Into the Impossible With Brian Keating - Studying Autism with BRAINS Grown In Space | Alysson Moutri on The INTO THE IMPOSSIBLE Podcast (#304)

Episode Date: March 20, 2023

Please support the podcast by taking our short listener survey: https://www.surveymonkey.com/r/intotheimpossible Be sure to watch the video of this episode on YouTube here: https://youtu.be/hDKGF5W4Qis?sub_confirmation=1 Where does consciousness come from? Can we cure autism? Can we grow a human BRAIN in Space? Dr. Alysson Muotri joins me to discuss all these fascinating questions and more. Brain organoids are lab-grown minibrains that mimic structural and functional features of full-size brains. They are created by culturing pluripotent stem cells in a three-dimensional rotational bioreactor, and they develop over a course of months. Brain organoids have emerged as novel model systems that can be used to investigate human brain development and disorders34, as well as evolutionary studies and neural network research Muotri is a Professor at the Departments of Pediatrics and Cellular & Molecular Medicine at UC San Diego, an Associate Director of CARTA, The Center for Research and Training in Anthropology, and Director of the Stem Cell Program, and of the Archealization Center (ArchC) at UC San Diego. He moved to the Salk Institute as Pew Latin America Fellow in 2002 for postdoctoral training in the fields of neuroscience and stem cell biology. His research focuses on brain evolution and modeling neurological diseases using human-induced pluripotent stem cells and brain organoids. He has an additional focus on solving one of life's greatest mysteries: What is it that makes us uniquely human? Our unique social brains are one of the key distinguishing factors between humans and other primates. We are even very different from our closest relatives, the Neanderthals. His work has implications for the generation of human disease models by determining the molecular and cellular mechanisms driving neurological complex disorders, such as autism. It is also creating opportunities for identifying and testing novel therapeutic approaches. Understanding the evolutionary path and the tradeoffs of the modern human brain will likely illuminate the origins of human disease. Dr. Moutri has received several awards, including the prestigious NIH Director’s New Innovator Award, NARSAD, Emerald Foundation Young Investigator Award, Surugadai Award, Rock Star of Innovation, NIH EUREKA Award, and two Telly Awards for Excellence in Science Communication. Links: Department of Cellular and Molecular Medicine: cmm.ucsd.edu Center for Academic Research and Training in Anthropogeny: carta.anthropogeny.org/users/alysson-muotri the Archealization Center: Archc.ucsd.edu Subscribe to the Jordan Harbinger Show for amazing content from Apple’s best podcast of 2018! https://www.jordanharbinger.com/podcasts  Please leave a rating and review: On Apple devices, click here, https://apple.co/39UaHlB On Spotify it’s here: https://spoti.fi/3vpfXok On Audible it’s here https://tinyurl.com/wtpvej9v  Find other ways to rate here: https://briankeating.com/podcast Support the podcast on Patreon https://www.patreon.com/drbriankeating  or become a Member on YouTube- https://www.youtube.com/channel/UCmXH_moPhfkqCk6S3b9RWuw/join To advertise with us, contact [e-mail] Learn more about your ad choices. Visit megaphone.fm/adchoices

Ambition comes in all shapes and sizes. At First Citizens Bank, we roll with your goals because we're built for what you're building. Fit for your ambition for Citizens Bank. Ivan, my son now, and I just fell in love. I mean, I didn't see autism, I see the individual. He has difficulties on his daily life. I mean, he's totally dependent because he has no sense of dangers.

He will cross the street and will put himself in a dangerous situation. And he's no verbal, so he cannot say anything about, I mean, how is his feeling, things like that. That creates some frustrations because you cannot express. He's a big motivation now on the translational side. I really want to make sure my science can help him and others like him to kind of cope with autism and daily life and become independent, right? But on the other side, I don't want to lose him and my interactions with him. Otherwise, I would be working like 24 hours and just doing that. But I want to enjoy his life.

And that comes a challenge. I mean, how you do the same things that would do with a we call neurotypical or normal person. But to be honest, I mean, makes life unpredictable. And I like it. I've been enjoying the process. What I would say to other parents or other families is not let the condition takes over your life. But embrace it. I mean, that's it.

I mean, better days will come. I'm highly optimistic about that. But until there, I mean, trying to make the best of your life. Have you wondered what evolutionary milestone separated us from Neanderthals and other early hominies to give us language and civilization? What's the mechanism and genetic source code for neurodivergent conditions such as autism? What happens to the brain during long-duration space missions? Are pluripotent stem cells, the gateway to a new era of medicine? Our guest on this episode of Into the Impossible is celebrated UC San Diego neuroscientist professor Alison

Mautry. He has wondered about all of these profound questions and turned that curiosity into experimental research that pushes the boundaries of anthropology, biology, and medicine. In this episode, recorded live in our studios at UC San Diego, your host Professor Ryan Keating and Professor Motry discuss his background, the scientist stem cells, and his personal motivations for pursuing his groundbreaking research. If you appreciate hearing firsthand from scientists, like Professor Motry, please consider adding to our dataset with a five-star rating and keep in touch with Professor Keating by joining his email list at Briankeating.com slash list. And if you have a dot edu domain, we'll send you a bit of space dust in the form of an authentic meteorite fragment.

Please help make the show better by filling out our listener survey linked to in the show notes. And please let us know what you think of the show in the form of a review like this one, Shane for good, a valuable use of time. Dr. Keating's podcast has never failed to teach me something interesting about our world and universe. Dr. Keating's curiosity and intellectual integrity and good moral nature are always reflected in the podcast. And now, be inspired and amazed as we go into the impossible with Professor Alison Motry. Any sufficiently advanced technology is indistinguishable from magic. Open the pod bay doors, please, help. Professor Allison Motry. Welcome to the Into the Impossible Studios.

Thanks, Brian. Long due. Yes, it has been overdue. I don't often get to chat with someone who's literally a rock star and has a grant to prove it. You are a professor here, a colleague, friend of ours here at the Arthur C. Clark Center for Human Imagination. You've been involved for quite some time. You're a rocket scientist. You're a brain surgeon. You do all these things people say, you know, they can't tell the difference between which is more interesting or difficult.

But you do them both. So that's really cool. We're going to talk about rockets. We're going to talk about brains. We're going to talk about everything. But first, I want to give a quick background and who you are, where you came from. Cool. You're kind of your origin story.

So you're from Brazil originally, as my sister-in-law is. And I wanted to kind of trace your path from South America all the way up to here and to become the leader that you are among many, many other projects. But the ones we're going to be speaking about today involve sending bits of brains into space and actually just studying them here on Earth. So take it away, Elsa. All right. Yeah.

