring will have blue eyes than brown eyes. 16 00:00:53,538 --> 00:00:58,437 But most people generally understand and accept that if they spend part of 17 00:00:58,520 --> 00:01:01,467 their life, let's say, studying architecture, 18 00:01:01,551 --> 00:01:05,797 that if they have children, that there's no real genetic reason. 19 00:01:05,880 --> 00:01:10,300 we assume, that their children would somehow be... 20 00:01:10,710 --> 00:01:13,927 better at architecture because they contain the knowledge 21 00:01:14,010 --> 00:01:17,352 through the DNA of their parents. They might be exposed to it in the home, 22 00:01:17,435 --> 00:01:19,759 so-called nature nurture, also nurture in that case, 23 00:01:19,842 --> 00:01:21,980 but that they wouldn't inherit knowledge. Today, 24 00:01:22,064 --> 00:01:23,707 I'm hoping you can explain to us why 25 00:01:23,790 --> 00:01:28,502 eye color but not knowledge is thought to be inherited and the huge landscape 26 00:01:28,586 --> 00:01:33,070 of interesting questions that this opens up including some evidence that 27 00:01:33,210 --> 00:01:38,259 Contrary to what we might think, certain types of knowledge at the level of cells 28 00:01:38,342 --> 00:01:41,617 and systems can be inherited. So DNA is the material, 29 00:01:41,700 --> 00:01:45,989 the genetic instructions that is contained in every one of our cells. 30 00:01:46,072 --> 00:01:50,551 We have the set of genes containing the entire set is called the genome. 31 00:01:50,635 --> 00:01:55,450 And this is present in every cell of our body, the same set of instructions. 32 00:01:55,890 --> 00:01:59,701 Genes are made of DNA and chromosomes that are contained in chromosomes. 33 00:01:59,784 --> 00:02:03,865 Chromosomes is the DNA and the proteins that condense the DNA because we have 34 00:02:03,948 --> 00:02:07,488 a huge amount of DNA in every cell that you need to condense it to. 35 00:02:07,572 --> 00:02:11,790 Sort of like thread on a spool. Right. Huge amounts that you have to condense. 36 00:02:12,420 --> 00:02:15,680 And we have the same genome, the same DNA in every... 37 00:02:15,900 --> 00:02:19,990 sell in our body. It's good to have an analogy to understand how it works. 38 00:02:20,074 --> 00:02:21,487 This is like the IKEA book 39 00:02:21,570 --> 00:02:25,355 that you have in every cell in your body the instructions to make everything 40 00:02:25,439 --> 00:02:28,766 that you need in your house, the chairs, the kitchen, the pictures. 41 00:02:28,849 --> 00:02:31,922 But in every room, you want something else. So in the kitchen, 42 00:02:32,005 --> 00:02:34,772 you want things that fit the kitchen. And in the toilet, 43 00:02:34,856 --> 00:02:38,590 you want things that fit the toilet. So you only remove one particular page 44 00:02:38,673 --> 00:02:42,001 of instructions, which is the instructions of how to build a chair. 45 00:02:42,084 --> 00:02:45,207 And this you place in the living room, okay? And in the toilet, 46 00:02:45,291 --> 00:02:49,178 you put it in the toilet. So the genome is the instruction to make everything. 47 00:02:49,261 --> 00:02:51,450 This is the IKEA book. And in every cell... 48 00:02:51,570 --> 00:02:52,207 we 49 00:02:52,290 --> 00:02:56,287 We take just the instructions for make one particular furniture, and this is the RNA. 50 00:02:56,370 --> 00:03:00,030 And then the end you'll build the chair, the chair is the protein. 51 00:03:00,113 --> 00:03:03,970 This is true for one particular type of RNA, which is messenger RNA. 52 00:03:04,140 --> 00:03:07,500 In fact, this is just a small percent of our 53 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 54 00:03:13,216 --> 00:03:18,401 for this messenger RNA. However, a lot of the genome is transcribed to make RNA 55 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. 56 00:03:24,360 --> 00:03:28,709 I think it's a beautiful description, and IKEA is not a sponsor of the podcast, 57 00:03:28,792 --> 00:03:32,804 so it's totally fair game to use the IKEA catalog as the analogy for DNA. 58 00:03:32,888 --> 00:03:36,732 The specific instructions for specific pieces of furniture is the RNA, 59 00:03:36,815 --> 00:03:40,603 and the furniture pieces being the proteins that are essentially made 60 00:03:40,686 --> 00:03:43,071 from RNA using messenger RNA. Correct. Okay. 61 00:03:43,155 --> 00:03:47,560 Despite the fact that the same genes are contained in all the cells of the body, 62 00:03:47,643 --> 00:03:50,280 is it fair to say that there's basically one... 63 00:03:50,400 --> 00:03:54,174 very important exception, which is somatic cells versus germ cells. 64 00:03:54,258 --> 00:03:58,090 And would you mind sharing with us what that distinction is? So yes, 65 00:03:58,173 --> 00:04:01,314 every cell type is different. We have cells in the legs, 66 00:04:01,397 --> 00:04:04,999 we have cells in the brain, we have cells that produce dopamine, 67 00:04:05,082 --> 00:04:09,317 cells that produce serotonin, and so on. But we can make one very important 68 00:04:09,400 --> 00:04:12,599 distinction between the somatic cells and the germ cells. 69 00:04:12,682 --> 00:04:16,540 The germ cells are supposed to be the only cells that contribute in 70 00:04:16,890 --> 00:04:21,342 to the next generation, out of which the next generation will be made. 71 00:04:21,425 --> 00:04:25,748 So each of us is made just from a combination of a sperm and an egg. 72 00:04:25,831 --> 00:04:30,690 These are two types of germ cells. And then they fuse, and you get one egg. 73 00:04:30,900 --> 00:04:35,554 fertilized egg. And out of this one cell, all the rest of the body will develop. 74 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, 75 00:04:39,709 --> 00:04:43,796 should stay in the soma. It should not be able to contribute to the next generation. 