Curing Autism, Epilepsy & Schizophrenia with Stem Cells

00:00:00.360 | - Welcome to the Huberman Lab Podcast,

00:00:02.320 | where we discuss science

00:00:03.760 | and science-based tools for everyday life.

00:00:05.940 | I'm Andrew Huberman,

00:00:10.320 | and I'm a professor of neurobiology and ophthalmology

00:00:13.520 | at Stanford School of Medicine.

00:00:15.080 | My guest today is Dr. Sergio Pasca.

00:00:17.760 | Dr. Sergio Pasca is a professor of psychiatry

00:00:20.120 | and behavioral sciences,

00:00:21.320 | and the director

00:00:22.160 | of the Stanford Brain Organogenesis Program.

00:00:24.960 | During today's episode,

00:00:25.960 | we discuss autism, schizophrenia,

00:00:28.200 | and human brain development generally,

00:00:30.200 | both brain development during pregnancy,

00:00:32.260 | as well as during childhood,

00:00:33.500 | and leading all the way up to our third decade of life.

00:00:36.420 | During today's discussion,

00:00:37.460 | you will get the most up-to-date information

00:00:39.760 | about autism and its treatments.

00:00:41.760 | You'll learn why the prevalence of autism is rising,

00:00:44.560 | the role that genes play in autism,

00:00:46.340 | and the novel treatments that Dr. Pasca is developing

00:00:48.860 | to treat what is called profound autism,

00:00:51.120 | which are the most severe cases of autism.

00:00:53.500 | Dr. Pasca is one of a small handful of researchers

00:00:56.340 | that pioneered the discovery and development

00:00:58.460 | of what are called organoids and assembloids,

00:01:00.700 | which are essentially human brain circuits

00:01:02.480 | derived from stem cells that form in a dish

00:01:05.560 | so that one can study them directly.

00:01:07.380 | And while that might sound artificial,

00:01:09.000 | today he explains why those organoids and assembloids

00:01:11.680 | are immensely powerful for understanding exactly what is wrong

00:01:15.080 | in psychiatric illnesses like profound autism,

00:01:17.640 | schizophrenia, and other psychiatric challenges,

00:01:20.060 | and for developing cures.

00:01:21.880 | So today you're going to learn a lot

00:01:23.640 | about human brain development and about stem cells,

00:01:26.420 | which is going to be important for anyone interested

00:01:28.360 | in how the brain wires up,

00:01:29.900 | how to treat various diseases of the brain,

00:01:31.980 | but also for anyone who is considering stem cell therapies.

00:01:35.260 | As you'll soon learn,

00:01:36.320 | Sergio is an extraordinary scientist,

00:01:38.340 | but also an extraordinary teacher.

00:01:40.520 | By the end of today's episode,

00:01:41.820 | you'll have the latest information on stem cells,

00:01:44.100 | organoids, autism, and what is being done to cure autism,

00:01:47.460 | and other psychiatric conditions.

00:01:49.500 | Before we begin,

00:01:50.340 | I'd like to emphasize that this podcast

00:01:52.060 | is separate from my teaching and research roles at Stanford.

00:01:54.680 | It is however, part of my desire and effort

00:01:56.740 | to bring zero cost to consumer information about science

00:01:59.240 | and science related tools to the general public.

00:02:01.840 | In keeping with that theme,

00:02:02.960 | today's episode does include sponsors.

00:02:05.340 | And now for my discussion with Dr. Sergio Pasca.

00:02:08.520 | Dr. Sergio Pasca.

00:02:10.380 | - Welcome.

00:02:11.220 | - Thank you, it's great to be here.

00:02:12.760 | - We're old friends.

00:02:14.360 | Shared a laboratory space years ago.

00:02:16.180 | We'll get back to that a little later.

00:02:18.120 | In the meantime, these days there's a ton of interest

00:02:22.120 | and I think misunderstanding about autism.

00:02:24.240 | As soon as the topic of autism comes up,

00:02:28.020 | immediately some people will say,

00:02:29.920 | why are we trying to cure this thing?

00:02:31.300 | I know autistic children and adults

00:02:33.900 | that are delightful people that lead functional lives.

00:02:36.620 | They might be a little bit different

00:02:38.340 | or a lot different than other people,

00:02:39.560 | but why are we trying to quote unquote cure autism?

00:02:42.080 | And then other people will say,

00:02:44.040 | well, there are people with autism who need constant care,

00:02:48.820 | who will never live independently.

00:02:51.140 | Tell us about autism, what this spectrum really is.

00:02:55.820 | And then we'll talk about what your laboratory is doing to try

00:02:59.460 | and literally find cures for the most debilitating forms of autism.

00:03:03.140 | - Well, autism is a complex condition.

00:03:06.080 | It's a spectrum, as you said.

00:03:09.080 | In a way, you could say autism and neurodevelopmental disorders.

00:03:12.940 | It's behaviorally defined.

00:03:15.640 | There's no biomarker.

