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

“If you think about glial cells, astrocytes in particular are very different before birth and after birth In astrocytes, as they approach nine to ten months of keeping them in a dish, they slowly not suddenly, slowly transition to a postnatal signature, as if there is some sort of program that once they start it just progresses. And we know that not just at a gene expression level, but at the chromatin level, epigenetic level, and even functional level. Many of the cellular processes are, and again,”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“No, I think it was like a slow process. And for me personally, it was difficult to accept as a physician. I always kind of thought as birth as being like this dramatic event to the brain that triggers a series of processes. But, you know, birth in humans is actually not even happening when it should happen. Yeah, it should happen three months later. It should happen much, much later. Exactly. But there are limitations because of head size. And so it's not really about the birth itself. It's just about the maturation of the brain.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“I think one of the first things is that they recapitulate many aspects of human brain function. Again, by maintaining them for very long periods of time, we show, for instance, that cell types are generated in a sequence, in the same sequence as they would in the brain. So for instance, you don't just get neurons in the brain. You also get glial cells, which for a very long time were thought to be like unimportant cells. They just glue the brain together. But they come late in development, especially in humans, for instance, astrocytes are essential for neurons to even form synapses with each other. But we know very little about them. Now, if you keep this organized for long enough, and it does take 20 to 30 weeks, but once you do that, you start seeing, for instance, astrocytes also appear at the right time and they actually mature. In fact, one of the most surprising things that we discovered by maintaining these cultures for a very long time and comparing them to primary tissue, to tissue obtained from actual patients, is that the cells do, they know the maturation time point. And for instance, they know when birth should happen. Oh my God.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Number of instructive signals that you provide, but then you can, you know, and we've shown this, you can derive multiple brain regions. You can make a midbrain, you can make a spinal cord, you can make a striatum, you can make a hypothalamus. Guide their differentiations with essentially small molecules.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“They make synapses with each other. So they do communicate. But of course it is not like the brain. Most of these brain organoids resemble very specific brain region. The brain is not a homogenous organism, not like the liver. It does matter which part you actually probe.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Right. So, in that sense, maybe that's a All of the organoids recapitulate some features of the organ. Of course, none of them recapitulates all the features of the organ, like neurons and brain organoids, fire action potentials.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“But in the organoid field, like I think there are lung and liver organoids that have some recapitulation of function. Right. So in that sense, maybe that's appropriate, but you're saying on the brain side, I mean, what aspect of function?”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Absolutely An organoid, broadly speaking, is a three-dimensional cell culture that self-organizes and recapitulates some aspects of organ function, but not all. Actually, the majority of the organoid field is about cells that are derived directly from patients.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“There's still a little bit of confusion in the field about the terminology, but some of these terms are definitely inaccurate. And I think they do not reflect the science. Probably even the term organoid is not really the most appropriate.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“It is truly the scene. And actually, you know, the amateur development biologist in me likes to point out that all this organization that goes on kind of recapitulates evolution to some degree too. And so, you know, we have the brain has all this complexity of lower brain and then other parts and eventually cerebral cortex gets added through evolution. That seems to be what you're talking about in terms of it being developed to recapitulate in developmental biology. So now the issue is since if we care about these disorders and probably most of these disorders are not going to be in the lower sort of animal brains, we'd have to be able to build models that have them. Right.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“It really does make me think about when you say, well, the original black box is the human brain, right? It is truly that we see nothing inside it except for studying the behaviors that are as a result of that.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Yes. I mean, if we really were to think like how the human brain comes together, there are a group of stem cells, which are cells that are capable of turning into other cell types under appropriate conditions. And those cells start organizing and forming the brain over a very long period of time. The human brain literally takes hundreds and hundreds of days and then years afterwards to mature and come together. And that, I think, is one of the most exciting possibilities for the cellular reprogramming technologies is that they allow us to essentially recapitulate in a dish. Some of the seller processes in a way that allows us to study them and of course to do this in the context of patients.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Exactly. You know what's interesting about this is that we're in many ways, the science here is just replicating the natural aspect of developmental biology. That developmental biology starts with, you know, originally these stem cells, and these stem cells have to then differentiate into becoming all different types of tissue. The fact that actually we can go backwards is interesting, and also the fact that actually in some ways the experiments will recapitulate that developmental biology is very intriguing.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“And it's interesting enough that then they don't really keep them for very long periods of time. And in fact, we've kept some of the longest, if not the longest cultures ever maintained, which went on for 800 days and beyond. Initially, we just thought, oh, let's just do that so we can keep them a little bit longer. But then we realized that that enabled the cells to self-organize because they're in a three-dimensional culture.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Essentially, I mean, I don't know if we can call this innovation, but around, I think, the summer of 2011 or so, I thought that maybe it would be easier to just move the cells to a plate that doesn't allow the cells to attach at all. It's essentially a plastic dish that is coated with a substance that doesn't allow the cells to sit down.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Precisely. And this is exactly what motivated us to even develop new methods because initial methods were keeping cells at the on a flat surface, on a dish, on a plastic flat surface. And so what happens when you start to keep cultures, these cultures, the cells for like, you know, 10 weeks, 12 weeks?”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Exactly. And it's well, the human, if you think about the human cerebrocortex, all the neurons in our cerebrocortex are made by 27 weeks of gestation. So that's the second part of gestation, but that's still a very long time for cultures. And essentially.