YouSaid · the spoken record

Santiago Schnell

lines on the record: 83
first: 2020-05-24
most recent: 2020-05-24
sittings or episodes: 1
sources: podcast

Every line below is reproduced as it was said and linked to the record it came from. Nothing here is summarised or generated. Directory · Search · Corrections

“But to go beyond, it's useful for us to really understand and to be able to probe deeply and then figure out what we want to do there. And then go beyond might be using neurons as an analogy as it is in machine learning right now and neural networks. Or it could be actually as literal neurons. At that back and forth is really interesting, and one of the most exciting things for me about the field of neuroscience is where it sits right now in that sort of hub between understanding the brain and understanding intelligence, understanding learning, and both at this sort of macro scale, which we talked about and the micro. Those connections, I think, will be useful sort of in many disciplines for years to come.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“It's really intriguing time right now. You think about one analogy I often make is that birds and fighter jets both have wings, but they fly very differently. And maybe one was the human version was inspired by the natural one, but that we can go beyond. Right.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“And I think some of the transplantation studies are also going to be critical in that regard. And then, of course, the implications about just understanding how the human brain function. I think what makes it so unique. There's a lot of interesting biology. We know very little about the actual human brain, not just the biology, but also the computing, how does it come together and computes.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Not for others. I think the next step is really applying it broadly, right? I think it's still early days in developing some of these technologies and applying it, but we really need to see it at work more broadly and maybe bringing psychiatry into a new era, like a molecular era, into what we would often refer to as molecular psychiatry. So I think on the long term, that's what I see the most exciting avenue. But of course, the models are going to get more complex in many ways. likely going to be able to build ever more complex circuits.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“So, I want to wrap up by just asking kind of what the next near term exciting steps are here and then what the wildest ones that you can imagine is when we have this new tool, this new way of understanding the brain, new model appropriate for some things, not for others. What is the sort of like the next major evolution that you see?”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Sensory input and many other external informations do shape that developing. So I think. That addresses some of the ethical concerns when we're maintaining them purely in vitro. But again, one can really see it as some sort of computing device, so to speak, which is biological.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Absolutely, and one can think that once we put the cells together and they connect to each other, they form small networks. Of course, there is some sort of computation. There's like some information that is transmitted among your cells. So I guess one question is how complex that is, how similar is that to the human brain. But we do know that”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“And running machine learning, it's interesting to think what you could do with this. Then that gets really kind of very science fiction-y, like, could you create a little visual cortex and use that to do computation? Could you do this and that? And there it's going to be a really interesting challenge on the bioethics side to figure out what makes sense.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“I think the long term implications of this is kind of amazing because we're talking about this very much in the context of scientific discovery and disease. And that's one direction just as a technology. It's also just kind of amazing. The fact that we can engineer silicon allows us to have chips. The transistor is cute, but sort of having that engineering aspect of it is what allows us to have microprocessors. So this reminds me of the early days of that in some ways where you're putting these things together and you're seeing what they can do. I can imagine that they could start, especially since on the silicon side, we're spending so much energy on the silicon side doing neural nets.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“We also think we have to put this into the broader context of how are we going to model psychiatric disorders. And we call this broadly surrogates, brain surge, because they're all kind of like trying to mimic the human brain. And I think it's very clear that we need better model for understanding psychiatric disorders. We need models that resemble more and more the human brain. And obviously, the closer they resemble the human brain, the more uncomfortable we also feel with anything resembling the human brain. So I think that's why ethicists and lawyers are in this, because of course there are also legal implications. First, the cells come from human individuals. What are the limitations to what are really the applications for which they can be used for? And so I think those are discussions that are active in the field at this point.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“I mean, we can build all kinds of ways of actually stimulating, but there are no sensory inputs. So that is the reason why overall we don't really think that there are like major ethical concerns with the cultures maintained in the dish. Now, there are some discussions, some ethical discussions around the transplantations of some of these cultures into animals. So for instance, one can take them and transplant them into a rodent and integrate them into the circuit of a rodent, in which case, for instance, they may receive some sensory input, they may participate to some of the circuit functions. So I think many of the discussions are around that. And of course, what is really considered not acceptable at this point is, for instance, transplantations into primates.