00:03:17.080 | So in a way, it's a condition that is defined exclusively by observing behavior,

00:03:22.540 | which is actually the case for most psychiatric disorders.

00:03:26.020 | But it's essentially diagnosed by the presence and absence of certain behaviors

00:03:32.720 | in a certain period of time or up to a certain age.

00:03:37.020 | And of course, what triggered, I think, a lot of discussions in recent years

00:03:40.820 | is because the number or the prevalence of autism has increased.

00:03:46.560 | So now it's close to almost 3% of the general population,

00:03:50.480 | which of course, it's a big number.

00:03:51.960 | - 3%?

00:03:52.920 | - Almost 3%, yes.

00:03:54.280 | - Wow.

00:03:54.860 | - So it has increased even since I was in medical school.

00:03:57.860 | When I was in medical school, actually, it was considered a rare disease.

00:04:01.180 | The reason why I actually studied autism, because it was a very rare disease

00:04:04.920 | and we had very few resources, so we thought studying a rare disease would be easier.

00:04:09.020 | But now we also know so much more about this condition.

00:04:11.980 | So we do know, for instance, that there is a strong genetic component to it,

00:04:18.460 | which for a while, obviously, we didn't.

00:04:22.480 | In fact, in early days, the psychoanalytic perspective dominated,

00:04:28.620 | especially in the '50s and '60s.

00:04:31.220 | So it was thought that it was resulting from having very cold parents,

00:04:36.260 | in particular, a cold mother.

00:04:37.660 | - Emotionally cold?

00:04:38.760 | - Yeah, emotionally cold.

00:04:39.600 | It was the so-called refrigerator-mother hypothesis of autism.

00:04:46.600 | And then in the '70s, some of the first biological studies were done,

00:04:51.160 | primarily in twins, that show something quite remarkable.

00:04:55.960 | That if you have twins that are identical, genetically identical,

00:05:00.100 | and one has autism, then the probability that the other one has autism

00:05:04.200 | is very, very high.

00:05:05.620 | - Even with different mothers? - Sure.

00:05:07.460 | - Mm-hmm. - Mm-hmm.

00:05:08.460 | - But generally, we think that there is a strong heritable component to autism.

00:05:13.460 | So that was like in the late '70s.

00:05:15.300 | And really, just in the last 10, 15 years, we've learned, actually, that there are genes associated with autism,

00:05:22.300 | and certainly with very specific forms of autism.

00:05:26.140 | And so that's what we would call generally profound autism today.

00:05:30.140 | conditions that are severe.

00:05:30.980 | conditions that are severe, that are causing an impairment, that are very often associated with other conditions,

00:05:37.980 | such as intellectual disability, so low IQ, epilepsy.

00:05:41.980 | So because it is a spectrum, of course, it creates a lot of confusion.

00:05:46.780 | And certainly, there's no doubt that there are individuals that have autistic traits that are fully functional in the general population.

00:05:54.820 | But the reality is also that there are kids that have autism who are very impaired and will require, actually, lifelong care of sorts.

00:06:04.820 | You know, another way of thinking about autism is that autism is not one disease.

00:06:09.820 | And I think, you know, no psychiatrist or even biologists who are studying autism would ever consider that this is one single disease.

00:06:17.660 | The way I look at it sometimes is, like, think about the fever of the 19th century in medicine, right?

00:06:25.060 | So you see this very often in movies, right?

00:06:27.020 | They will say, "Oh, he has a fever, high fever.

00:06:29.980 | He's going to die from high fever."

00:06:31.660 | Well, that fever could have been a viral infection, a bacterial infection, could have been cancer, metastatic cancer, right?

00:06:38.220 | Could have been an autoimmune disease.

00:06:40.620 | The treatments are very different.

00:06:42.460 | But in that time, that's all we knew.

00:06:44.860 | It was we were observing that behavior, in which case, raising of the temperature.

00:06:49.260 | But we didn't know the biology.

00:06:50.540 | Today, we will use very different treatments for those conditions.

00:06:53.500 | And some of them, of course, we don't even treat, right?

00:06:55.300 | We just observe.

00:06:56.860 | So I think in autism research, as it is the case for many psychiatric conditions, they are defined behaviorally.

00:07:05.420 | But there is a disconnect with the biology.

00:07:07.740 | Very often, we don't have good biological, we don't have biological markers by definition.

00:07:12.540 | And so that disconnect, I think, creates a lot of confusion.

00:07:17.420 | I have a couple of questions.

00:07:19.180 | First of all, is the prevalence of autism higher in males?

00:07:23.500 | I've been told yes.

00:07:24.620 | If it's 3% overall, what's the distribution for males versus females?

00:07:31.660 | The ratio varies, also based on severity.

00:07:34.620 | But generally, it's been one to four.

00:07:37.420 | So more males than females.

00:07:41.100 | And we just recently had our colleague Nirao Shah on the podcast, who basically said the difference

00:07:47.820 | between a biological male and female comes down to this SRY gene.

