Science Friday - Brain ‘Organoids’: Lab-Grown Cell Clusters Model Brain Functions

Episode Date: January 17, 2024

Brain organoids are grown in a lab using stem cells, and can mimic the functions of different regions of the brain like the cortex, retina, and cerebellum. Though it may sound a bit like science fiction, this technology is increasingly being used to better understand brain disorders and eventually develop better treatments.Ira talks with neuroscientist Dr. Giorgia Quadrato, assistant professor of stem cell biology and regenerative medicine at the University of Southern California, about the state of brain organoid research and her model that mimics the cerebellum.Transcripts for each segment will be available after the show airs on sciencefriday.com. Subscribe to this podcast. Plus, to stay updated on all things science, sign up for Science Friday's newsletters.

There's a fascinating way to study the human brain. It sounds a bit like science fiction. We're talking brain organoids. Simply put, a brain organoid is a miniature replica of the human brain. It's Wednesday, January 17th, and yep, you guessed it, it's Science Friday. I'm sci-fi producer Shoshana Bucksbaum. Brain organoids are clusters of human brain cells grown in the lab. More and more, they're being used to better understand brain disorders,

and eventually they might even help develop better treatments too. Iroflato talks with a neuroscientist who created a new brain organoid model, which mimics the cerebellum. Dr. Georgia Quadrato is an assistant professor of stem cell biology and regenerative medicine at the University of Southern California based in Los Angeles. Welcome to Science Friday. Thank you. Thank you. It's a pleasure to be here. It's so nice to have you because you work on something really,

exciting, which I want to get right into. What exactly is an organoid? And how do you grow brain organoids in the lab? Yes, simply put, a brain organoid is a miniature replica of the human brain. And to grow this brain organoid, we start from human pluripotent stem cells. And these are cells that have the capability to differentiate into any cell type of our body. So we start with those. We make aggregate, small aggregates of these pluripotent stem cells. And then we use some chemical factor to differentiate them into different brain tissue. So the size of these organoids is about 2mm, so they are really, really tiny.

Is that like a grain of rice or something like that? Yeah, it's like, I would say like a lentil. So typically we can culture them up to one year. Over time, they don't only survive in culture in our laboratory. They actually keep on changing, much like our brain does. So they keep on develop new cell type, new type of neurons. So you can coax these stem cells into becoming one kind, a certain kind of brain cell.

And you're talking about the cerebellum, correct? Yes, yes. Why? Why are you so interested in that? Actually, most brain organoids have been generated to model the cerebral cortex, but my lab is particularly interested in generating cerebellar organoids, because the cerebellum is a very fascinating structure of the brain. So first of all, not many people know that about 80% of our neurons of our brain are actually localizing the cerebellum. So it's a real powerhouse. Wow. I would have not known that.

Yeah, it's a very high computing power because, you know, 80% of neurons are there. Classically, it has been always defined as responsible for the execution of, like, locomotion or for keeping balance. But actually, in the last few years, it's become more and more evident that the cerebellum is very important also for controlling, for example, emotional responses and behavior, reward behavior. So, in general, cognitive function. And also something that is very interesting about the cerebellum is that during evolution has changed a lot.

So, for example, if we compare the cerebellum of animals in the gray tape clade with the cerebellum of a human, they are quite different. And so this is, I think, very interested, especially if we compare the cerebellum with other brain structure, because other brain structure didn't really change so much throughout evolution. Instead, the cerebellum did. And so this really speaks for the ability of the cerebellum perhaps to be responsible for some of the function that really makes us human. And so this is why we are very much interested. We believe that problems in the cerebellum can actually also lead to neuropsychiatric disease, which is something that is very much of interest for my laboratory. So we're really much interested in modeling neuropsychiatric disorders.

And are you cultivating a certain kind of cerebellum cell? Actually, so what I think is exciting about this new research from my laboratory is that we have been able to generate a cerebellar organoids that contain all the main cell types that we have in the human cerebellum. So they are really all there. In particular, we are very much excited that we have been able to generate some progenitor cells that have been recently associated with the pathogenesis of medulla blastoma, that is one of the most common pediatric cancers. And also, I think, the most important relevant innovation in our

organoids is that we have been able to generate purkingi neurons. So these are specific neurons of the cerebellum that are among the largest neurons in our brain. And these neurons are affected by different type of issues. For example, they can be affected by toxic exposure. For example, alcohol or lithium can damage Pekingi neurons. They are also damaged in some genetic condition, for example, for cerebellar ataxia. And also in the individual with intellectual disabilities or autism spectrum disorders, we see problems and the generation of these porkingi neurons. And so you think maybe you can, by understanding the cerebellum and the perkinji neurons, better perhaps find treatments for those kinds of illnesses? Yeah, exactly. So this is really

our final goal is really to, now that we are able to generate purkingi neurons in vitro, so we can really use them to screen for new therapies. So first of all, understand better this disease, and then trying to find new therapeutics. Basically, before we published this work, previous research was able to generate Purkinji cells, but only co-culturing them with mouse cells, other type of mouse neural cells. The beauty of our system is that they develop in an all-human system.