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“But there are parts, there are incomplete parts of the human brain. And there are another very important aspect of human brain that is also missing here, which is actually sensory experience. We know that the sensor experience, everything that comes through our senses during development, absolutely that shapes the circuits. We know that that's critical.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Of course, there are a lot of discussions in the field, and what is clear is that these structures that we're building in a dish are very different than the actual human brain. First of all, because they're not a miniature version of the human brain. That's why we don't like the term mini-brain, because it's inaccurate. But they're like sliced.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“So, I have to ask now we're in this new world of sort of beginning to grow essentially small human brains or versions of brains that have some functionality to them. They're firing, they're doing some stuff, how do we begin to think about sort of some of the ethical and legal issues around that? I mean, is there a line at which you can say clearly like, no, this is a thousand miles away from consciousness? Or if you let that organoid grow in a dish for, I don't know, five years, like would you begin to be approaching like how do you start thinking about what's actually happening there in terms of consciousness?”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Well, and that is what I would expect from that type of engineering approach because if you had to do this purely as rolling dice and seeing what comes out, it's going to be really hard to start building these more complex structures versus sort of getting better year after year.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“And so in that case, we can say, oh, now we have the perfect assay in the first system. But if you would have tried to do that a priori, it would have been very difficult because you wouldn't have had the tool. Now we can make more defined brain regions. And when we assemble them, we can actually get cells projecting at a long distance, connecting and forming small circuits.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Time of this. And very often also our disease modeling has actually moved in that direction. I mean, initially, very often we would say, okay, here's a disease, a psychiatric disease, let's try to model it. But now very often we say, what is an aspect of human brain function? That nobody has had access to. Let's try to model it in a dish and then say, okay, here are interns moving into the other side. What are the molecular machinery behind it? And very often we would identify disease-related genes.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“It's almost which type of engineering because you could have an electric engineer get hung up on the fundamental physics and we're going to get stuck there. Or they can sort of accept that these are working blocks. And they're somewhat black box working blocks. Absolutely. But then let's see what you can do to put them together.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“The beauty, I think, about biology is very often that a lot of this information is encoded in the genome. So once you start the process, the cells actually find each other in a meaningful way. And actually, very often we do reverse engineering in the sense that we make parts and we put them together and we see that they connect in a specific way. And then we start asking, how did they actually connect”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“I actually think a lot about this like these days because I. I never really wanted to become a tool developer. I kind of like became one by chance. And I just wanted to understand disease and turned out to start using this new methods. And initially I also thought that we really need an engineering approach. But the engineering approach actually is not working that well here. If you think about it, because an engineer, and I see this actually when I have. Students have an engineering background, they want to understand Every single part of the system before they would put it together.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“You know, part of what really intrigues me about this too is that you can basically nudge the systems to build these things and that it's repeatable and you can build upon your past successes. I mean, these are the hallmarks of an engineering process. I'm curious how you see that bearing out. What does the future look like? How far do you think you can push the engineering of these things?”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Pathway. So I think the same thing is probably going to be for brain disorders. It's probably going to be more circuit based, maybe even cellar-based in some of these disorders. But we're going to have to accept that autism is not one disease, but it's a group of disorders because schizophrenia is not one disease, but a group of disorders.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“I think it's also important that I think we started the conversation with this all psychiatric disorders are behaviorally defined. We are ultimately going to have to define them in a different way biologically. The way we've discovered that the fact that cancer is in the pancreas, it doesn't necessarily mean that it's going to have the same treatment, right?”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Absolutely Precisely And our approach has been precisely to try to identify genetic forms of disease, some of them actually very common. So for instance, there is a large deletion of chromosome 22. Which is present in 1% of all patients with schizophrenia. These patients have a 40% chance of getting schizophrenia lifelong versus 1% in the general population. So studying some of these patients that have a high susceptibility to developing this disease would probably represent at the end a window into maybe other forms.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Is again Behaviors. We don't have behaviors in the dish Well, you know, something that I've seen in other areas is that it's common outside of sort of neuroscience that just even a cellular phenotype can recapitulate disease enough that at least you can see how that cell responds to small molecules. And that is predictive of whether it's going to work in animals or humans. So if cells are enough to predict phenotypes in some areas, you can imagine this is one step beyond. Precisely. It's a group of cells. It's more complex. It's not all the way to a full organ or a full organism. But that, you know, it seems very reasonable that when you go up a level of sophistication, you can get to a lot more.