00:07:50.940 | Not even necessarily on the Y chromosome.

00:07:54.060 | If a baby has the SRY gene, you're going to get a fully functional male.

00:07:59.180 | If not, you're essentially dealing with a female.

00:08:03.740 | So presumably, something about the SRY gene is conferring a vulnerability to autism.

00:08:08.860 | I think it's fascinating.

00:08:10.060 | Well, there are a lot of discussions, of course, like what causes this difference.

00:08:14.060 | And some discussions are just in terms of diagnosis, that perhaps some of the girls are not getting

00:08:19.260 | diagnosed properly, that we do know that some of them are very good at what we call masking the

00:08:25.260 | symptoms or learning the skills, social skills, and covering for that diagnosis.

00:08:30.940 | But what we do know for sure is that there are differences in how the male and the female brain,

00:08:37.260 | especially around birth, can actually take up injury.

00:08:40.860 | So think, for instance, about premature birth.

00:08:43.340 | You know, one of the best predictors for a premature baby in terms of outcomes, it's actually to be a female.

00:08:49.980 | Just in general, females, preemies will do much better for whatever reasons.

00:08:55.980 | You know, the way the nervous system is built, the resilience.

00:08:59.980 | We know that the maturation stage is also different, right, for the male and the female.

00:09:04.060 | You know, think about like acquisition of certain milestones that happen much faster in girls.

00:09:08.620 | They generally tend to speak a few months earlier, to walk a few months earlier.

00:09:12.940 | So just the nervous system is maturing at a different pace and can take injury differently.

00:09:20.860 | So it could be that that is certainly the cause.

00:09:25.260 | But at the same time, and as we were talking, since autism is not one single disease,

00:09:30.540 | it is very hard to point out to one specific factor that is behind it.

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00:11:56.220 | You mentioned that autism is diagnosed by behavioral measures or the lack of

00:12:01.260 | behavioral symptomology, what we call positive and negative symptoms,

00:12:04.940 | which can be confusing language because people think positive means good.

00:12:08.060 | No, positive is the presence, negative is the absence.

00:12:11.820 | I haven't looked at this literature in a while, but the last time I did,

00:12:15.180 | it seemed that babies or young children failing to focus their own gaze on the eyes of other people

00:12:23.260 | is one of the major diagnostic criteria.

00:12:25.500 | It seems they look at the face more holistically or they'll zoom in just on the nose,

00:12:31.020 | but they're not really making as much eye contact.

00:12:33.740 | Is that still a diagnostic criteria?

00:12:36.220 | It's not part of the diagnostic criteria.

00:12:38.060 | Interesting.

00:12:39.660 | It's, uh, but it is one of the features that has been observed.

00:12:43.180 | Uh, of course, it also has to do with just in general, like joint attention is one of the earlier.

00:12:48.460 | So, you know, uh, if you just tell a child like, oh, look here.

00:12:52.300 | Right.

00:12:52.620 | So if they kind of like have that attention, if they engage in that attention,

00:12:57.020 | uh, it's one of the features that is associated with autism is not certainly diagnostic is not, uh,

00:13:05.340 | pathognomonic, so to speak.

00:13:07.420 | So it's not specific to the disease in any way.

00:13:09.580 | Uh, but there's certainly many deficits and some of them can actually be compensated later.

00:13:14.300 | Interesting.

00:13:15.260 | There were some other things I've heard over the years, for instance, that when children with autism

00:13:20.380 | have a fever, that their symptoms improve.

00:13:24.300 | Yeah.

00:13:24.780 | Is that still the case?

00:13:26.060 | Yeah.

00:13:26.540 | So those are mostly anecdotic reports, um, of patients who would have a very high fever and then,

00:13:35.340 | for instance, they were nonverbal.

00:13:36.700 | So many patients with autism, uh, or individuals with autism will have, you know, will be nonverbal.

00:13:44.060 | They have very few words or if they, you know, they're, they're not able to communicate.

00:13:48.220 | And so there are a few reports of parents saying that when they spike the very high fever,

00:13:53.740 | they'll start talking in sentences like very briefly or like engage.

00:13:58.380 | And in fact, I mean, that is known, uh, you know, kids in general, when they have a high fever,

00:14:03.340 | they tend to be more talkative.

00:14:04.780 | It activates somehow the nervous system.

00:14:06.380 | There've been a lot of hypotheses about this.

00:14:08.140 | Some of them, uh, having to do with how the neurodienergic system is activating during fever.

00:14:14.940 | Others saying that there are some of the cytokines, the immune molecules that are present during fever,

00:14:22.220 | that are somehow getting into the brain, activating the nervous system.

00:14:25.340 | And others as simple as, oh, ion channels, right?

00:14:28.460 | Ion channels will open, uh, more when the temperature rises.

00:14:32.460 | So something about the circuits functioning differently during that, but it's, it's mostly

00:14:37.180 | anecdotic, uh, at this point.