And so all the cell types in the cerebell organs are human. And this is important for screening therapeutics that then can be used in human beings. That's interesting. And because you have human cells, you can get a much better comparison than you would, let's say, using mouse brain cells here. Yeah. So I think, you know, obviously using mouse models, it's very important to understand disease. And these are, you know, in vivo models. So they have their advantages.

But I think what's the beauty about these human cerebellar organoids and human cell-based essays in general is that we really can replicate the human genetic background. So, for example, for neuropsychiatric disorders, the genetic of the person that is affected by the disorder is very important. If the same mutation in the same gene can really lead to completely different clinical manifestation into different individual. And this is due to the fact that different individuals have different genetic background. So it is very important to develop models in which we can replicate the genetic background

that then leads to basically the clinical manifestation and so the development of some of these neuropsychiatric disorders. Is the idea that you might take individual cells from people, and use their own stem cells so that the genetics is very close to that person and then craft an organoid. Is this personalized medicine or not, or is this just basic research? This is really, I think, one of the most important point that you brought up. Our ability with this human-induced pro-ipotent stem cells to really do personalized medicine.

So, yes, we basically, we can, if we have a patient, for example, with a certain, disorder that we want to study, we can take somatic cells from this patient, which means, for example, skin cells or blood cells, and then revert them to pluripotency. So we can make stem cells, prerpotent stem cells out of these. And then these cells will actually retain the genetic background of the person, obviously. And so we can make mini replica of the brain of that specific person. And so we are able to then understand the disease of the disease of, that person very well. And, you know, ideally what we would like to do to understand what went wrong, you know, in the development of the brain of specific person is to go back in time and

look at how, you know, that brain develop in the womb. Obviously, we cannot do that. But what we can do is grow a brain organoid and see how it develops. So, yeah, exactly. So, you know, this is personalized medicine. Okay. So everybody who hears this, right, is going to want to know, how do I Take advantage of that. When will it be available for me or my loved ones who may be suffering from some kind of illness? We're years away, right? Yeah, I think, you know, we are years away and there are all these issues also, hectic issues related to inform consent, how we deal with this information that we generate from things related to privacy. So there is a lot that we need to work out for these. And also,

it's a matter of cost. Ah, cost. We've never heard that before. You love working on the cerebellum, and that's what your lab is working on creating organoids, which mimic that part of the brain now. There's got to be other people working on different parts of the brain, right? To make organoids for those.

Here I'm thinking, is it possible to link all of them together so they can all work similar? to how our actually whole brain works. Yeah, so this is a really fantastic question. Actually, in my lab, we also work with other brain, organoids from other brain regions, and we are already thinking along this line. There are some other laboratories that have been fusing organoid

from different brain region to study communication between different brain regions. We think that there is a lot of improvement that we can actually, We need to work on this so that we can, so the goal for us is to connect these brain organoids in a way that resemble connection in the actual brain. And again, I think to be able to achieve this, we need to bring in people with expertise in tissue engineering, which is what we are doing. There is really a big opportunity in really connecting organoids from different brain regions. Because, for example, if there are some disease that affect only specific brain regions. But we are unable sometimes to discriminate and to understand which brain region is actually causing the disease

because brain regions communicate with each other. And so ultimately, when we look at an MRI or some functional imaging, we see that there is a problem in multiple brain regions. But we cannot understand which, from which one the problem. problem is stemming. Organids really give us the opportunity to sort of mix and match brain organoids from, for example, health individuals that do not have the disease. So we could use, for example, an organoid that is healthy and then link it to an organoid that is disease. And so, and then do the contrary. And basically try to understand which brain region

is basically important for causing the disorders. So I think this is very important. Wow. How exciting is this for you to be able to do this? Yeah, it's really super exciting. I mean, I really think, if we think about neuropsychiatric disorders that I said, are really very complex from a genetic point of view. In the last like 70 years, we really haven't been able to come up with effective treatments for these disorders.

And as I said, I think one of the main reason is that incredible. complexity of the genetic of this disorder. So I think now with these organoids, we really have the opportunity to understand a lot more about these disease. And so I'm very excited. This is fascinating, Dr. Quadrato. This was just terrific. Thank you for taking time to be with today. Yeah, my pleasure. Thank you so much. Dr. Georgia Quadrato, assistant professor of stem cell biology and regenerative medicine at the University of Southern California in Los Angeles. That's it for today. A lot of helped make the show happen, including Nehima Ahmed, Emma Gomez, Sandy Roberts, Robin Casmer,

and many more. Tomorrow, mapping the human brains billions of cells, we're talking about the human brain cell Atlas. I'm Shoshana Bucksbaum. Catch you then.