So I'm originally from San Paulo, Brazil. My family is a middle-class family, oranges from Italy. So I think we are third generation of Italians in San Paulo in Brazil. And I was always like a scientist. I didn't know exactly what kind of scientist, but I was always very curious, very into natures and exploring everything. And that drove me to do biology, to study biology. So that was when I joined the University of Campinas, which is in the countryside of San Paulo for my undergrad studies.

And after that, I moved straight directly to a PhD program at the University of San Paulo. This was on DNA repair, learning about the DNA metabolism in cells. At that stage, I was already into genetics, trying to understand human genetics. So my PhD was human genetics and potential like gene tithe. therapy ways to interact with the genome. And that was back in 2001. So in 2002, I moved to the Salk Institute to work with Rusty Gage, a good friend, a good mentor. And I learned more about stem cells and neuroscience. And in 2008, 2009, that's when I got my first faculty position here in U.S. and I decided to stay. And I've been here for several years now. And you're in both

pediatrics and you're also in cellular molecular medicine and that's a kind of a unique department or division that most universities don't have so pediatrics people you know should know more or less they were once you know seen by such physicians but what is a cellular and molecular medical department what is that about yeah no that that's a great question and this is a very unique to use a CD we have within the school of medicine a very deep fundamental department at this studies, the molecular level at what happens inside the cells to, I mean, the cell structures itself.

And it's a small department, it's a group of people really interesting on basic stuff. So there is no potential application. Of course, I mean, we all diverge and start working on diseases and conditions like that. But most of these guys are really into how the cell works. And so is it helpful that, you know, in the future we'll be able to actually maybe perhaps avoid

certain invasive medical procedures by actually engineering molecules and cells to do the bidding for us? Yeah, I think that's, I mean, I don't think it's no longer science fiction. I think this is on the pipeline. It's just that the tools when we start are not the best ones. I mean, I think you can relate to that. So you build something that seems to be working. You have a proof of concept.

And then it takes several years to make that something that will go into clinics, that people would use every day that the MDs, the medical doctors will understand. So we are in this process with lots of these tools from gene therapy, from genome editing, from the stem cells, from predicting how tissue cells works. But I think we are in the right path. So what are organoids? We hear about these objects. It sounds like an organ.

It sounds like an android. Are they sort of more towards the organ or more towards the android? Yeah, so the organoid is really, I mean, from the word, is a small version of the tissue, right? I mean, you have brain organoid, you have lung organoid, you have pancreas organoid. So it's a small, miniaturized version of the tissue. It gives you the impression that you really have, like, an entire tissue is just like a small version, but that's not the case. Usually we have pieces of that tissues that are not complete, but good enough to serve as a model. and there are limitations

I mean you don't have all the cells the size is different these organoids are not vascularized and that's one of the main limitations why they don't grow even bigger so but even with those limitations they are useful because they are mimicking the organ in a three-dimensional version

which is something that we know it works but back in the lab it's hard to control things in 3D so most of the lab or I would say like for the past 100 years people are looking into cells in a two-dimension configuration. And more recently, we are applying, it becomes more routine to use three-dimensional organoids to study how the tissue works.

How does an organoid differ from a stem cell, or are they related to each other? They are related, yeah. The organoids are most of the time, I mean, coming from human pluripotent stem cells. And pluripotent stem cells are those stem cells that can make any type of tissue in the body. So these are your primordial embryonic stem cells back into the blastocyst inside the uterus. That's the first cells that start to differentiate, specializing the different tissues in the embryo. So scientists, I mean, learn how to isolate these pitipotent stem cells, either from the embryo or more recently from live people and created these pluripotent stem cells that can be then induced to become the different cell types or different tissues. that you want. And most of these knowledge has been accumulated over the years with the most

fundamental basis in embryology, especially mouse embryology, and we try to apply to humans. Sometimes it works. Sometimes it doesn't. So there's a little bit of trial and narrow until you figure out exactly what is the formula, the recipe to create a brain organoid and not a pancreas organoid. So over the time, we're learning how to do this better and better, becoming more reproducible and reliable. Are there more or fewer kind of ethical considerations when it comes to using organoids as opposed to stem cells? I remember when the Stanford consortium and the stem cell initiative, which you're a big part

of or we're a big part about it. We'll talk more about that in a bit. But when that first came about, there were a lot of controversy within and without of the state of California. Are there, as I say, more or less kind of concerns ethically speaking on the practice of extraction and engineering and utilization of organoids as opposed to stem cells. Right. Yeah.

So the stem cell field is always with some kind of a controversial, right? I mean, and I think the biggest controversial that we're probably alluding to is the use of human embryonic stem cells, because to use those cells requires the destruction of the embryo, and some religious peoples are against about that. So when I arrive in U.S., that was 2001, 2002, that was under the Bush administration, who prohibit to use embryonic stem cells with federal grants. So people have to use like private funds to work with these cells. But fortunately, what happens in 2007, 2008,

was someone called Shina Yamanaka, a colleague of mine, was able to show that you can take a piece of your somatic cells. These are cells that are available, not your germline cells, and reprogram these cells back to these cells cells back to this pluripotent state. So by doing that, you avoid the use of embryonic stem cells. So that's no longer a issue because we can use these induced pluripotent stem cells now. But also the good news is that by doing that, by reprogram cells from a specific individual,

I capture the genome of that individual. For example, if I now take like a piece of your skin, go back reprogram into this purportent state, I can make a brain organoid from you, from Brian. And that brain organoid contain your genetic information to show how your brain were formed or was formed during the embryonic. I kind of replay your embryonic stages in the lab. Oh, wow. We can replay my first kiss with my wife.

Quite attractive, right, honey? So I have a brain here. No, this one was donated by my graduate students. So it has many different components to it. Right. So, you know, the only connection I have with the brain, is that most people confuse and conflate my name with the word brain. In fact, you did, and I'm saving and printing out that email for posterity,

or else foremost expert called me brain. I appreciate that. So here's a brain. There's many different parts. We don't have to get into all of them. I believe it's true, though, that, you know, the frontal cortex, which I think is this sign, right? Right. It's sort of the sine qua non, the most interesting and exciting part about what differentiates,

you know, both the size and the capability of the human brain from bonobos or something else. What part of the brain is being replicated or modeled by an organoid or is it just generic? Because it seems just looking at there's gray matter or the way, man, can you, you know, put it around with it and let me know. Where is it actually coming from? Yeah, no, absolutely. Yeah. Your frontal cortex is really the region for the computational capacity, the complexity, your

emotions, it all boils down to the frontal cortex. And that's why it's very interesting for scientists, not to understand. not only to understand evolution of the human brain, which is kind of cool, but also several diseases have problems in the cortex, like autism, schizophrenia. So all these conditions, psychiatric conditions, have problems specific with the frontal cortex. So, I mean, it's no surprise that this was one of the first regions that scientists decided to focus, and we have, like, good protocols to create the frontal cortex. So there are other regions, as you pointed out, I mean, you have like a nice,

nice cerebellum here, which is also implicated in autism, but also help you to coordinate your movements. So that is a structure that happens a little bit late in life, and we don't know exactly how it happens in humans, or what are the factors that we need to recreate that perfectly. So the protocol to create like a cerebral organoid is lacking behind, because we are not all that focus on creating that. But there are other this triatom is a, it's focused for

the dopaminergic neurons. These are the center of dopamine. And it's a region that gets damage if you have Parkinson's, you lose the dopaminergic neurons inside your brain. So we are learning how to create these dopaminergic neurons or brain organoid

from this triatum so we could replace that for Parkinson. So you can see how these organoids can also be useful for regenerative medicine down the road. Some of these clinical trials are already like in the pipeline and it will be happening soon. So a big picture question. We've had on people like Sir Roger Penrose, one of the original guest on this podcast. And he's been asked by me and many other people, is the brain a computer?