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“That I think could be very useful. I think if we say broadly schizophrenia, I think that's going to be difficult because schizophrenia is again. And that's why we never really say, oh, we're modeling schizophrenia because schizophrenia is a combination of behaviors. We don't have behaviors in the dish. What we're modeling is the molecular biology behind some of this patient's genetic makeup.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“I think the neurodevelopmental disorders, so the ones that arise because of the human brain developing in some unusual way or in an abnormal way, I think those are the primary disorders that we can study. The ones that, for instance, have a later onset, such as Alzheimer's disease, neurodegenerative disorders. I think those are a little bit more challenging to study right now. And of course, the ones that have an immune component as well as the immune system has to be brought into. I mean, there are going to be ways, I think.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“One mistake very often in the field is to really think that this model is really the answer to anything. And I think as George Box famously said, all models are wrong, but some are useful. And so I think the idea is like, what is it useful? I think very often people confuse, oh, are they fully recapitulating the brain? Of course not. The question is, what is the question that you're trying to answer? What process, what disease are you really trying to answer? And I think there are a lot of things that are missing. There's like, for instance, novascularization. Many of the immune cells are missing. For instance, all the microglia are not. They can be added. But I think it's fair to look at this as an incomplete model that can be tuned in a way and engineered so that you can ask questions.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“And this is species specific just to make it. I mean, we, for instance, if you take chimp, chimpanzee derived stem cells and you compare them side by side, the brain argonoids, they do develop at different paces. So the chimp finishes earlier development and the human continues. So this is recapitulated in vitro as it is in vivo. So the question is like, what is the molecular mechanism? How can we figure out? Because I think as you were mentioning, of course, that is a challenge because today we have to keep hundreds of days.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“It's funny one of the parenting books I've read talked about actually took this analogy of development mirroring evolution one step further, which they talked about after they get out of the womb, the babies are first in little caveman stage and then in a little billard stage and you've probably seen this video. And it's, I mean, Caveman to Villager is the social development of that frontal cortex.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“The main, I think, hypothesis is that this allows the human brain. We have enough brain to do the basic functions, but we also have enough brain that we can allow to slow down its development and allow for social learning. So if you just think about the prefrontal cortex, that is the last one to myelinate, to mature. And it's thought that because we're allowing social learning to happen. More than any other species, more than any other primate. And so there are very clear mechanisms. And we know this is true. I mean, this is very well conserved across species.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Right, right. It's also very clear that the human brain has slowed down in general, like even versus other primates, slowed down its development. Really? So many parts of the brain are actually developing at a much slower rate through a process that is called neotany, essentially just putting a break on brain development. Yeah.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“And especially in the context of development of an organism, you might want certain things to time out with other things. You have to have the body being developed while the brain's being developed. But in the context of just the brain. Maybe those constraints go away, and you can imagine speeding it up.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“No, I agree. One of the limitations is obviously how long this cultures really take. But I think that's both a limitation and I think an opportunity because now that we know that in a dish, some of this timing is recapitulated, it would allow us to really try to understand the molecular machinery. What is this clock? And I'm hopeful that once we're going to identify what that clock really is, it would allow us to maybe accelerate or decelerate it.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“So one of the big limitations seems like that you're kind of constrained to the time of human development. Is that for the foreseeable future you're stuck with like this pacing or would the next Kind of iteration of engineering this process be speeding that up somehow”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“So they wouldn't do a very good job They don't move very well. Now, the good thing is that there are drugs that can modulate this channel, and once you add them and you block the activity of the channel, we show that within essentially a few hours, you can completely restore this abnormal cell behavior. And the reason why I think some of this technologies are so exciting is because they offer us access to certain cell states, cell behaviors that would be very difficult to access otherwise. And so understand some of these molecular, subtle molecular mechanisms in that context.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“And then we took those pluripotent stem cells and guided them to become either cortex or ventral forebrain and then put them together. And what we notice is that the patient cells had the cells jump much more often. So they would just engage in these jumps prematurely, so to speak, and every single time they would jump.