00:14:39.340 | It's, and it's certainly, again, probably not present in all individuals with autism also because

00:14:44.620 | autism is again, not one single disease.

00:14:46.940 | So we would not expect it to be present in all.

00:14:49.820 | A few years ago, there was a lot of excitement about the idea that autism might somehow be

00:14:54.540 | related, perhaps even caused by deficits in the microbiome.

00:14:57.820 | There were some mouse experiments of doing fecal transplants from what we call wild type or healthy

00:15:03.580 | mice into mice that were, uh, had some symptoms that resemble autism and there were improvements

00:15:10.300 | observed, um, to the point where I think there were some human clinical trials using fecal transplants.

00:15:15.340 | Um, whatever became of that?

00:15:17.420 | You know, I think, again, almost everything has been associated or thought to be causal,

00:15:23.500 | but generally demonstrating this is very, very difficult.

00:15:26.380 | So, you know, we cannot deny that perhaps improving the microbiome will improve the, you know,

00:15:33.180 | the quality of life of some of these individuals, but whether it's really causal, there's no, uh, clear

00:15:39.180 | evidence for it.

00:15:39.980 | Think about it.

00:15:40.700 | Just to give you another example, think about sleep.

00:15:42.780 | Many patients, uh, will report, especially the ones that are profoundly impaired, will have severe

00:15:50.860 | sleep disturbances.

00:15:52.060 | I mean, 70, 80% of them, you know, they can have nights where they sleep very little, right?

00:15:56.780 | Then do that for like a week.

00:15:57.980 | So just imagine even just improving the quality of sleep for those patients can do miracle.

00:16:03.660 | I mean, all of us, right?

00:16:04.700 | If we don't sleep for three, four days, our social skills, you know, we become socially impaired.

00:16:09.580 | So I think, of course, correcting, uh, a lot of this issue.

00:16:13.260 | So for instance, many patients are picky eaters, you know, they don't like certain textures.

00:16:17.900 | So they will never eat, for instance, veggies, right?

00:16:21.020 | So that creates in the early days, for instance, we thought that, uh, you know,

00:16:25.260 | there are dietary disturbances that really at the core, of course, it remains to be seen

00:16:29.340 | whether just simply correcting those is gonna be just improving or certainly reversing, uh,

00:16:35.820 | some, some of these forms.

00:16:36.940 | But again, most of the evidence points out towards a very strong genetic component, uh, behind it.

00:16:43.740 | And in fact, we now have hundreds of genes that we know when, when they are mutated,

00:16:48.860 | there are strongly associated with specific forms of autism.

00:16:51.740 | I'm curious, uh, what sorts of, um, proteins those genes are upstream of.

00:16:57.020 | And I ask because, uh, David Ginty at Harvard, um, and did these really beautiful experiments

00:17:03.340 | where he induced mutations just in the periphery.

00:17:06.300 | So outside the brain of these mouse models for autism and saw a lot of the same symptomology.

00:17:11.820 | Yeah.

00:17:12.300 | Raising the question of whether or not autism originates in the brain

00:17:15.420 | or whether or not the deficits in the brain are the byproduct of changes in the body.

00:17:19.580 | Yes, microbiome, but perhaps, um, their skin, their hearing, et cetera, are more sensitive.

00:17:26.860 | And maybe that's why they, you know, you could imagine if you were ultra sensitive to an environment

00:17:31.260 | that your brain would eventually wire differently according to kind of overwhelmed by what was

00:17:36.780 | happening in the sensory landscape.

00:17:38.620 | Yeah, absolutely.

00:17:39.260 | And those are really elegant experiments that he's done.

00:17:41.500 | Many of the genes, you know, they fit in different categories.

00:17:45.420 | Like you would have genes that would produce proteins that sit that synapses, uh, which

00:17:50.380 | was sort of like to be expected.

00:17:52.540 | Some of them are, you know, ion channels.

00:17:55.340 | They're proteins that would let ions inside or outside of a neuron.

00:17:58.940 | There are many of these conditions, so-called channelopathies.

00:18:01.740 | And they're the ones that are like synaptic related.

00:18:04.940 | So synaptopathies.

00:18:06.700 | There are a lot of chromatin genes, so like proteins that pack the DNA in cells.

00:18:11.020 | Those are chromatinopathies.

00:18:13.100 | Um, so they're really, again, many, many categories of genes.

00:18:17.660 | And then what is also interesting is that many of these genes are also expressed in the periphery.

00:18:21.420 | So I think the experiments that you were mentioning are really elegant

00:18:24.220 | because it showed that indeed that can perturb the development of the nervous system,

00:18:28.300 | even if they're affecting just the periphery.

00:18:30.540 | Of course, now in patients, there are present also in the central nervous system.

00:18:34.380 | So it's always difficult to distinguish.

00:18:36.540 | But just missing some of these critical periods or perturbing some of these critical periods of

00:18:41.340 | development can have certainly devastating effects later on.