I'd love to get your perspective on that. We're on the computational spectrum is a computer relative to a brain and what things do they have in common from your perspective? Well, I mean, from the simple concept of a computer, something that you add an input and gives you like an output with some process information, in that sense, I would say yes. But I think the way the brain computes is kind of quite unique, and we don't know that yet. And by the way, that's one of the exciting projects that I have here with colleagues at UCSD is to really understand how the brain compute.

And if we do that, then you can imagine, I mean, all the kind of a processing that is happening in our minds while we are here talking with a very low cost of energy. And to do something with AI, it would take way more energy and way more computational power to execute that. So how come the brain learns how to do that with so low energy? So this is one of the questions that I'm fascinating about to learn how the brain does, how the brain learns.

It's about 100 watts equivalent power. It's pretty amazing. And it's a squishy computer. It's a wet computer. Right. Which I don't want to take my iPhone into that environment again because that'll invoke Apple care. But the notion that there is this ability for now we live in this era where everybody's using GPT and chat bots and so forth. But I always like to remind people that, you know, the famous famous physicist in history,

you know, present company excluded, was Albert Einstein. And Albert said the happiest thought of his life was that an observer in freefall would not experience a gravitational field. And that led him along the way to the what we call the Einstein equivalence principle and other things. But I always point out, you know, to what extent could a computer replicate the feeling of A, happiness to have, oh, it's my happiest thought of my, you know, my CPU was really operating at maximum efficiency.

And B, how could it visualize the sensation of freefall? So I'm very curious from your perspective. To what extent can a computer ever potentially replicate what the creative, you know, capability is of the, you know, cerebellum or cerebrum of a human being? You think it's possible. Will we be replaced with AI, AEs like Albert Einstein? Yeah, I think, I mean, from, and maybe, I mean, if we have, if we ever had like a computer that my process, information as the brain. Let's suppose that that we have now. I think it will be able to articulate that as long as you teach them. What is the feeling of happiness? Right? I mean, you have to

teach a computer how to do that. But once you do that, I think it will be able to learn and apply to different conditions that are similar, having like this sensation of feeling or doing good based on other previous sensation, which is more or less how the brain does as well. Right. I had a friend in college. I won't give his name because he is a listener out there. How are you doing out there? I won't say his name. But his father was an orthodontist. And he had braces for 11 years. And, you know, it's kind of cruel that, you know, his father basically was using him for experimentation. Now, I understand that both the first, you know, organoid, some of the first organized material, perhaps, came from a father who had a son with autism. and I understand that your stepson also has autism. So there's a personal angle. I wonder if you could explore that. What is it?

I mean, I'm a father of many children. You know, and I've been involved with the Simon's Foundation who supports a tremendous amount of autism research, or their safari program. First of all, what is it like having a child with autism? And, you know, are there any tips? We have a lot of listeners who do have children on different varieties of neural divergence, but in particular on autism.

So I wonder, could you kind of share your experience as a father and of your son? And then we'll get into the scientific experimentation that we'd love to do in our case. Right, right, right. I mean, let me step back on this story first, because I was studying autism way before him. And the major motivation at the time was really to understand how the human brain evolved. If you look around the other species, I mean, you don't really see they are trying to get to the moon, right? I mean, they're not doing anything like that. And there are no evidence that the Neanderthals, which would be like really close to us, would do the same thing, even though they have been on Earth for longer than us.

But there is no evidence that they were in that level of sophistication and debatable about all these reasons. But that was I was trying to understand why. what happens to the human brain that make us so unique? And that led me to study autism because one of the key components of being human is your social ability, the way that we talk, communicate, interact with others. And we can do that in a high order of magnitude

compared to other primates who are limited on that amount of connections that they can make and deal in a daily basis. So we can surpass the chimpanzee by three times, I believe. And then autism was one way where this system is not functioning well, because autistic individuals tend to be more introspective and make less social contact. So I went to study autism. In the same time, there's another syndrome called William's syndrome,

and it's a deletion in chromosome 7 that makes you hyper-social. So in a way, it's in a very simplistic way. It's an opposite of autism. So these are people that are attracted to new faces, attracted to strangers. So I was dealing with those two syndromes. And by studying them, I mean, you make discoveries. And one of the discoveries that we did was that the alterations that we see in the autistic brains are not permanent,

which was a major doggy mind neuroscience. People would think that alterations during early development would stay there forever. And I think we have to revisit that idea. I think some of these syndromes are reversible. And so we made that discovery using like stem cells. And then I went for a talk in Brazil, and that's how I met my wife. And she was there as a mom with someone with autism. And so that's, then we met, we start the conversation, and then I met Ivan, my son now.

And I just fell in love. I mean, I didn't see autism. I see the individual. And Ivan is quite severe. I mean, he has difficulties. on his daily life. I mean, he's totally dependent. I joke, but he's not a joke

that if we leave him inattended for one hour, he would die. Because he has no sense of dangers. He will cross the street and will put himself in a dangerous situation. And he's no verbal, so he cannot say anything about, I mean, how is his feeling, things like that. That creates some frustrations because you cannot

express. But over the years, I mean, living together and learning how to do it. I think I put that aside, and of course, he's a big motivation now on the translational side. I really want to make sure my science can help him and others like him to kind of cope with autism and daily life and become independent, right? But on the other side, I don't want to lose him and my interactions with him.

Otherwise, I would be working like 24 hours. And just doing that, but I want to enjoy his life. And that comes a challenge. I mean, how you do the same things that would do with, we call neurotypical, a normal person, right? I mean, going to a restaurant, it's complicated. You never know how he's going to react. How long will last. And sometimes, yeah, sometimes he will not last a minute.

We sit down and then, I mean, he starts becoming agitated and we have to leave or the food arrive and we have to pack and leave. I mean, there are all these uncertainty. But to be honest, I mean, makes life unpredictable, and I like it. I've been enjoying the process. What I would say to other parents or their families is not let the condition takes over your life. But embrace it. I mean, that's it. I mean, better days will come.