76 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 77 00:04:47,801 --> 00:04:52,087 have for the inheritance of acquired traits, the inheritance of memory, 78 00:04:52,170 --> 00:04:56,707 and so on. Because, for example, like the example that you gave with learning 79 00:04:56,790 --> 00:04:58,230 architecture, if I learn 80 00:04:58,440 --> 00:05:02,360 about architecture. The information is encoded in my brain. 81 00:05:02,640 --> 00:05:08,820 and since migraine cells can't transfer information to the sperm and the egg, 82 00:05:09,180 --> 00:05:13,748 because the information is supposed to reside in synaptic connections between 83 00:05:13,831 --> 00:05:17,191 different neurons, in particular circuits that developed. 84 00:05:17,275 --> 00:05:22,145 So what happens is the brain shouldn't be able to transfer to the next generation. 85 00:05:22,228 --> 00:05:27,000 Even simpler, a simpler example, if you go to the gym and you build up muscles, 86 00:05:27,390 --> 00:05:30,693 you know that your kids will have to work out on their own. 87 00:05:30,776 --> 00:05:34,767 This shortout won't happen. This is something that we know intuitively, 88 00:05:34,851 --> 00:05:37,522 even if we don't have any background in biology. 89 00:05:37,605 --> 00:05:41,195 This is connected to the fact that, as we said at the beginning, 90 00:05:41,278 --> 00:05:43,605 every cell in the body has its own genome, 91 00:05:43,688 --> 00:05:48,024 and the next generation will only form from the combination of the genomes in 92 00:05:48,107 --> 00:05:49,370 the sperm and the egg. 93 00:05:50,160 --> 00:05:55,537 even if you somehow acquire the mutation or change in your DNA. 94 00:05:55,620 --> 00:05:59,278 in one of particular brain cells, it wouldn't matter because this mutation, 95 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 96 00:06:03,253 --> 00:06:04,403 to the next generation. 97 00:06:05,130 --> 00:06:07,942 I'd like to take a quick break and acknowledge our sponsor, 98 00:06:08,025 --> 00:06:11,622 Eight Sleep. 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Again, that's 8sleep.com slash Huberman to save 117 00:07:21,346 --> 00:07:22,179 up to $350. 118 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 119 00:07:28,620 --> 00:07:31,613 Lamarck and Lamarckian evolution, very controversial, right? 120 00:07:31,696 --> 00:07:35,560 And maybe not even controversial. I think it's very offensive even to certain 121 00:07:35,644 --> 00:07:39,540 people. This idea of inheritance of acquired traits, the idea that one could 122 00:07:39,840 --> 00:07:43,333 change themselves through some activity. Use the example of going to the gym. 123 00:07:43,417 --> 00:07:46,771 We could also use the example of somebody who becomes an endurance runner, 124 00:07:46,854 --> 00:07:50,154 then decides to have children within another endurance runner. And 125 00:07:50,370 --> 00:07:53,508 has in mind the idea that because they did all this running, 126 00:07:53,591 --> 00:07:57,427 and not just because they were biased towards running in the first place, 127 00:07:57,510 --> 00:07:58,507 but because they... 128 00:07:58,590 --> 00:08:03,126 of the distance they actually ran that their offspring somehow would be fabulous 129 00:08:03,209 --> 00:08:05,230 runners. This Lamarckian concept is 130 00:08:05,430 --> 00:08:09,979 We believe wrong. So how do we talk about inheritance of acquired traits? 131 00:08:10,062 --> 00:08:14,294 What's the proper language for us to frame this discussion? Lamarck, 132 00:08:14,378 --> 00:08:18,990 this is what he believed. And he thought this is how evolution progressed. 133 00:08:19,073 --> 00:08:22,798 And later, Darwin showed that it's really natural selection. 134 00:08:22,881 --> 00:08:27,620 The selecting of the organisms that already contain the particular qualities 135 00:08:27,704 --> 00:08:32,590 are selected based on whether they survive or not in particular environments. 136 00:08:35,430 --> 00:08:38,839 they become more common and take over. This is very different. 137 00:08:38,923 --> 00:08:43,234 Two different explanations. The most common way this is contrasted is the neck 138 00:08:43,317 --> 00:08:46,896 of the giraffes. This is a classic example. According to Lamarck, 139 00:08:46,979 --> 00:08:50,190 the giraffes had to stretch their necks towards the trees 140 00:08:50,460 --> 00:08:54,013 to eat when the trees were high. And because of that, 141 00:08:54,097 --> 00:08:58,837 they transmitted these traits long next to their children who also had 142 00:08:58,920 --> 00:09:02,967 And according to Darwin, just that a giraffe that happened to be born with 143 00:09:03,051 --> 00:09:07,433 a long neck survived because it ate. So it's genetic heritable materials in know 144 00:09:07,516 --> 00:09:11,898 about genetics, but I take over and the rest of the giraffes that have different 145 00:09:11,981 --> 00:09:16,196 heritable materials just die. So this is natural selection versus inheritance 146 00:09:16,279 --> 00:09:17,340 of acquired traits. 147 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. 148 00:09:33,216 --> 00:09:37,014 The first barrier, we mentioned it, this is the separation of the soma from 149 00:09:37,097 --> 00:09:41,258 the germline. Right, the somatic cells, they can change in response to experience. 150 00:09:41,341 --> 00:09:45,773 The sperm and the egg, the so-called germ cells, cannot. That's the idea. 151 00:09:45,856 --> 00:09:48,941 Or they are isolated from what happens in the soma. 152 00:09:49,025 --> 00:09:52,917 The man who first thought about this barrier is called Weizmann. 153 00:09:53,001 --> 00:09:55,775 August Weizmann, this was in the 19th century. 154 00:09:55,859 --> 00:09:58,530 So it is called today the Weizmann Barrier. 