00:18:44.700 | So if a parent comes into the clinic nowadays with a child that's diagnosed with profound autism,

00:18:52.380 | what is the treatment?

00:18:53.340 | Let's set aside the potential for epilepsy, which hopefully they would treat as well,

00:18:58.620 | or other things that might be secondary.

00:19:00.460 | But what is the typical treatment?

00:19:04.140 | Are they doing?

00:19:05.100 | And let's assume infinite resources, which of course nobody has.

00:19:08.220 | Most people don't have.

00:19:09.340 | But if one had infinite resources, what would be done?

00:19:13.580 | Would it be behavioral training?

00:19:15.020 | Would it be something to control the activation state of the brain?

00:19:18.700 | I mean, as far as I know, there's no single treatment for autism.

00:19:22.380 | No, there's no single treatment for autism.

00:19:24.380 | Again, in the context of this not being one single disease.

00:19:27.900 | What we can say today is that if, you know, family walks into the clinic with the diagnosis

00:19:34.300 | of autism, or perhaps like they receive it into the clinic,

00:19:37.580 | there's still like a 20% probability that they leave the clinic with the genetic diagnosis,

00:19:42.700 | meaning that it will be pointed out to them that this gene is mutated in your child.

00:19:47.660 | And it may be sometimes a mutation that was present in one of the parents and got transmitted,

00:19:53.580 | or maybe it was present in both.

00:19:55.020 | And somehow, you know, the child got two copies that were modified now.

00:19:59.820 | Or many of the genes were actually mutated de novo, meaning that the mutation was not present in either

00:20:06.140 | parents, but something went wrong during development, perhaps early in the sperm cell, in the egg cell,

00:20:12.700 | or perhaps in early stages of development, and a new mutation was acquired.

00:20:16.220 | But that is also, we acquire a lot of mutations, all of us, we have a lot of new mutations, right?

00:20:22.620 | About like 80 new mutations, 30 of them are protein truncating.

00:20:27.180 | So certainly, the challenge very often is to, even when you see a gene that is mutated,

00:20:32.140 | to know whether that gene is truly causing the disease.

00:20:34.540 | So very often, the way we know is that we find many patients that have a similar presentation clinically.

00:20:41.020 | Let's say maybe they'll have syndactyly.

00:20:44.620 | So they're webbing of the finger, and they have autism, and let's say epilepsy.

00:20:49.420 | And they all have a mutation in one single channel, let's say in a calcium channel.

00:20:54.540 | So that would be Timothy syndrome, a genetic form of autism, where the mutation is very clear.

00:20:59.820 | Actually, there's one single letter in the genome that is changed and causes a relatively similar

00:21:05.100 | presentation in all of these patients.

00:21:07.340 | So about 20% of the patients will get a genetic diagnosis.

00:21:10.860 | Now, sadly, that doesn't do that much today, because we don't really have specific therapies

00:21:17.340 | for those forms.

00:21:18.220 | I think the hope is that perhaps we will have individual treatments, whether they're going

00:21:22.140 | to be genetic or otherwise.

00:21:23.900 | So being part of that community is generally useful.

00:21:26.860 | And then the rest of the patients will essentially fit into this larger category of idiopathic,

00:21:33.100 | meaning that we don't really know the precise cause.

00:21:36.860 | I want to talk about Timothy syndrome.

00:21:38.940 | And I also want to talk about genetic approaches for fixing genes, so-called gene therapy.

00:21:44.780 | Before we do that, would you be willing to just speculate on why you think there's this

00:21:51.180 | fairly dramatic increase in the incidence of autism?

00:21:55.340 | People will always say, well, maybe it's better detection, better diagnosis.

00:21:59.660 | So I'd like your thoughts on that.

00:22:01.340 | And if there are increases that can't be explained with that, I just would like your thoughts.

00:22:07.180 | I realize we're not talking formal biostatistics here.

00:22:10.620 | I just, in your experience, you're an MD, you think about autism a lot.

00:22:14.220 | You're working on potential cures for autism and other neurologic conditions.

00:22:20.540 | How do you think about this increased prevalence issue?

00:22:23.100 | Well, certainly the increase is still puzzling, right?

00:22:26.700 | So I think on one hand, there's no doubt that the changes in diagnostic criteria,

00:22:32.780 | which have happened over time.

00:22:34.220 | I mean, we had to just refine what autism really is.

00:22:36.780 | That changed, you know, to some extent, the prevalence.

00:22:41.260 | We've also seen, you know, a diagnostic migration, so to speak.

00:22:45.100 | So some children, for instance, you know, 30 years ago would have been diagnosed with intellectual

00:22:49.740 | disability, and today they fit the criteria for autism.

00:22:54.060 | You know, about a third of individuals with autism also have intellectual disability.

00:22:59.020 | So there is also a great overlap between the conditions.

00:23:01.260 | So there's been a move sometimes between the diagnosis over time.

00:23:06.060 | Of course, there are all kinds of discussions about, you know, availability of services,

00:23:10.380 | and to what extent that is also contributing, right?