I'm highly optimistic about that. But until there, I mean, trying to make the best of your life. Your summer starts now with Memorial Day deals at the Home Depot. It's time to fire up summer cooking. with the next grill four burner gas grill on special buy for only $199 and entertain all season with the Hampton Bay West Grove seven-piece outdoor dining set for only $499. This Memorial Day get low prices guaranteed at the Home Depot. While supplies, price invalid May 14th or May 27th, U.S. only exclusions apply.

See Home Depot.com slash price match for details. Yeah, it's interesting. Just hearing you describe it that way, Aristotle was wrong about most things in physics, but he was right about almost everything else, including the laws of logic and even philosophy and theatrics and so forth. But he speculated on why is it that children love their parents more than, why is it that parents love their children more than children love their parents? And after a long, you know, kind of meandering a set of discussions, he basically comes up with the fact that, well, parents sacrifice for the child, but it's usually unidirectional.

It's, you don't expect our kids to sacrifice their time, their effort, their money, their, you know, all their resources for us, at least when we're, you know, in the kind of age bracket that you and I are in. Later on in life, we hope that they'll take care of us as we become more dependent on them and sort of symmetrical. So the extrapolation that later, you know, philosophers and psychologists described was that, well, the more you sacrifice, the more you love. And in case of parents with, with children with special needs, but also have children. that don't have special needs, you say neurotypical, I guess, is the right phrase. There's almost more of an attachment to the child that has the special needs because you do have to sacrifice so much,

and it is so admirable that you have not only the dedication that you obviously do, but the cheerful attitude. And I think that's really touching. And I want to ask when you first made an organoid, were you the first to kind of think of these ideas and how you could apply them? Or you mentioned your mentor or a colleague at Salk, was it at Kate? Yeah, Rustigate Gage. Yeah, that's a cool name made up of two different, you know, two different English words.

Can you explain what is the genesis of the organoid phenomenon? When did it start and when did you get the organoid bug, so to speak, were the coincident? No, that's a great question. And again, I mean, the stem cell history goes really back to the seven. when people were experimenting with brain tissues, even some biopsies, and putting them in culture. And some of these brain tissues were already in 3D, and they were observing that, well, 3D is more activity. I mean, the neurons behave differently. The complexity of the neurons is much different than what we are used to see in 2D.

But that's taken directly from the brain or from the mouse or from human and place into the lab. Nobody has recreated that from the beginning. I think that's the differentiation. The first guy who actually did that was another fantastic Japanese investigator called Yoshiki Sasai. That was in 2008. That's when I was starting my lab. And I remember reading that publication. And by the way, he didn't call it a brain organoid or anything.

He was just like describing how he would do it. And I said, oh, my gosh. I mean, he can actually create like a fetal brain tissue that remarkably look like a fetal brain tissue using stem cells. That's so cool. That's what I want to do it in my lab. So it was right in the beginning. But as I mentioned, I mean, the protocols were not robust enough.

I mean, we were trying, we were failing. It was so much easier to get it going with the traditional two-dimensional cultures that people were like really getting frustrated. But then more and more people in the stem cell field were joining and realizing how important would be to kind of improve that method. And over the past 10 years, we see really a gigantic effort on recreating this and make it more reproducible, characterizing them better, understanding the limitations, overcoming the limitations. So this is all happening in the past 10 years.

To me, a crucial moment was when we were optimizing the cortical protocol to make like a piece of human cortex in a dish. and we were frustrated because the protocols, including the protocol from Sassai, when we tried to record the electrical activity of those neurons, the activity was quite low, very low activity, meaning that there was something missing in the recipe. And everybody seems okay with that because the organizers were already providing you with the structure,

you could study cell migration, things like that, but I was into the network, because that's how the brain computes, right? And that's the problem with autism, schizophrenia is not much about the malformations of the brain, but rather how the connections are formed. So I wanted to get that down.

So I asked like a postdoc of mind to really put like an effort on optimizing and starting from scratch, looking at the culture media that we use, how many salts are there. And then we realized that everybody was using the wrong cosmolarity to grow human neurons. So we fixed that.

And we were fixing like pieces by pieces until we had like some very simple formula where we remove more things than we add and it seems to work beautifully. And then I mean they plate that on a multi-electrods array. So this is electrodes that are printed in a bottom of a dish and you plate your organoid on top of it and the electrodes will capture

the electrical activity. And usually as I mentioned we saw very little activity here and there. And others have tried to do the same thing with organoids and didn't see much as well. But then, I mean, in the beginning, the first week or so, we see a little bit more, but not striking.

But as the days were passing, we saw that the electrical activity started to almost exponentially jumping. And I said, I can believe it. This is like a malfunction machine. I mean, check your electrodes. I mean, go back because, I mean, nobody would buy this, right?

And this postdoc, he was a cleverer Grisillo, he's now a friend of mine, saying, no, no, it's real, it's real. We reproduce that many times. And I said, all right, I mean, if that's real, that that would change something. Because, I mean, having a tissue that start to have that level of activity and never seen before, was unprecedented in science, made me think about, well, maybe we are recreating the right connections in the brain.

And to show that, we team up with Brad Vojtek, who is also a colleague and faculty, here, the cognitive neuroscience and he showed us how to evaluate those networks to measure these brain oscillations which is something that you can see with EEG. And then we realized that these organoids

were mimicking these preterm development up to post-natal development. So we can actually keep them alive for several years. The electrical activity was growing up for 40 weeks and then plateau when they reach about nine months of age.

which is the gestational time for humans. Is that just a coincidence or is that? It could be. We are still trying to figure out if it's just a coincidence because my initial reaction was, no, this would never happen because it's a tiny thing. The organoid has 5 million neurons. Human brain has 86 billion neurons.

So these are orders of magnitude. But then, I mean, we did it. We used all the controls. We eventually published that. And it's right. So what does it mean? It means that the brain can have kind of a miniaturized version of itself that can reproduce itself. So it's like a fractal.

Exactly. And synapses are as well, right? Networking, right? Otherwise, communication is almost impossible. If it relies on each individual unique personality of each neuron, it probably wouldn't have survived evolutionarily. And that brings me to a question that you are involved with evolution. you mentioned Neanderthals earlier today. So I wonder, is it true you created a Neanderthal brain, you know, deep underground in your,

laboratory? I don't make it over to the medical school very often. But explain this, the Neanderthal mini brain that's hypothesized to come from you. Just a quick pause to ask you for a small favor while my thumb is occupied with old Albert on it. Yours is presumably freed up to leave a thumbs up on this video. helps me a lot with a good old-fashioned YouTube algorithm. Thanks a lot. Now back to the video.

Yeah, it is not a Neanderthal brain. To create a Neanderthal brain, you need a Neanderthal cell. And we know that right now there is no cells available from Neanderthals. You can get their bones, and from their bones, you can extract their DNA.