155 00:09:58,830 --> 00:09:59,927 Separation of the sum 156 00:10:00,010 --> 00:10:03,416 From the germline, only the germline transmit information to the next 157 00:10:03,499 --> 00:10:06,551 generation. And this is also called the second law of biology. 158 00:10:06,634 --> 00:10:10,242 So this is very, very fundamental. So natural selection is the first one. 159 00:10:10,325 --> 00:10:13,882 This is the second one because it's so important to how our bodies work. 160 00:10:13,966 --> 00:10:17,050 The other main barrier, it's called epigenetic reprogramming. 161 00:10:17,380 --> 00:10:24,122 which is that we acquired our cells, the genetic material in our cells acquires all 162 00:10:24,206 --> 00:10:29,880 kinds of chemical changes, but these modifications are largely erased 163 00:10:30,610 --> 00:10:36,250 in the transition between generations. So in the germline, in the sperm and the egg, 164 00:10:36,430 --> 00:10:41,390 and also in the early embryo, most of the modifications are removed 165 00:10:41,500 --> 00:10:45,510 So we can start a blank slate based on the genetic instructions 166 00:10:45,760 --> 00:10:48,300 and this is cool shot, otherwise 167 00:10:48,760 --> 00:10:51,170 According to the theory, it's not clear that it's actually true, 168 00:10:51,253 --> 00:10:53,687 because in some organisms it doesn't really happen. 169 00:10:53,770 --> 00:10:59,254 we will not develop according to the species' typical genetic instructions. 170 00:10:59,337 --> 00:11:04,375 So to preserve this, we erase all these modifications and start anew. 171 00:11:04,459 --> 00:11:08,829 And this is in mammoths and in humans. This is largely true. 172 00:11:08,912 --> 00:11:13,728 Most of the modifications in the sperm and in the egg are removed, 173 00:11:13,811 --> 00:11:18,280 so about 90% of them. So the idea, if I understand correctly, is that 174 00:11:18,730 --> 00:11:25,007 there's some advantage to wiping the slate clean and returning to the original plan. 175 00:11:25,090 --> 00:11:28,414 In the context of the IKEA furniture analogy, 176 00:11:28,497 --> 00:11:34,607 the instruction book is the one that's issued to everybody, or every cell, right? 177 00:11:34,690 --> 00:11:37,156 Only certain instructions are used for certain cells, 178 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. 179 00:11:41,470 --> 00:11:43,849 through the course of the lifespan of the organism, 180 00:11:43,932 --> 00:11:46,552 those specific instructions are adjusted somewhat. Okay, 181 00:11:46,635 --> 00:11:48,724 so maybe the idea is to take the instruction, 182 00:11:48,807 --> 00:11:51,331 but go through and erase all the pen and pencil marks, 183 00:11:51,414 --> 00:11:54,565 erase all those additional little modifications that the owner used 184 00:11:54,648 --> 00:11:57,799 or introduced to it, and return to the original instruction. Right, 185 00:11:57,882 --> 00:12:00,454 because if you want to bring back the instruction book, 186 00:12:00,537 --> 00:12:03,592 you want it to have all the potential to make all the furnitures. 187 00:12:03,675 --> 00:12:06,425 You don't want it to be restricted to the ones that you 188 00:12:11,470 --> 00:12:16,030 is based on theoretical grounds because of these barriers 189 00:12:16,810 --> 00:12:20,740 and because of the controversies. On the other hand, 190 00:12:20,823 --> 00:12:26,650 people really want to believe it because It sort of gives your life meaning. 191 00:12:27,190 --> 00:12:30,270 If you can change your biology, 192 00:12:30,760 --> 00:12:34,786 of your kids through changing your biological disorder. Psychologically, 193 00:12:34,869 --> 00:12:38,838 I can understand why many people want this to happen. Even Schrodinger, 194 00:12:38,921 --> 00:12:40,097 the famous physicist, 195 00:12:40,180 --> 00:12:44,286 So he wrote a very important book in 44. And he talks about the heritable material. 196 00:12:44,370 --> 00:12:46,457 It also talks about evolution. And he said, 197 00:12:46,540 --> 00:12:49,697 inheritance of acquired traits is untenable. It doesn't happen. 198 00:12:49,780 --> 00:12:51,860 And you're right. 199 00:12:51,970 --> 00:12:56,281 This is very, very sad or unfortunate because unlike Darwinism or natural 200 00:12:56,365 --> 00:12:59,950 selection, which is gloomy, It doesn't matter what you do. 201 00:13:00,460 --> 00:13:04,771 The next generation will be born based on the instruction in the sperm and the egg. 202 00:13:04,854 --> 00:13:08,900 You can't influence it. Of course, you can give your kids money and education, 203 00:13:08,984 --> 00:13:11,494 but you can't biologically influence it. However, 204 00:13:11,578 --> 00:13:15,783 there's one additional thing to mention, which is there are also other mechanisms 205 00:13:15,866 --> 00:13:20,260 that might transmit information, including transmission between generations of RNA. 206 00:13:20,830 --> 00:13:24,914 And there are different types of RNA, not just messenger RNA, 207 00:13:24,998 --> 00:13:28,331 which encodes the information for making proteins, 208 00:13:28,414 --> 00:13:31,830 but also other RNAs that regulate gene expression. 209 00:13:32,230 --> 00:13:37,487 And I think that in recent years, also in the mammalian field, RNA... 210 00:13:37,570 --> 00:13:42,059 as the molecule that has the potential to transmit information between generations 211 00:13:42,142 --> 00:13:43,090 took center stage 212 00:13:43,360 --> 00:13:47,537 So I think this is the cutting edge. A lot more to understand and know, 213 00:13:47,620 --> 00:13:51,677 but RNA has a lot of potential for doing that, as we'll explain soon, 214 00:13:51,760 --> 00:13:53,740 but we have to go to worms first. 