00:23:13.900 | But, you know, we don't really, you know, we don't truly understand all the reasons behind

00:23:21.500 | like this increase.

00:23:23.100 | There's no doubt.

00:23:24.300 | We can't explain.

00:23:24.940 | We know that it's highly heritable based on genetic studies.

00:23:27.500 | So we know the heritability is very high, one of the highest for psychiatric disorders that

00:23:32.380 | we know of.

00:23:32.940 | But of course we can, we don't have the genes for every single form.

00:23:38.060 | So it is likely that some of them are very rare, right?

00:23:41.180 | So essentially just think of it as like, you know, they're individually rare form,

00:23:45.500 | but collectively common.

00:23:47.260 | So it will take a while until we sort of like map all of them.

00:23:50.220 | And then of course, there are environmental factors that we do know historically can contribute

00:23:54.940 | to this.

00:23:55.260 | So there are various exposures to environmental factors like in early days,

00:24:01.340 | thalidomide, for instance, was one of them that we know increases the risk for autism.

00:24:07.340 | So of course those are contributing.

00:24:08.540 | But thalidomide was a drug given to pregnant mothers to try and prevent miscarriage, right?

00:24:14.140 | Exactly.

00:24:14.460 | It's no longer prescribed.

00:24:15.340 | It's no longer prescribed.

00:24:16.060 | It's caused major birth defects.

00:24:17.980 | Defects, exactly.

00:24:18.940 | Yeah.

00:24:19.660 | So they're certainly, you know, it's quite complex because first of all,

00:24:24.460 | the definition of the condition is quite difficult, right?

00:24:27.340 | And I think that is in general like the challenge with psychiatric disorders, right?

00:24:31.100 | And perhaps one of the reasons we've made such slow progress in understanding these conditions,

00:24:37.420 | because of course the power of modern medicine is in molecular biology.

00:24:41.420 | You know, we kind of deploy this remarkable force of an understanding.

00:24:47.420 | And in order to do that, you need two things.

00:24:50.460 | You need, first of all, to have a very clear definition of what that disease is generally,

00:24:55.660 | biologically, right?

00:24:56.700 | Think about like myocardial infarction, you know, very clearly defined in terms of like what it actually

00:25:01.500 | means.

00:25:01.660 | You immediately have biomarkers, right?

00:25:02.620 | The patient walks in, you take blood, you can immediately tell, yes, in 20 minutes,

00:25:07.020 | you can tell that they have a myocardial infarction based on a biomarker.

00:25:10.540 | And then the other one, which is certainly very important, which to a large extent is sort of

00:25:14.780 | like, you know, is the source of all the work that we've done is the unbearable inaccessibility

00:25:21.340 | of the human brain, so to speak.

00:25:23.420 | And to a large extent, the human brain is inaccessible for most of its development.

00:25:28.300 | And so if you look actually across branches of medicine, you can see that there is a very

00:25:33.180 | strong correlation between how accessible an organ is and how many cures or therapies we actually have.

00:25:39.580 | Think even just in cancer, right?

00:25:41.740 | Think about in cancers, you know, which used to be, of course, an incurable disease, right?

00:25:47.820 | A century ago.

00:25:49.100 | Think about like leukemias in children.

00:25:52.540 | They were like 90% lethal in the 50s and the 60s.

00:25:57.260 | Today, there are maybe 10% lethal.

00:26:00.140 | And that is because a lot from this patients, right?

00:26:03.740 | It's very easy to collect.

00:26:05.260 | We've been bringing it to the lab, studying it, like what goes wrong,

00:26:08.620 | and then deploying molecular biology to develop therapeutics.

00:26:13.820 | With the brain, sadly, you know, there's no way of doing it.

00:26:18.060 | And so largely to, you know, what we've been trying to do is to like find a way of shortcutting that process.

00:26:24.620 | But I do believe that the major challenges that we're facing in understanding brain disorders, whether

00:26:30.220 | they're neurological or psychiatric, are on one hand, you know, the inaccessibility of the organ of interest, the brain.

00:26:37.500 | And on the other hand, our challenges are very often defining some of these conditions with biological markers because they're much more complex.

00:26:45.340 | The degree to which correlation has been leveraged to try and understand neurologic disease is kind of staggering.

00:26:51.500 | I'll just share a couple and I would love your reflections.

00:26:54.780 | I remember when I was an undergraduate and in graduate school, there was this prominent theory that a mother who contracted influenza, the flu, toward the end of her second trimester had a much higher probability of having a schizophrenic child.

00:27:08.380 | And there was so much said of that and then now we barely hear anything about it at all, although I think schizophrenia is more prominent at the toward the poles where you have harsher winters as opposed to around the equator.

00:27:20.060 | But someone needs to check me those on that because those statistics might have melted away with more careful analysis.

00:27:25.260 | I don't know.

00:27:26.220 | The other thing is that you'll nowadays hear a growing interest in populations for which a given disease is very rare.