So going back to that idea that maybe our brains are unique because they are different from other species. What we did was to align the genome of the Neanderthals with the modern humans, us. And we ask the following question. What is unique about us? What are the genetic variants that we only have and no other species, even the Neanderthals, have them?

And we end up with a list of 61 protein coding genes. There are more variations in the other regions of the genome, but for the protein coding genes, there are only 61. And those genes are interesting. These are genes related to bone formation, the immune system. But there are a couple of them related to brain development. So what we decided to do to study the impact of those specific genetic variant was to use genome-editing technology to neanderthalize the human genome. So we did that in one of the pluripotent stem cells.

What does neanderthalase involved? So it means that we can use, for example, a CRISPR enzyme or some genome-eum-earned. editing enzyme to change the DNA from humans, from me, from you, and add the sequence of a Neanderthal inside the cell. But you don't have the brain. So in other words, you can isolate that which would become the brain from the bone DNA and then use that to forecast, or you can see how similar you can get to a Neanderthal bone DNA or whatever using CRISPR enzyme technology. That's it. Yeah, yeah. Yeah. So the DNA, I mean, should be identical in all your cells, right? I mean, we take from the bones from the Neanderthal.

There's a sequence over there. Which includes the brain, which includes the nose. Exactly. Where the ear should go. Okay. And in that specific gene, the gene is called Nova One. It's an interesting name. That specific gene, which is a master regulator of downstream,

hundreds of other genes, it's different between us and the Neanderthals. So we went to Noval 1 and we swapped the modern version of the gene that we have by the Neanderthal version of the gene. And then, from that proteopoten stem cells, then we create a brain organoid. So that brain organoid will have that protein that is not a modern human protein, but it's a Neanderthal protein,

and how it will downregulate all the other genes that are supposed to do that. And it did in a very different way. And that was a big surprise, because even the morphology of the brain looks slightly different. we see alterations in cell migration

and proliferation but the most interesting aspect to me is that when we record the electrical activity of the neanderthalized brain organoid it shows a maturation much faster than a modern human

so and that mimics well that goes well with this idea that we are really is developers, right? I mean, a baby chimpanzee

can outsmart a human baby. They are born. They already know how to jump the trees and then find food. Our babies require attention, way more attention. So, when we neanderthalized the human brain organoid,

the maturation of these networks resemble much more at the chimpanzee. So most likely, I mean, you can extrapolate this is just speculation. I mean, there's no way to prove that, that maybe the networks of the cortex of the Neanderthal would mature faster than us. So that mutation that we acquire, and it's almost fixed in the human population, makes every single brain develop as law. Interesting.

So I wonder if you could kind of join me on a speculative fictional, because we are part of the Arthur C. Clark Center. We've got to pay homage to Sir Arthur. And I haven't really formed this question very well in my own brain, but let me try it out on you. And we can always edit it out later, if it doesn't make sense. So there's claims I can't remember exactly the figure, but something like 99.7% similarity between humans and chimpanzees. You mentioned Neanderthals, obviously. And I don't remember which came first, Denisovins or Neanderthals. But the historian and kind of demographer, Yuvald, Noah Harari, has made a case that,

Homo sapiens emerged superior because we had the ability to construct language and complex thoughts and storage. And it wasn't because of our strength because probably, I mean, chimpanzees are probably a lot stronger and possibly even Denisovans and so forth were stronger. But it was the capability for language. Now, I wonder, you know, if we could maybe ask you to speculate. Is it sort of a chicken or the egg thing? We don't know which came first.

the brain development, the physical capacity, the hardware of the brain, or the software, to run the language app, to run the history app, et cetera, the art app. What is it? What is that missing 0.3%? Where is it? Is it pure hardware?

Is it pure DNA? What do you think? And I don't know this is speculative. Most likely a combination of both, right? But I do think that without the hardware will not be there or will not be here. So it means that we need to acquire this set of mutations that would make our brain susceptible to language, to socialization,

much higher than the other species. And I think this is a set of mutations that we acquire in the DNA that proved to be positive because we are all selected for that over the years. So there are many missing things. I mean, how these mutations emerge in the first place? It could be random, but how do you fix them in the population? There is probably like a strong selective pressure to fix them. And those we don't know. I mean, probably for each one of these mutations, we have like a huge history behind it. And it's the same way, it's the same type of speculation that people are doing on the other

way around. For the sequences of the Neanderthal that we now have in our genome, not the ones that we don't have, but the ones that we have. And it's becoming clear that there are sequences that makes us susceptible to diabetes, COVID-19, those are some of the sequences that we acquire from the Neanderthals for probably reasons of adaptation to the environment. But there are things, for example, addiction to nicotine seems to coming from the Neanderthals. Why? Why? Why is that?

So, I mean, we can create hypotheses, but nobody knows. Interesting. I'm listening to a book and possibly helping to have the author on of a book called The Mind of a Bee, which is a really fascinating book so far. It's one of the few books that I can listen to with my kids. You know, I start listening to a book. It was called Salt, a history of salt.

And I'm like, this has got to be totally, you know, kosher. My kids go, and it's all about sex and like how, you know, saline it. Anyway,

I don't want to get into it. But this book, The Mind of the Be so far as of, you know, chapter four is, is quite remarkably, you know, G-rated.

So I love that. But one of the cases that they make that the author, I think his name is Lars, I forget his last name. Anyway, hopefully I have them on Lars, if you're listening out there. The, the, you know, kind of idea that honey was, is the most natural nutrient-rich, you know, kind of material with high calories and caloric intake that it was actually used by Neanderthals and Denisovins and whatever, going back to pre-recorded history and their, you know, cave paintings on, you know, where to find it and so forth. But he obviously goes through the famous, you know, Nagelian exercise of what's it like to be a bat, this case,

what's like to be a B. But I wonder, you know, this, the caloric needs of a Neanderthal versus a modern-day human. And you mentioned things like diabetes and Parkinson's, can we someday envision taking an organoid, which I think you might have brought some organoid, you know, material with you. So I was hoping I could take that into my lab down the hall and start working on an upgrade. I'm due for an upgrade. My hardware is a little bit out of date. I need a new hardware, not just new software.

Can you envision a day when there are materials, there are augmentations, not like Neurrelink, which I want to discuss with you later on, but you could actually have a plug-in, you know, kind of upgrade or replacement, and augment and, you know, even achieve superintelligence, as past guest, Nick Bostrom has talked about. Yeah, I know that's a great point.