215 00:13:54,010 --> 00:13:58,363 Many, if not most of our listeners are focused on humans and human biology 216 00:13:58,446 --> 00:14:02,919 and health, et cetera. But I cannot emphasize enough the importance of model 217 00:14:03,002 --> 00:14:07,475 organisms and the incredible degree to which they've informed us about human 218 00:14:07,558 --> 00:14:11,431 health, especially when it comes to very basic functions in cells. 219 00:14:11,515 --> 00:14:15,148 Before we start to go into the description about worms per se, 220 00:14:15,232 --> 00:14:16,937 could you just explain to the 221 00:14:17,020 --> 00:14:23,700 a general audience, what a model organism is and why you've selected or elected 222 00:14:23,784 --> 00:14:24,640 to work on 223 00:14:24,760 --> 00:14:29,490 a particular type of worm to study these fascinating topics that there's zero 224 00:14:29,574 --> 00:14:32,554 question also take place in humans at some level. 225 00:14:32,637 --> 00:14:35,242 Model organisms mean that it's an organism. 226 00:14:35,325 --> 00:14:39,868 There's a huge community of researchers that combine sources to create all 227 00:14:39,952 --> 00:14:43,807 the resources and the tools and understanding that accumulates. 228 00:14:43,890 --> 00:14:47,183 We learned about every aspect of biology through them, 229 00:14:47,266 --> 00:14:52,434 including many important diseases. And the reason that we can learn a lot also about 230 00:14:52,517 --> 00:14:53,351 humans by 231 00:14:54,760 --> 00:14:57,860 that we all evolved from The same end system. 232 00:14:58,180 --> 00:15:01,609 We share a lot of our functions with them, and also a lot of our genes. 233 00:15:01,692 --> 00:15:04,726 They sometimes have things that are much more apparent in them, 234 00:15:04,809 --> 00:15:08,139 that we can study. Another important reason to study them, of course, 235 00:15:08,223 --> 00:15:11,454 is you can actually experiment on them. We can't do this to humans, 236 00:15:11,537 --> 00:15:15,037 the things that we do to these animals. And we can change their genes. 237 00:15:15,640 --> 00:15:19,354 Do all kinds of things for them. The community of people that study C. 238 00:15:19,438 --> 00:15:23,532 elegans has literally numbered and named each neuron so that two laboratories 239 00:15:23,615 --> 00:15:27,275 on opposite sides of the world can publish papers on the same neuron, 240 00:15:27,358 --> 00:15:30,964 knowing that it's the same neuron in the two different laboratories. 241 00:15:31,047 --> 00:15:33,760 Something that is extremely hard to do in any way. 242 00:15:33,880 --> 00:15:37,526 mammalian model, a mouse or certainly in humans, 243 00:15:37,609 --> 00:15:43,897 and has posed huge challenges that give great advantages to studies of things like 244 00:15:43,980 --> 00:15:48,014 C. elegans. C. elegans nematode always has 959 cells, 245 00:15:48,098 --> 00:15:53,450 out of which 302 are neurons. We have a connectome, Since the 80s, 246 00:15:53,590 --> 00:15:58,208 like a subway map that tells us which neuron talks with which other neurons 247 00:15:58,291 --> 00:16:01,990 and it is the same not only that, the worms are transparent 248 00:16:02,080 --> 00:16:07,487 So we can actually see the neurons fire using particular tools. 249 00:16:07,570 --> 00:16:12,178 And we can activate genes and silage genes using optogenetics. On top of that, 250 00:16:12,262 --> 00:16:15,630 we have great understanding of the genetics of the worm. 251 00:16:16,450 --> 00:16:22,138 of the genome. Silicone is the first animal to have its genome sequenced before 252 00:16:22,221 --> 00:16:26,970 humans. And we know that each worm produces, each mother produces 253 00:16:27,220 --> 00:16:31,300 about 250 babies which are almost genetically identical 254 00:16:31,540 --> 00:16:35,057 And we know where we grow them. The environment is very controlled. 255 00:16:35,141 --> 00:16:37,720 So we grow them in the plate with just bacteria. 256 00:16:37,810 --> 00:16:40,779 So we can easily separate between nature and nurture. 257 00:16:40,863 --> 00:16:43,570 The generation time in C elegans is three days. 258 00:16:43,780 --> 00:16:47,635 Three days. So you can do hundreds of worm generations in one PhD. 259 00:16:47,719 --> 00:16:51,872 This is very important. Not only that, every worm will produce hundreds 260 00:16:51,955 --> 00:16:54,378 of progeny that are genetically identical, 261 00:16:54,462 --> 00:16:58,460 so you will have great statistics for your experiment. In the worm. 262 00:16:58,810 --> 00:17:03,257 We now have very... Obviously, and clear-cut 263 00:17:03,340 --> 00:17:06,640 proof that there is inheritance of acquired trades. 264 00:17:06,730 --> 00:17:11,770 So much so that I don't think that anyone pretty much in the epigenetic field 265 00:17:12,100 --> 00:17:13,400 argues against it. 266 00:17:13,540 --> 00:17:17,182 I'd like to take a quick break and acknowledge our sponsor, AG1. 267 00:17:17,266 --> 00:17:20,559 AG1 just launched their newest formulation called AG1 Pro. 268 00:17:20,642 --> 00:17:24,459 And right now you can get an extra 20% off your first subscription. 269 00:17:24,542 --> 00:17:27,021 AG1 takes the clinically backed AG1 formula, 270 00:17:27,104 --> 00:17:30,921 which is a blend of vitamins, minerals, probiotics, and adaptogens, 271 00:17:31,004 --> 00:17:35,345 and adds three important new ingredients, creatine monohydrate, calcium HMB, 272 00:17:35,429 --> 00:17:39,944 and zinc carnosine. 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I continue to take it and back it here on the podcast because it 281 00:18:10,664 --> 00:18:12,880 is an excellent formula, and it's now even 282 00:18:13,540 --> 00:18:18,620 the AG1 Pro formula. For a limited time, you can get an extra 20% off your first 283 00:18:18,703 --> 00:18:23,332 subscription to AG1 Pro by going to drinkag1.com slash Huberman and using 284 00:18:23,415 --> 00:18:26,881 the code back to routine. So that's with a numeral two, 285 00:18:26,965 --> 00:18:31,160 back numeral two routine. Just go to drinkag1.com slash Huberman. 