00:27:33.820 | So one of the things that's circulating out there now that's related to the vaccine debate.

00:27:39.420 | And by the way, I'm just going to myself go on record.

00:27:42.620 | I don't think there's any solid evidence that vaccines cause autism.

00:27:45.580 | And there's not epidemiologically.

00:27:47.020 | There's not.

00:27:47.660 | There's not.

00:27:48.140 | I mean, there's this open question as to whether or not vaccines of all kinds can increase inflammation

00:27:52.300 | and there might be things downstream of inflammation.

00:27:54.220 | But for the record there right now, there are no published papers that have not been retracted that that support the vaccine autism link.

00:28:02.140 | I think those papers are being reinvestigated under the new administration.

00:28:05.740 | But let's leave that aside for now.

00:28:07.500 | People will say, well, you have groups like Amish populations where the incidence of autism is significantly lower.

00:28:17.900 | Turns out it does exist.

00:28:19.100 | I looked at these data, but it's significantly lower.

00:28:21.420 | And then people will say, well, it's the absence of food dyes.

00:28:24.620 | It's the absence of vaccines, perhaps, et cetera.

00:28:27.820 | But then as a genetic disease, we could say, well, there's also there's a tendency for people in the Amish community to reproduce with other people in the Amish community.

00:28:36.540 | So it's a more restricted genetic pool.

00:28:38.300 | Yeah.

00:28:38.780 | And so that could explain it as well.

00:28:40.620 | And I raise this not to create any additional arguments.

00:28:44.620 | There are enough out there between people.

00:28:46.860 | But just because I think the correlative nature of all this is what kind of raises the opportunity for anything that's observed.

00:28:55.180 | Like a fever, they get better.

00:28:56.700 | Sure.

00:28:57.340 | But as you said, healthy kids without profound autism also talk more when they have a fever.

00:29:02.860 | And so there's been so much made of autism in the various conditions that could create it.

00:29:07.500 | Yeah.

00:29:07.740 | And I think it's been very confusing for the general public, even as a trained scientist.

00:29:11.980 | It's been very confusing for me.

00:29:13.660 | I feel like every six months or so, every year, we have a new pet hypothesis.

00:29:18.220 | Yeah.

00:29:18.700 | And, um, but nothing's really, except for these genetic data, nothing really is rock solid.

00:29:24.300 | Right.

00:29:24.780 | And then of course it's the, the other issue is also that this conditions are disorders of the human brain.

00:29:29.580 | So if you think about it, right, even talking about schizophrenia, right?

00:29:34.220 | Hallucinations, right?

00:29:36.060 | Or, or phenomenon that are very difficult to study.

00:29:38.460 | And of course we don't know this.

00:29:40.380 | We know that schizophrenia is present in almost every population that we know of, even isolated population at 1%, right?

00:29:47.500 | And again, it's a little bit easier because it's done in adults, right?

00:29:51.100 | I think in children is much more difficult.

00:29:52.620 | And in fact, many of the genes that were early on identified for autism were identified in this

00:29:58.300 | populations in the Amish populations.

00:29:59.980 | For instance, there is a very classic example of a gene that is associated with severe epilepsy

00:30:04.780 | and autism that was identified there for the first time is present in other places as well.

00:30:09.100 | So, uh, yeah, I think of course the, the, the complexity of the problem is that you also want to

00:30:16.220 | make sure that you don't just associate something, you also want to reverse it in a way, right?

00:30:19.900 | So you would want to do the other experiment where you change it and then it goes away,

00:30:23.580 | but you can never do that in the human brain.

00:30:25.660 | We can just turn things on and off to see whether they're truly causal.

00:30:29.740 | And then of course, human brain development also takes an incredibly long period of time.

00:30:33.820 | Mm-hmm.

00:30:33.820 | Right.

00:30:34.700 | If anything, it seems that the human nervous system has done everything possible to slow

00:30:39.420 | down that process, right?

00:30:40.860 | I mean, we myelinate all the way to the third decade, right?

00:30:43.820 | Like neurons are born and migrating through the nervous system into early postnatal, uh, years.

00:30:49.340 | Wait, you're telling me that our, our neurons continue to get myelinated, uh, which of course,

00:30:54.940 | for those that don't know is, uh, the building of the achievement that allows electrical signals to be

00:30:59.180 | passed down neurons more, more, um, efficiently, uh, in until we're 30 years old.

00:31:04.620 | Yes.

00:31:04.940 | There's evidence that myelination, especially in the frontal areas of the brain are, are continuing

00:31:09.100 | up to the third decade.

00:31:09.980 | Our, uh, unfortunately now deceased, uh, former colleague, Ben Barris, he used to shout at people

00:31:16.060 | in lab lab meetings.

00:31:17.420 | Yeah.

00:31:17.820 | When they'd say something he didn't like, he'd say, what do you know?

00:31:19.900 | You're not even myelinated yet.