I have mixed feelings about that. Because there are, I mean, sometimes, I mean, if you pay attention, nature gives you answers. There are cases of people who have their brains fused. These are twins people who are born with the brains fused, right? And there is no evidence that they are exceptionally smart. So I don't think that adding neurons or adding things in there would make a difference. But it might be there are instances where, for example,

maybe if we learn how memories are restored, and then you can create some kind of outside brain to store specific memories that you could retrieve with your thought. Or take the organoids of a bee, which has these electro-thermal sensors and ultraviolet sensitivity, which we don't have, and just have that as your package. Oh, yeah.

And by the way, that's the beauty of the organoid, because you can explore those things. And in a similar way that we are looking to the past, looking for genes of Neanderthal, things like that. We are also looking to the future. So we are using these genome editing technologies to recreate senses in the brain that we either lost or we never had.

Like what? Give me an example. Magnetic perception. We have the genes, but they're heavily mutated. So other mammals can probably sense that better than us. Wayo is a great example. I mean, that's how they move around. But we lost that.

So a blind person in a forest will starve and die. So why? I mean, probably there's a selective pressure to lose those senses, but they are there. So we can use genome editing to reconstruct that and test if the brain organoids now can sense magnetism. It would be cool to see if we can sense polarize light. There are animals that are very sensitive to polarization. I study the polarization in the microwave background. I'm not going to get into that.

But, yeah, to augment the senses, not just to have more is better, because it's not exactly, as you say, clear that she's having more. I mentioned Neurrelink, and I'd love to get your opinions. We've got his, you know, SpaceX mugs here, Elon, so don't think we're hating on you. We paid great, you know, full retail price for these. Tell me, what are your thoughts about Neurrelink and, you know, kind of the opportunities and maybe some of the risks of such a technology? Yeah, I'll be honest that I'm not fully immersed on what Neurrelink is,

doing. But I have like a vague idea of what what Neurrelink and others are trying to do. And I think my I mean, when I see the medical side of it, I like it. For example, can you imagine if

those electrodes that you are implanted there can block seizures? My son has hundreds of seizures per day. So if I can stop that or even himself, by touching himself or by thinking, could stop the seizures when it's approaching, that would be fantastic.

Rehabilitation, this interface, if you lose a member and a hand or something and you can use like electrodes implemented in your brain to kind of move like a robotic arm, things like that. That I like it. For normal average person trying to mess up with a brain, I worry a little bit because, I mean, there is a reason why it's so protected. Probably don't mess up with the brain. But that's my word. If you find ways to do that,

that is non-invasive, even better. And I think these are the discussions that some people have. There are some people that prefer to use EEGs to capture the electrical activity. Of course, I mean, in neuroscience, it's all about how close to the action you are. I mean, the closer you are to the neurons, the better.

And that's why people want to stick electrodes in the actual thing. Yeah, but there is a risk associated with that. Yeah. So former UCSD professor now Stanford professor Andrew Humerman, who hopefully we'll have on the podcast at some point, he has made the point that the eyes or the retina is really a part of the brain that's outside of the cranial vault, which you did suggest is the kind of the armor that protects is really vital organ.

Would there be work to, you know, that seems to be, say the most accessible and then perhaps most medically therapeutic or beneficial to restore sight or things like that. Are there subspecialties within the work that you're doing to grow new retinal cells? And again, I don't know all the diseases. I know there's, you know, our P and all these different destructive degenerative diseases of the eye and the retina. Is that a focus, no pun attendant of your research? It is. We are creating retina organoids. And I, do that in collaboration with another professor here to see a CD in

ophthalmology called Walling. So his lab is an expert in retinas. So we use the stem cells. From the same stem cells, we create a retina and we create atalumous because between the retina, between the eye and the brain, there's a thalamus there, and then your cortex

where the photoreceptors will actually send the information. And we put those three pieces together. So we have the retina sending the photoreceptors to the thalamus, crossing over the talemus, and now sending connections to the cortex.

That would be, so that's the interesting part. I mean, these are the organoids, how they look like. So you can see that there are tiny white balls in there. Those aren't bubbles,

then. No. We'll get close a picture. Yeah. So when we make this cortical organoids, there is no identity to them, And this is an interesting concept.

Like blank slate. I call it a blank canvas, right? I mean, they can be anything. And it's different from the brain that is formed with you. I mean, this is without the body, right? When we have a brain with the body, you already receive in context from other regions, sensory information that shapes, oh, this is a visual cortex. This is a motor cortex.

And as you grow up, those regions become with higher identities. even anatomically you can distinguish them, the morphology, the type of neurons. So when we make a cortical organoids, it's an empty canvas, there is nothing there. But now we want to plug the retina. So will they become more retina-like? Can we stimulate, visually stimulate the retina

and record from the cortex? Can we store memories in there? These are the kind of questions that we are making. And there are conditions where all the pieces are correct, and I forgot, I'm blanking the name of the condition right now, but the photoreceptors, their axonal projections, are not getting there for some reason. So we plan to study that condition as well.

Oh. Can you describe, I mean, is it understood the process by which a memory is formed and by which it's read out? I know basic things, you know, dopamine is sometimes involved and strings that involve survival, you know, food finding, things like that. But, you know, how does it actually work at a computation? level, or do we not understand it? We always see these neural networks, and here's a picture of learning it and training it,

and now it knows a cat versus a dog. But how does the brain actually read a memory, store it? You know, it's not a zero or one like a computer chip. So how does it actually store a memory, and then how do we actually retrieve a memory? Yeah, so I think the best answer is we don't know. So that's for someone to get a no-go prize. Okay, good. No, but I think we all know that this.

this is all so fast and happens so efficiently. So it doesn't seem to be in a cell or a synapsis. It could be like phosphorylation of proteins, a process that happens much faster. If we think that this is all material-related, because it might, I mean, there are people who doesn't even believe that those process happen in a material side. It may happen on the electrical side.

And I haven't seen any good arguments against or for that. You're still like really open question. But that's exactly the questions that I want to get with the organoids. Awesome. Because I have the experimental model in the past. I mean, we have to do it in a mouse, but the mouse is very different from that. There's a meme on the internet, you know, whenever somebody makes a discovery of some new drug or something, and it says, just say mouse, you know, in mice. In mice, yeah.

For us, it's, you know, just say dust because, you know, dust is really the mouse of the astronomical world. Now, speaking of space and things in the astronomical kingdom, you were involved with the mission, from sponsored in part, supported in part by NASA to the International Space Station. Now, I've had the honor and distinction to have on, not only a NASA astronaut, but a NASA astronaut alumna of UC San Diego, not only that, but while she was on the International Space Station, that's Dr. Jessica Mayer, who hoping will be the first woman on the moon in the next five years or less. So talk about the board's missions. the brain organoid, uh, advanced research development in space mission. What is it? What's your

involvement? What was the origin of that particular mission? You said this place was steps from the water. We just haven't found the steps yet. How much did we save? Enough. Enough to get lost. Or you could book a stay with Hilton. Welcome to your ocean front room. Just steps from the water. The Hilton sale is on now. Book on Hilton.com or The Hilton. Hilton app and save up to 20% to get the stay you expected. When you want savings, not surprises. It matters where you stay. Hilton, for the stay.