286 00:18:31,840 --> 00:18:35,219 What was the first experiment that you did on C. 287 00:18:35,302 --> 00:18:40,629 elegans that confirmed for you that inheritance of acquired traits is real? 288 00:18:40,712 --> 00:18:46,472 We set to test whether worms can produce transgenerational resistance to viruses. 289 00:18:46,555 --> 00:18:50,583 These worms don't have dedicated immune cells like we do. 290 00:18:50,666 --> 00:18:55,847 They don't have T cells or B cells. They defend themselves from viruses. 291 00:18:55,930 --> 00:18:58,450 using RNA that destroy viruses. 292 00:18:58,660 --> 00:19:00,420 And these are called small RNAs. 293 00:19:00,580 --> 00:19:04,520 2006, two researchers that were studying C. elegance, 294 00:19:04,810 --> 00:19:07,810 Andrew Feier and Craig Mello got the Nobel Prize. 295 00:19:08,050 --> 00:19:12,310 for showing that there is a mechanism that regulates genes 296 00:19:13,060 --> 00:19:18,100 that happens for small RNAs. What they've shown is that if you... 297 00:19:18,490 --> 00:19:20,160 inject The warmth. 298 00:19:20,800 --> 00:19:26,560 with RNA molecules, which are double-stranded. They shut off the genes, 299 00:19:26,680 --> 00:19:28,900 that match in sequence to this RNA. 300 00:19:29,020 --> 00:19:34,122 So sort of like taking the specific instructions for the coffee table 301 00:19:34,205 --> 00:19:36,760 from your IKEA handbook and you... 302 00:19:36,880 --> 00:19:40,370 insert a copy of that into the book. And in doing so, 303 00:19:40,453 --> 00:19:44,887 you prevent the expression of, you sort of erase the original page. 304 00:19:44,971 --> 00:19:49,960 Perfect explanation. They found that double-strand RNA RNA is two strands. 305 00:19:50,050 --> 00:19:54,502 is what starts the response, leading to the production of small RNA molecules, 306 00:19:54,586 --> 00:19:58,689 which are the ones that actually find the messenger RNA and leads to its 307 00:19:58,772 --> 00:20:02,030 destruction. Silence it so you don't get proteins in the end. 308 00:20:02,600 --> 00:20:06,997 For that, they got the Nobel Prize after people found that this is conserved 309 00:20:07,080 --> 00:20:10,829 in many organisms, including humans. And now there are now drugs. 310 00:20:10,912 --> 00:20:14,955 This was only in 2006, the Nobel Prize. The paper was published in 98. 311 00:20:15,039 --> 00:20:19,460 There are now drugs that use this mechanism. It is called RNA interference. 312 00:20:19,760 --> 00:20:23,856 RNA interferes in the expression of a gene in the function of a gene. 313 00:20:23,939 --> 00:20:28,459 And it's also called gene silencing because these RNAs enforce the silencing 314 00:20:28,542 --> 00:20:32,540 of genes. Instead of the genes being expressed, they are silenced. 315 00:20:32,660 --> 00:20:37,137 and you don't manifest the function. They've shown Two very important things. 316 00:20:37,220 --> 00:20:39,440 You don't only see the... 317 00:20:39,830 --> 00:20:43,649 action in the cell that you injected or in the tissue that you injected, 318 00:20:43,732 --> 00:20:46,497 but you see it all over the worm's body. It spreads. 319 00:20:46,580 --> 00:20:49,590 This includes also The Joneses. 320 00:20:50,150 --> 00:20:53,870 So if you inject the davenant RNA just to somatic cells, 321 00:20:54,650 --> 00:20:57,530 even to the head, you will get also 322 00:20:57,650 --> 00:21:00,597 the effect in the germ cells and in the next generation. 323 00:21:00,680 --> 00:21:05,730 Later they've shown that you can just take worms and feed them. 324 00:21:05,900 --> 00:21:09,620 on bacteria that produce this double-strand RNA. 325 00:21:09,740 --> 00:21:13,288 And that the double stand and the silencing would move from the site 326 00:21:13,371 --> 00:21:16,220 of ingestion from the gut where the Bacteria are eaten. 327 00:21:16,640 --> 00:21:19,487 to the rest of the body and also to the next generation. 328 00:21:19,571 --> 00:21:23,600 And this is not controversial at all. This is being done routinely every day, 329 00:21:23,870 --> 00:21:26,170 by any C. elegans biologist. in the world. 330 00:21:26,630 --> 00:21:29,127 This has been replicated a million times. 331 00:21:29,210 --> 00:21:33,648 When I started my work, I wanted to see whether in addition to artificial 332 00:21:33,731 --> 00:21:36,790 double-stranded RNA, some natural traits 333 00:21:36,920 --> 00:21:41,038 can also transmit across generations because of RNA, 334 00:21:41,122 --> 00:21:47,341 because of small RNAs. Right, because injecting RNAi or short-term interfering 335 00:21:47,424 --> 00:21:51,250 RNAs, that is, or... you know, putting Thank you. 336 00:21:51,650 --> 00:21:54,820 worms into an environment with an abundance of inhibitory RNAs as 337 00:21:54,903 --> 00:21:58,924 an experiment is very different than worms experiencing something and then passing 338 00:21:59,008 --> 00:22:01,110 on that acquired trait to their offspring. 339 00:22:02,450 --> 00:22:05,811 It's a world apart, in my opinion, because one is extreme manipulation 340 00:22:05,895 --> 00:22:09,237 that illustrates an underlying principle. The other is something that 341 00:22:09,320 --> 00:22:12,665 in theory, occurs in the passage of generations just naturally. 342 00:22:12,749 --> 00:22:15,931 We're going from the less artificial to the more artificial. 343 00:22:16,014 --> 00:22:18,816 There are advantages, just like with model organisms, 344 00:22:18,899 --> 00:22:21,646 that the more artificial it is, the easier it is to, 345 00:22:21,729 --> 00:22:26,000 you know exactly what you did. Just now, introduce one factor and you can follow 346 00:22:26,083 --> 00:22:28,260 the result. So this is always the trade. 