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Now, one of the things that we discovered, and I think this brings us back to how can we use this model. We've been studying for a while a form of autism and epilepsy called Timothy syndrome. And this disease is very, very rare. There are only probably a couple dozen patients all around the world. What makes them really unique is that they only have a point mutation. That means one single letter in their entire genome is changed in a calcium channel. And it's been known that this calcium channel is important for cells to migrate. And so we thought, could it be that in patients this mutation affects this cellular process? We, again, recruited patients that have this disease, which are very rare. We brought them to Stanford. We got skin cells from this patients. We took those skin cells and we turned them back in time to make them look and behave like pluripotent.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“And even if you fuse different combinations, even if you put two spheres, two organoids, a ventral, they don't move. So there's something that are attracted to. And so they move on to the other side. And once they arrive, they even change their shapes.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“I think what was really surprising because we really thought it's gonna be really difficult to actually do this experiment that we're gonna have to develop all kinds of like engineering tools to like stick them to each other until somebody in the lab came and said look it's very simple you put them at the bottom leave them overnight the next day they're essentially fused but I think what is even more surprising is what they do after because you can color the cells differently and you can watch them under a microscope and you start seeing over the coming weeks that those inhibitory cells that are migratory start to all move towards the other side and the migration is actually quite specific because the other cells don't care”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Essentially involve deriving these two brain regions separately in a dish from pluripotent stem cells. So for instance, making the cortex that has all the excitatory cells and then making this ventral forebrain region that has all the interons, developing separately, we put different cocktails of small molecules. And at one point at the right point, we essentially put them together in a tube, essentially at the bottom of a tube. We leave them to sit close to each other overnight. And next day they essentially are fused to each other.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Right, so we know very little about this. So, a number of years ago, we wanted to really model this complicated process in a dish. And we did so with a new approach, which we often call second generation organoids or assembloids.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Yes. In humans, interestingly, there is like recent evidence that shows that in humans, in primates, but in humans particularly, this continues up to the second year of life in humans. So towards the prefrontal cortex, there is a population of interns that continues to migrate.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Precisely if anything, the rule of development is that cells have to move from where they were born to reach Inches, yeah, yeah, and this happens actually, there is evidence in rodents this migration stops before birth.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Yes. Well, I think it has to do with the fact that this When they're like developed, it's interesting, like, one of the most surprising things for students is just to learn that most of the cells in the brain are not born in the place in which they reside. You just assume that they're like there.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“A region called MG and they have to literally, again, one by one migrate. and reach the cortex. They don't just crawl on a surface What they do is they have a very peculiar way of movement, the cells, and they have a very long process that they point towards the direction which they want to move. And at one point, their cell body almost breaks into”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“And that is a very important because if you think, for instance, about epilepsy in epilepsy, there's more excitation or there's not enough inhibition. This balance just goes awry. It's also thought that to a large extent this balance also goes awry in autism. So very often autism is thought to be a disease of excitation to inhibition imbalance. But here's an interesting fact about the developing of the human cortex. All of this inhibitory cortical neurons, all of these neurons that put a break are actually not born in the cortex, in the brain. But they're born literally inches away from the cortex in another part of the brain. And sometimes around mid gestation, start all of them to migrate one by one, and they go up to reach the cortex and populate that region.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Well, I think the fact that we can even model in a dish in a non-invasive way, right? Because it doesn't involve taking anybody Tissue, brain tissue, right? I think the greatest opportunity is in accessing this stages of brain development that were previously inaccessible. They're likely related to disease. Just to give you an example, a very specific example about modeling disease and asking questions about disease. The human cortex doesn't have just cells that excite other cells. It also has about 20% of the cells that inhibit other cells, other neurons. So there is a very clear balance. Yes, precisely between excitation and inhibition in the cortex.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“I mean, that's amazing in its And in a sense, these IPS cells or these stem cells are seeds of sorts. Absolutely. And then we put them together, they interact with each other, the cell-to-cell communication creates this developmental profile. There's probably a cellular clock. And it's just a machine going tick-tick, tick, tick, tick, rolling along. As long as you just don't get in its way and create an environment that's kind of close enough to what it needs to be.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Is it surprising? Sure, it's surprising for us, but if you think from a point of view of developing a brain, the mechanisms for making a brain must be very robust because you have to make the same brain over and over again. And of course, there are a lot of differences between our brains, but to a large extent, they're quite similar structurally and functionally.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source