Yeah, no, that's another great project. And it always starts with conversation with a good friend of mine. That it's a common friend here, Eric Fiehe. And Eric has this interesting in his space. And it's always asking me about, I mean, what are the consequences of space? or what's the impact of space in the brain. We know from NASA twins' experiments

and other experiments that was done in mouse, in cells, that this space environment, either microgravity or together with space radiation, is not really the environment that the brain was made. Any cells, human cells, are not supposed to be there. So when you expose yourself that environment, there are consequences. Some of these consequences to the astronauts can be reversible.

Others are not. And the brain is particularly important because we've seen in the animals and humans as well some potential cognitive decline. So this is bad news for Naz and anybody who wants to do like interplanetary exploration or long flights. How would you keep the brain protected? So that was one of the questions that we had to start working on this project. Well, I mean, it's hard to analyze the brain of the astronaut when it comes back. You cannot make a row in there and look for the synapses what happens, right? I mean, it's all post-morton waiting for the astronaut to die so it can have access to the tissue.

But it's not going to be real time. But an organoid can be a proxy of the astronaut in the space station, and that was the idea. Okay, let's send brain organoids to the space station and let's see what happens. That was kind of the space colonization idea. I mean, let's see what happens with the brain, how to mitigate the process. So, NASA would help the astronauts. In parallel, there is another thing that Eric and I were also very interesting is what happens to human neurodevelopment in space.

We read all these science fiction books talking about people living in other planets, but we never ask ourselves, can we cope? from the beginning, from the embryogenesis to microgravity, what kind of a human, what kind of a human brain would have? And that was the first picture that we took from the organoids inside the space station. It already shows that the organoids, the way they were growing was slightly different. So there was perfect spheres. So if you see the organoids here, they're not perfect.

I mean, they are unperfect, right? Right. But over there was amazing. We said, oh, my gosh, they actually shaping a bit. ball. Wow. And so if you have a baby in a space, maybe their brains will develop in a different shape. And we don't know the consequences of that, but probably not so good.

So I'll think twice about having a baby in this space. Okay. Yeah, it may be more likely for you than me, given my wife's cut us off. No more kids. Now, the microgravity environment, of course, is unique to a handful of people. and I'm curious because, you know, we spoke about the, obviously, the relationship in autism and your personal connection there. I understand you also study another condition called Pitt Hopkins Syndrome. Yeah. That is, you know, reputed to afflict only 500 people around the world,

which is, you know, okay, it's more than the number of astronauts, but we're talking about low numbers statistics. And I'm just curious, what drives you to study things like this? Where the, you know, it's not going to make you billions and billions of dollars. I'm going to patent something that's, you know, going to make you the richest guy on Earth. But there must be something else that drives you to study things that were other scientists, either don't tread because they might be motivated like me by more venal considerations or just the time and the pressure and research. But talk a little bit about the interest, both in studying this Huyken syndrome and also studying things that would afflict, you know, 30 people in the NASA Artemis program at most.

Yeah, yeah, no, that's a great question. I mean, for these rare orphan syndromes, I was always attracted to that because the idea is that they are telling you something. I mean, all these syndromes have specific genes that are mutated or, and affects how the brain works. So by studying them, the mutants, and in genetics, that's what we do. We always study the mutants to understand the normal. So that was the first drive. So let me understanding all these genes. What are these genes doing?

So I can understand how the brain works. And so that was the main motivation. The board's mission, I mean, for the astronaut. So there is another motivation behind all of that, which is to help to treat diseases that are uncurable here on Earth. And I'll give you one example. One thing that we are learning with this mission in space is that a little time under microgravity, when you are back to Earth, your cells age faster.

So this is a phenomenon that has been reproducible in different systems. And nobody has done in the brain because we didn't have brain cells in there. But we see that in the organoids as well. So if you can now age the brain cells, I can use this organoid to establish. study other types of conditions that are not pediatric or neurodevelopmental conditions, but are conditions that happens later in life. Alzheimer's, dementia, things like that. So now suddenly, we have a model that can age the cells really fast by just sending them

to space and come back, and I have a model for Alzheimer's. So that's where we are now. Talk about the future of things like Space Tango, Cube Lab program, and the board's mission. Will there be another board's mission and so forth? What is the future of the space investigation? Yeah, so we are very fortunate here to SECD because we received a donation from Danny Sanford, who has been our cheerleader here for stem cells.

And with this new donation, it will allow us to expand the board project across other disciplines. So now we have colleagues sending amatopoietic blood stem cells to space, liver cells to space, and for all kinds of different projects. So we are expanding that, and we're also making partnership with the big players

that might have commercial space stations down the road, Sierra Space, Axiom Space, and we continue to work with the companies that make the logistics, the hardware for these cells to grow like Space Tango has been a partner from the beginning. So I think in the next, year or so, this program will start really to slowly expand, expand, expand, and it might become something like really an institution here at this SD.

Yeah, it's such a remarkable kind of series of projects that you're involved with. It's so exciting. And like Eric, it makes me want to be involved in it, but you can only do so much time in a day. Before we wrap up here, and you've generously agreed to let us pry into your lab and take some footage over there later, which we'll fold in. kind of a part two of this interview or maybe, maybe appended to this conversation. I want to talk about brain health and in particular as pediatrics.

What, you know, kind of in terms of your routine, do you have any sorts of tips or hacks or things that you do to kind of optimize your brain to prevent neurodegenerative things in the future potentially, obviously these are, you know, not, this is not medical advice at this point. You should not take medical advice from an astrophysicist anyway. But anyway, are there things that you do personally? supplements, are there things that we can do? Especially, in particular,

for those of us with young children, are there things that are particularly important? Yeah, I'm in school of medicine, but I avoid hospitals. So I try to be as healthy as possible not to go there. And I mean, I don't follow any specific diet or anything like that, but I try to be conscious of everything that I do, everything that I eat.

But I think the most important, aspect to me on my health is physical exercise is to do to take our time to do at least like one hour per day or something and could be surfing could be running could be walking but just to keep the body moving moving I think that's it works for me I mean it keeps me healthy and I realize when I travel too much or when I'm so busy that I'm kind of skipping those days um that's when I feel miserable so I need to go back to do some physical exercise to kind of forget the blood flushing again. And there's been some talk I've heard about something called the lymphatic system,

which is like the lymphatic system processing lymph in the lymph nodes, but supposedly in the brain, can you say anything about that and the role that sleep might play in neural degenerative diseases and so forth? Yeah, so, yeah, this is an exploding area, and I have lots of colleagues who are actually working on that. So the brain is really like part of this interaction with the immune system. It's stronger than ever. And the immune cells in the brain called microglia has been neglected for a long time

because, I mean, we, neuroscientists, we like neurons and we forget about the other cells. But there are, I would say, like a renaissance of the glia cells, including the cells from the immune system. And we know how important they are, not only on maintenance. of the proper function of the brain, but shaping your networks, especially during development, we are seeing that with the organoid model, we are adding these cell types that they currently don't have to the organoid and observing how it reacts. And the differences are dramatic, things that we're never expecting, levels of synapses

or the strength of the synapses are much different after and before you add, for example, these immune cells in there. So totally, totally important. Yeah. Okay. So now we've reached a segment of the interview before we go, sorry, and we reach a segment of the interview before we go into the laboratory, where we go into the impossible.