347 00:22:28,610 --> 00:22:32,161 In fact, this is probably the reason that these small organes evolved in the first 348 00:22:32,244 --> 00:22:33,077 place. 349 00:22:33,320 --> 00:22:36,810 to get rid of viruses and other 350 00:22:36,950 --> 00:22:41,550 parasitic genomic elements, and this is a mechanism to fight them. 351 00:22:41,750 --> 00:22:44,830 We demonstrated this very clearly, 352 00:22:45,950 --> 00:22:49,974 using a fluorescent virus. If the virus replicates successfully, 353 00:22:50,057 --> 00:22:54,600 the virus just turns green. And if the virus is destroyed, The warm stays black. 354 00:22:54,950 --> 00:22:57,770 This is very simple. It's a clear cutoff. We took worms. 355 00:22:58,190 --> 00:23:01,140 We infect them with the fluorescent virus. They destroy it. 356 00:23:01,310 --> 00:23:06,170 This also has been done in the past. But then what we did is we neutralized... 357 00:23:06,590 --> 00:23:11,120 the machinery that makes small RNAs in the 358 00:23:11,660 --> 00:23:15,620 descendants of the worms. So they cannot make small RNAs 359 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 360 00:23:20,058 --> 00:23:24,061 to make this model. And then we ask, what will happen when we affect these worms 361 00:23:24,145 --> 00:23:26,490 with the vows? Will they be green? 362 00:23:26,960 --> 00:23:29,840 or black. They can't make their own small RNAs. 363 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 364 00:23:34,490 --> 00:23:38,103 for them not having the virus replicate is if they inherit a small amount from 365 00:23:38,187 --> 00:23:42,179 their parents. And this is exactly what happens. All the worms' progeny, 366 00:23:42,262 --> 00:23:44,250 although they don't have the gene, 367 00:23:44,570 --> 00:23:48,070 that is needed for making the small RNAs are black. They silence the virus. 368 00:23:48,153 --> 00:23:50,703 And this also continues for additional generations. 369 00:23:51,290 --> 00:23:54,590 So the parent worms effectively... 370 00:23:54,860 --> 00:23:58,871 put something into the genetic instructions of the offspring that would 371 00:23:58,955 --> 00:24:01,928 afford them, let's call it an advantage in this case, 372 00:24:02,011 --> 00:24:06,426 but afford them an advantage if they were to be confronted with the same thing 373 00:24:06,510 --> 00:24:10,636 that the parents were. Right. And we know exactly what this advantage is. 374 00:24:10,720 --> 00:24:16,090 The advantage is. are small RNAs that match the viral genome. 375 00:24:16,190 --> 00:24:19,132 Then just chop up the virus in the next generation. 376 00:24:19,215 --> 00:24:21,410 And we can identify these small RNAs. 377 00:24:22,460 --> 00:24:24,740 in the inhibitory RNAs in the descendants, 378 00:24:24,823 --> 00:24:29,241 although they don't have the machinery to make it, just because they inherit it. 379 00:24:29,324 --> 00:24:32,110 We can identify them by sequencing. RNA sequencing, 380 00:24:32,194 --> 00:24:36,443 which is like DNA sequencing, you actually get the actual sequence of the RNA 381 00:24:36,526 --> 00:24:39,819 molecules. And we can see that they correspond to the virus, 382 00:24:39,902 --> 00:24:44,320 and they inherit these small RNAs only if their parents were infected with them. 383 00:24:44,403 --> 00:24:48,220 It is true that also in mammoths, RNAs and small RNAs. 384 00:24:48,350 --> 00:24:53,150 are a leading candidate for something that could mediate the transmission of virus. 385 00:24:53,510 --> 00:24:58,205 stress protection or also of harmful effects that transmit between generations. 386 00:24:58,289 --> 00:25:02,742 Perhaps RNA do it. And it's very interesting to think about it when we talk 387 00:25:02,825 --> 00:25:07,097 about inheritance of memories. Can brain activity of some sort transmit, 388 00:25:07,181 --> 00:25:11,694 at least in these words? I said, Noah, I said this disclaimer multiple times 389 00:25:11,778 --> 00:25:13,257 in members we don't know. 390 00:25:13,340 --> 00:25:17,997 Times will tell. In worms, we know a lot. So can worms transmit brain activity? 391 00:25:18,080 --> 00:25:22,677 Do they have the specificity to do? I think that any tissues that transmit RNA 392 00:25:22,760 --> 00:25:26,900 to the next generation and affect the next generation is interesting. 393 00:25:27,230 --> 00:25:30,117 the guts Muscles, everything, but the brain. 394 00:25:30,200 --> 00:25:35,097 can synthesize information about the environment and about 395 00:25:35,180 --> 00:25:40,687 internal state and can also think ahead. And the most provocative thing you can say 396 00:25:40,770 --> 00:25:43,017 is that you could plan how somehow 397 00:25:43,100 --> 00:25:45,624 the fate of your nation using your brain. You know, 398 00:25:45,707 --> 00:25:49,458 after taking many things into the code. - Without talking to them. - Right, 399 00:25:49,542 --> 00:25:52,730 without talking. - Again, we go back to this instruction manual. 400 00:25:52,814 --> 00:25:56,463 It's like writing something into the instruction manual based on your own 401 00:25:56,546 --> 00:25:59,460 experience. - Right. We have to understand that the brain 402 00:26:00,170 --> 00:26:03,657 uses a different language. than the language of inheritance. 403 00:26:03,740 --> 00:26:09,038 It keeps information... In... synapses in the connections between different neurons. 