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Starts again absolutely. Humans erbo cortex has a diversity of cell types which are arranged in layers. But those layers are not borne all at the same time. They're born in a specific sequence. And initially you get layers of deep layers, like layer five and six, and slowly you get upper layers. Now, if you start to recapitulate that process in a dish, Then you start seeing that you don't have to provide all the cues all the time. You just have to provide the initial cues. And once the process starts, the progenitor cells start making first deep layer neurons and then slowly start to make upper layer neurons.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“So it comes from cells from an adult That then become under differentiated. And then the fun begins. It's kind of mind-blowing, so to speak, to take a skin cell or a blood cell, turn it into a brain cell, neuron cell, with others. And then developmental starts again.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Living cells, embryonic stem cells maintained in a dish. Another paradigm shift has happened 12 to 13 years ago when it was shown that development is really not Put them in a dish and then just overexpress a series of genes that are important for a cell to be pluripotent. And that is sufficient to actually push that cell in time to look like a pluripotent stem cell. So this is like...”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“There are a number of important discoveries that have happened over the last few decades that I think brought us in this unique position right now to start asking questions about human brain disorders with human patient cells. And the first one is probably even the fact that we were able to maintain some stem cells in a dish, which was done in the 80s. For a long time, we were unable to really maintain pluripotent stem cells in a dish.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Can we, as it happened in, I guess, in the cancer field, start thinking about therapies that have been designed for specific disorders rather than identified by chance? Because many of the drugs that we have for psychiatric disorders today have actually been identified by chance.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Of course, the behavioral repertoire is much closer to that of humans, but as you can imagine again, the limitation there is how scalable is that, how many primates can we really use for this type of studies? And who can afford to do this experiment on a large scale? The truth is that most of the psychiatric have a very complex genetics. It is very rare like one single gene or one single variant. But very often a combination of this, and it's not just obviously about the genes, but what are the cells and the circuits that are affected by this? And I think that only once we start to understand some of the molecular machinery behind the psychiatric disorders.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Well, I think, of course, there are imaging studies that you could use, for instance, MRI and functional MRIs. The problem with those studies is that you don't really get the molecular resolution. You don't get to really study the tissue. An alternative, which has been used in the last decade or so, has been to model many of these disorders with animals. And that has been quite an exciting field that was primarily accelerated by identifying genes associated with psychiatric disorders. But I think we always have to be aware of the differences between species, right? Even in how the brain, the structure of the brain, the fact that there are millions of years that separates us in evolution, that the behavioral repertoire is very different across species.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“So you're getting a very small amount of information that may not even be accurate or very anecdotal. Or very anecdotal, yes. And that's the only real tool that you have at the moment besides behavior.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“And it's right. Another limitation is actually the age of these individuals, but very often also the cause of death because in most of these cases it's actually traumatic. And most of the psychiatric patients will take many, many medications and undergo various therapeutic interventions across their lifespan. We don't know, for instance, how is that influencing what we're seeing in postmortem tissue?”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“For me as a neuroscientist, it is really important to be able to record electrical signals from cells, to really look at how they're communicating with each other. But at the same time, another limitation is actually the availability of tissue. I mean, if you were to just think, for instance, about autism spectrum disorders, which is very common, one in 60 or so individuals. And there is even an autism brain bank. But the number of brains that we have in a brain bank is really in the hundreds, not in the thousands for a disorder that is like so common.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“You said something really interesting about just never being held back by not really having the tissue. And you mean by that the first time we get to look at the tissue is after somebody who has suffered from a psychiatric disorder has died, right? That is our primary.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“And the complexity. I mean, it's fun to think about in the 80s, molecular biology was this hot new term. I mean, you're talking about something almost like molecular psychology, taking this big sort of emergent phenotype that is a behavioral and then trying to connect it, not just at the tissue level, not just at the cellular level, but all the way from the molecular level. That is a hard thing to do. It's hard to imagine if someone has schizophrenia or severe depression, what's the target to hit? Right.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“And so again, we are defining psychiatric disorders based on combinations of behaviors, presence or absence or certain patterns of behavior. We've made, I guess, a lot of progress into classifying these disorders and reclassifying them. But the truth is that our molecular understanding of psychiatric disorders, of brain disorders more broadly, is very limited. And probably behind any other branch of medicine, which I think is reflected in the therapeutics that we have.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Has gone in the last few decades from really like no treatment whatsoever to almost completely curing certain forms of cancers. And if you look carefully at it, you realize that one of the reasons for this incredible progress is that oncology has really made you use of the revolution in molecular biology. And it has done so because it actually has access to tissue, to the tissue of interest. We know almost nothing about how the human brain develops because it's completely inaccessible.”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“Now psychiatric disorders are still behaviorally defined, and there are very few biomarkers that are considered reliable for diagnosis. The truth is that our understanding of psychiatric disorder is actually quite limited. I often like to joke that I suffer from an oncology MV syndrome, which is essentially this deep frustration that you feel as you see just like how fast cancer research has”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source
“We're here today to talk about understanding brain disorders and some of the new tools we're developing for how to do so. So let's start where we actually are in that. Are we actually anywhere significantly more advanced than we were in the days of hysteria? You know, thinking about things like labeling these sort of conditioned societal conditions that we had no clue, like where are we actually right now?”
2020-05-24 · a16z Podcast · Don't Call it a Brain in a Dish! · IDENTIFIED FROM THE TRANSCRIPT · source