And we want to ask you some existential questions if you're willing to play along with us, Alison. So the first one has to do with your far future. Hopefully you reach the biblically mandated age of 120 years old. I want to ask you what kind of life advice or wisdom, not monetary or physical accoutrements, but what kind of ethical or wisdom, you know, would you like to bequeath in sort of what we call an ethical will or Zavaha in Hebrew to future generations, not just your biological progeny, but your ideological progeny, your students and so forth as well? What would you like to convey as wisdom when you do depart at aged 120? That's a great question.

My hope would be like some kind of contribution about the brain understanding. And to me, it's all about breaking the dogmas, right? I mean, in neuroscience, we start with a strong dogma. The brain is formed and does not change through life, right? It's immutable. You were born with certain neurons. Those neurons stay with you for the rest of your life. If you lose them, there is no regeneration.

And I think the experiments that we are doing with the brain organoid shows that this is a system that it's way more plastic, more adaptable than we ever imagine. And if I can contribute to unlock that potential, I think that that would be like my legacy that I would like to leave. So a famous quote from Sir Arthur C. Clark, you're probably familiar with it,

that any sufficiently advanced technology is indistinguishable from magic, and we always open each interview on the podcast with Sir Arthur actually saying that in his own voice. Thanks to my super producer, Stuart Volkow, for finding that summer in the internet. We also have when Dave, the astronaut in 2001,

a Space Odyssey, says to how to open the pod bay doors. And that's actually the origin of the word podcast. Comes from Pod Bay doors into the... in Sir Arthur C. Clarke's 2001. Anyway, what magical discovery? What's the most magical thing about what you've discovered as a scientist? And it may not even have to be your work, but what sufficiently magical technology is indistinguishable from magic as far as you've encountered?

Yeah. I would say the first time that we generate these brain organoids with electrical activity on the same level as the human brain on the same trajectory, I think that was a eureka moment and almost magical because we don't know how to explain. We still don't know how to explain. and it's kind of the data show us to us that we were wrong and we couldn't find the explanation because together with my colleague scientist, I was very skeptical.

This is a tiny thing. They're not controlling it. They are variable. They are really full of limitations, but still they're doing something that the brain does. And these days, I mean, I'm joking to the lab because there are so many people doing organoids. You're going to see,

we have like a factory of organoids now. And I always joke with them that they take the cells, they kind of kickstart the process, and then the organoids, they become by themselves. Meaning that everything is genetically pre-programmed. The cells know how to migrate, where to position their cells. We don't have to do that.

They do it by themselves. And I call that a miracle. Yeah. Because, I mean, how come? I mean, you have like a stem cell, and then you kind of kickstart them to become like the nervous system and they would do it. So it's a miracle. It is magical, yeah, yeah, that's right.

You know, people only look at miracles as things that happened long ago. But in a certain sense, every breath that we take, every rainbow we see, these are all miracles. To be here. Witness, yeah, that we have this short window of time to share together and to learn about the magic of the universe. Okay, third question, penultimate question. Name of this podcast is Into the Impossible, and it comes from Sir Arthur's famous statement that the only way of determining the limits of what is possible is to go beyond those limits into the impossible. I don't use that as a way to convey advice to your former self.

If you could go back and spend 30 seconds with your 20-year-old self, what advice would you give to him to give you the courage to do as you've done to go into the impossible? I think this other self would just say keep going. Maybe trying to be a little bit more open-minded, because this is true for the scientists, especially in the beginning of your career, you care so much about the opinion of others. And if everybody says that, oh, it's impossible that an organoid will ever reach a level of consciousness or self-aware, well, it is really impossible that is.

So, I mean, if I just believe everybody, I will never do the experiments that I'm doing right now. Absolutely. And that brings us to our final question, our final statement from Arthur, who said, when a brilliant but and distinguished, elderly scientists, I'm not calling you elderly, says that something is possible, they are most certainly right. But when they say something is impossible, they are very probably wrong.

So I'm going to ask you, Alison, what have you been wrong about? Is there anything you've been wrong about? You've kind of had second thoughts about that you've changed your mind about as you've become distinguished, though not yet elderly. I think there are certain circumstances where I could have moved forward if I could have moved forward, would trust myself and that's that's related to your previous question on the advice care less about the others just do what you I mean your intuition is pointing you to do it I think for example would have like better organoid protocols way earlier than I thought if I would invest my time because I would think that I would get there earlier earlier and for reasons

that I'm social reasons in science force me to have like a narrow-minded at the time so I'm learning along as time passes how to avoid that. And one thing that I recently decided to do was kind of inspired, not inspired, but causality of the pandemic is to go to less meetings, less scientific meetings. Because when you go to these meetings, I mean, you see that everybody's doing the next step, right? And I never thought about doing the next step. I want to do like orders of magnitude from where I am.

But when I go to those things, I mean, I see that everybody's doing like one or two steps ahead. Incremental, incremental. And I said, wow, I mean, if I force myself to be in the incremental group, I always going to be doing incremental science. I need to step away. My colleagues might not like that. But at the end of the day, I mean, we all show the incremental stuff in this meeting. That's important. To make a real impact, you need to go to order of magnitude sometimes.

And I want to thank you. I want to say, oh, braggato. Did I say that right? Go ahead. Yeah. For being on The Into the Impossible podcast. Thank you. And for sharing so much of your spirit and your intellect with the audience.

And I know this is going to be just a delight for them as it was for me. We're now signing off, Associate Director of the Arthur Clark Center for Human Imagination, Brian Keating. And my friend, colleague, Professor Alison Motry of UCSD School of Medicine, Pediatric, cellular, molecular medicine. I think I got all that right. You got it. Rockstar all the way. Thank you so much. Thanks, Brian.

Fantastic. Thank you. Any sufficiently advanced technology is indistinguishable from magic. Thanks for listening to this edition of Into the Impossible. Keep in touch by signing up for Professor Keating's email list at briankeating.com slash list. And if you have a dot-ed-u domain, we'll send you a particle from the belly of an exploding star in the form of an authentic meteorite fragment. Please help make the show better by filling out our listener's survey linked to in the show notes.

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