404 00:26:09,122 --> 00:26:13,201 When you learn something, you make some connections stronger and other connections 405 00:26:13,285 --> 00:26:17,030 weaker. And you wire the nervous system in a different way. 406 00:26:17,113 --> 00:26:22,488 On the other hand, heritable information of any sort has to go through a bottleneck 407 00:26:22,571 --> 00:26:27,210 of one cell. the fertilized egg, because we all start from just one cell. 408 00:26:27,410 --> 00:26:30,969 So the question is, can you or do you translate the information, 409 00:26:31,052 --> 00:26:35,408 this 3D structure information of synapses and the connection between brains in 410 00:26:35,491 --> 00:26:39,506 the architecture of the brain? Can you somehow translate it to heritable 411 00:26:39,589 --> 00:26:41,367 information to a molecular form? 412 00:26:41,450 --> 00:26:44,171 You can teach worms, even though they have just 302 neurons, 413 00:26:44,254 --> 00:26:47,069 you can teach them simple things about the world. For example, 414 00:26:47,152 --> 00:26:50,007 you can take an odor that the worms like. The worms have... 415 00:26:50,090 --> 00:26:53,827 thousands of odorant receptors, and they can recognize many, many, 416 00:26:53,910 --> 00:26:58,169 many molecules. They can smell them so they can find food or avoid enemies. 417 00:26:58,252 --> 00:27:02,220 You can take an odor that the worms like and pair it to something bad, 418 00:27:02,304 --> 00:27:03,230 like starvation. 419 00:27:04,190 --> 00:27:06,830 And then the worms will learn to dislike this auto. 420 00:27:08,390 --> 00:27:13,342 We don't know that this learning involves necessarily changing in the strengths 421 00:27:13,425 --> 00:27:17,486 of synapses. It's a possibility, but it doesn't have to be the case. 422 00:27:17,570 --> 00:27:20,820 It could be that just the receptor for this particular odor 423 00:27:21,710 --> 00:27:23,250 is being removed. 424 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, 425 00:27:26,883 --> 00:27:29,247 they won't like the odor. This is a possibility. 426 00:27:29,330 --> 00:27:31,610 This type of thing you can perhaps... 427 00:27:31,790 --> 00:27:34,073 not that anyone has showed it convincingly, 428 00:27:34,156 --> 00:27:38,311 transmit to the next generation because all it would take is an RNA that will 429 00:27:38,394 --> 00:27:40,210 control this particular receptor. 430 00:27:40,700 --> 00:27:43,566 People have shown things like that, not in C. elegans, 431 00:27:43,649 --> 00:27:46,380 but people have shown things like this in members. 432 00:27:47,570 --> 00:27:50,970 They said that you learn certain things and then Thank you. 433 00:27:51,260 --> 00:27:54,800 Just in the next generation, that's a particular receptor would be... 434 00:27:54,950 --> 00:27:58,490 Methylated or would change and this would transmit the response. 435 00:27:58,730 --> 00:28:01,620 And On the one hand, it could be 436 00:28:02,360 --> 00:28:05,420 True. On the other hand, you need to understand 437 00:28:05,510 --> 00:28:09,006 They'll need to prove, and this wasn't done convincingly enough yet, 438 00:28:09,090 --> 00:28:13,375 how exactly does the information transfer from the brain to the germ cells and then 439 00:28:13,459 --> 00:28:17,692 in the next generation from the germ cells back to the brain to where the receptor 440 00:28:17,775 --> 00:28:18,670 needs to operate. 441 00:28:19,250 --> 00:28:22,365 And this is a challenge. This is the current state of the field that this 442 00:28:22,449 --> 00:28:24,299 is something that needs to be proven. 443 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 444 00:28:28,340 --> 00:28:31,812 can communicate with the next generations using small RNAs. 445 00:28:31,895 --> 00:28:36,693 And that this can change behavior. And it doesn't require any translating between 446 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, 447 00:28:41,630 --> 00:28:45,650 and you change the production of small RNAs just in its brain, 448 00:28:46,220 --> 00:28:49,578 In the next generations, their behavior will be different, 449 00:28:49,661 --> 00:28:52,247 even though you don't mess with their brains. 450 00:28:52,331 --> 00:28:56,757 This is a paper that we published in 2019 in Cell. We show that you just... 451 00:28:56,840 --> 00:29:01,712 manipulates the production of endogenous, natural RNAs in the worm's brain that are 452 00:29:01,795 --> 00:29:06,727 always made, but you change their amount. And this changes the capacity of the worms 453 00:29:06,811 --> 00:29:08,960 in the next generation to find food. 454 00:29:09,260 --> 00:29:12,500 Not only in one generation, but three generations down the road. 455 00:29:12,800 --> 00:29:15,297 And the way that it works is that 456 00:29:15,380 --> 00:29:20,560 perturbing the production of these small RNAs in the brain, affects in the end 457 00:29:20,720 --> 00:29:23,240 the expression of a gene in the germline. 458 00:29:23,840 --> 00:29:27,685 one gene, it's called SAGE2, we can do all kinds of controls where we manipulate 459 00:29:27,768 --> 00:29:31,018 the activity of the gene and see that this also affects behavior. 460 00:29:31,460 --> 00:29:35,570 And this gene It works in the jumpsuits. 461 00:29:35,780 --> 00:29:38,213 The information needs to go from the brain to the germ-sys. 462 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. 463 00:29:41,960 --> 00:29:46,261 And this depends, we know that this is a true epigenetic effect because it goes 464 00:29:46,344 --> 00:29:50,340 on for multiple generations, and also because it requires the machinery. 465 00:29:51,470 --> 00:29:55,163 that transfers RNA between generations. If you don't have the protein that physically 466 00:29:55,246 --> 00:29:57,627 carries the RNA between generations, it doesn't happen. 467 00:29:57,710 --> 00:29:59,110 So it has to be RNA. 468 00:30:00,000 --> 00:30:03,000 We can also find alienating the next generation to change. 469 00:30:03,180 --> 00:30:07,460 We sequence the actual RNAs the change in the next generation. 470 00:30:07,770 --> 00:30:08,670 It sounds weird. 471 00:30:09,030 --> 00:30:12,311 that you change germ cells and it changes behavior, sperm and egg. 472 00:30:12,394 --> 00:30:15,350 But if you think about it, the germ cells affect the soma, 473 00:30:15,630 --> 00:30:19,110 including the brain, in many ways by secreting 474 00:30:19,200 --> 00:30:24,412 certain chemicals. And also because the other cells develop from the germ cells, 475 00:30:24,495 --> 00:30:29,111 so some information could be transmitted over development or the course 476 00:30:29,194 --> 00:30:34,406 of development could be altered because of changes that occur in the germ cells. 477 00:30:34,489 --> 00:30:39,436 For example, in MEMES, one of the explanations for how heritable information 478 00:30:39,520 --> 00:30:43,117 transmits is that it just affects something very own in 479 00:30:43,200 --> 00:30:47,857 I told you that the secret to worms' inheritance is that they have the capacity 480 00:30:47,940 --> 00:30:52,777 to amplify these small RNAs all the time. This is what keeps it going and prevents 481 00:30:52,860 --> 00:30:57,277 the dilution. In mammals, we don't know of such an amplification mechanism. 482 00:30:57,360 --> 00:30:58,627 So you ask, how can... 483 00:30:58,710 --> 00:31:03,651 A little bit of RNA or something without amplifying affect the entire organism. 484 00:31:03,734 --> 00:31:08,103 And it could be that you just perturb something in the very beginning, 485 00:31:08,186 --> 00:31:13,381 when you just have a few cells, or even in the placenta that develops in pregnancy. 486 00:31:13,465 --> 00:31:17,070 And this later throws everything off. And because of that, 487 00:31:17,153 --> 00:31:20,059 you have many problems in metabolism and so on. 488 00:31:20,142 --> 00:31:24,193 And this is called the idea of the developmental origin of health 489 00:31:24,276 --> 00:31:28,410 and disease. Many of the functions occur early on in development. 490 00:31:28,980 --> 00:31:32,223 I'd like to take a quick break and acknowledge one of our sponsors, 491 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 515 00:33:00,301 --> 00:33:01,135 pack. 516 00:33:01,230 --> 00:33:06,128 In terms of the work in either C. elegans or in other model organisms, 517 00:33:06,211 --> 00:33:10,825 but in particular in C. elegans, where do you see this going next? 518 00:33:10,908 --> 00:33:13,447 So assuming that we will discover... 519 00:33:13,530 --> 00:33:17,713 similar things in humans, which we don't know that this is the case, 520 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 521 00:33:22,627 --> 00:33:27,814 change it. You could also change a parent inheritance by having the parent exercise, 522 00:33:27,897 --> 00:33:32,202 for example. And some things like this have been done. For example, 523 00:33:32,285 --> 00:33:37,300 there are experiments in rodents where they show that overfeeding the rodents 524 00:33:37,384 --> 00:33:41,290 creates problems for the next generation, for the children. 525 00:33:42,780 --> 00:33:47,513 If you let the rodent exercise, then it corrects the aberrant inheritance. 526 00:33:47,597 --> 00:33:52,265 So this is one possibility. And you can also manipulate it at the source. 527 00:33:52,348 --> 00:33:56,025 You can change it. If it's RNAs, let's say you could, in the future, 528 00:33:56,108 --> 00:33:59,791 perhaps if we understand how it works, actually change the composition of 529 00:33:59,874 --> 00:34:01,657 the heritable RNAs. If you do IVFs, 530 00:34:01,740 --> 00:34:06,664 if you need vitro fertilization you can perhaps change the composition of the RNAs 531 00:34:06,747 --> 00:34:09,370 in the stuff that you introduce Thank you. 532 00:34:09,480 --> 00:34:14,622 But way before that, what you could do, perhaps even in the not so far future, 533 00:34:14,705 --> 00:34:16,837 is... use this for diagnostics. 534 00:34:16,920 --> 00:34:21,417 DNA-based diagnostics for every couple that wants to have a kid. In Israel, 535 00:34:21,500 --> 00:34:25,997 this is done for most couples. You can look at the DNA and look for genetic 536 00:34:26,080 --> 00:34:29,500 disease. But no one is looking at the RNA at the moment. 537 00:34:29,880 --> 00:34:33,247 If we understand how it works better, we'll have another level, 538 00:34:33,330 --> 00:34:37,628 a whole new world to look at. And perhaps there will be some RNAs that correlate 539 00:34:37,711 --> 00:34:41,133 with disease. The beauty is that this, unlike DNA, it's plastic. 540 00:34:41,216 --> 00:34:44,857 So with DNA, this is your DNA. Perhaps we can choose another embryo. 541 00:34:44,940 --> 00:34:48,515 But here you could say, Perhaps, again, in the future, this is science fiction, 542 00:34:48,598 --> 00:34:51,227 it doesn't happen now, but if we understand this and it's true, 543 00:34:51,310 --> 00:34:54,702 we can say... Maybe you should run on the treadmill a little bit. 544 00:34:54,786 --> 00:34:58,536 This will change the profile of your RNAs, and then we will use it for IVF. 545 00:34:58,770 --> 00:35:01,670 This seems more because just it correlates 546 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 547 00:35:06,545 --> 00:35:11,354 great potential. Again, with a disclaimer that we don't know how it works in humans 548 00:35:11,437 --> 00:35:15,880 at all. Yes. But of course, this is why it's so interesting. Today, 549 00:35:15,963 --> 00:35:19,884 you've taken us on an amazing journey through the genome RNA, 550 00:35:19,967 --> 00:35:24,347 in particular the work in your laboratory, which is just incredible, 551 00:35:24,431 --> 00:35:28,811 and also this introduction of model organisms. So thank you so much. 552 00:35:28,895 --> 00:35:33,030 It's been a real pleasure. Pleasure was all mine. Thanks a lot.