00:31:21.100 | Exactly.

00:31:21.500 | So he was right.

00:31:22.220 | He was absolutely right.

00:31:23.420 | Okay.

00:31:23.580 | So if you're in a disagreement with somebody younger than 30 and you happen to be older than 30,

00:31:27.580 | you can, um, leverage the argument.

00:31:29.260 | What do you know?

00:31:29.740 | You're not even myelinated yet, completely myelinated yet.

00:31:32.220 | Right.

00:31:32.780 | Um, all kidding aside, before we get into the incredible experiments that you're doing and

00:31:38.620 | the direction that you're taking to tackle these really hard diseases, I have to ask two questions.

00:31:43.660 | First, is the incidence of autism also increasing outside of the United States, or is this something

00:31:49.980 | unique to the United States and Northern Europe?

00:31:52.460 | Um, I don't know why we always pair those two or I should just be fair to the United States

00:31:56.780 | and Australia or whatever.

00:31:58.540 | Um, or is there something going on in the United States in particular that autism is increasing

00:32:03.820 | faster here?

00:32:04.780 | Yeah, no, this, the, you know, the, so like the prevalence for autism, you know, has been actually

00:32:09.180 | reported to be higher in other countries, even before this.

00:32:12.220 | Some of the early reports many years ago showed that in Korea, for instance, you know, the, the prevalence

00:32:16.780 | was very high, uh, now that the studies are done, uh, also like in Scandinavian countries,

00:32:23.020 | it shows that it's probably around the same, um, you know, kind of like rate one in 30 to one in 40.

00:32:30.140 | So somewhere between.

00:32:31.020 | Okay.

00:32:31.660 | So it can't be whatever is, uh, attached to whatever United States specific, um, conditions.

00:32:39.660 | It, I mean, uh, yeah, well, because you hear these arguments, oh, you know,

00:32:42.860 | it's the glyphosates in the, in the, uh, the crops in the United States.

00:32:46.620 | And while I don't favor that argument, I do think we need to be cautious about what's in the food

00:32:50.620 | supply, but, um, those same people often will, uh, leverage the argument that, well, in Europe,

00:32:55.900 | they're not using these things.

00:32:56.860 | Well, if the incidence of autism is the same and rising, that sort of does away with that.

00:33:01.420 | Right.

00:33:01.820 | At least the clean logic of that.

00:33:03.100 | And perhaps another argument, which is very important to, you know, bring is that

00:33:06.860 | we find the same mutations, right?

00:33:09.340 | I mean, the same mutations, if we're talking, let's say a mutation, a specific calcium

00:33:12.540 | channel, you know, you'll find it in a patient in Denmark, right?

00:33:17.180 | As well as like one in Africa or in, let's say Australia.

00:33:22.140 | So I think some of these genetic mutations are sort of like the same.

00:33:24.780 | Could we briefly talk about gene therapy and CRISPR just briefly?

00:33:30.140 | Because I think in the context of a discussion about these neurologic diseases for which

00:33:34.860 | currently there aren't perfect cures or even cures in many cases, uh, gene therapy does hold some

00:33:41.340 | promise, um, in simple terms, uh, that I, and everyone else, uh, can understand.

00:33:47.420 | Could you just explain what CRISPR allows physicians potentially to do?

00:33:53.980 | In other words, can genes be fixed in adulthood?

00:33:57.340 | Do they have to be fixed in the embryo?

00:33:59.020 | Um, just give your thoughts generally about, about CRISPR and gene therapy, because I think most people

00:34:03.980 | have heard of it, but I think most people don't have an intuitive sense for, for how, how it works.

00:34:08.860 | So gene therapy is a rather actually broad term, and it covers many ways in which you can correct

00:34:15.500 | generally a gene or a genetic defect that we think it's causal. So on one extreme, for instance, you can

00:34:23.180 | envision a gene is broken, has a mutation. So what you want to do is you want to put it back. So those were some of the early efforts where you would put it in a virus,

00:34:32.620 | you would put it in a virus and deliver it to the patient.

00:34:36.540 | An adult?

00:34:37.100 | In an adult or in a child, depending on like the condition, with the idea is that the gene is not

00:34:42.220 | there or like there's not enough of it. So I'm just going to deliver more. That's one extreme.

00:34:47.420 | Is it injected into the blood or do you have to go into the specific cell type that's lacking the gene?

00:34:51.820 | Many of the studies were done for blood disorders, of course, because it was easier. So you would inject them.

00:34:57.820 | Of course, the other possibility, sometimes you don't want to put the gene, you want to put the protein already made.

00:35:03.900 | And that is the case for many conditions where an enzyme, so protein that, you know, does some interesting

00:35:11.260 | chemical reactions that are essential to a cell is missing. So sometimes you just make that enzyme and then

00:35:16.300 | you deliver that. It's not always working, but in some cases actually works really well.

00:35:21.660 | Now, the other thing that you can do is you can try to correct that defect directly.

00:35:27.180 | That means you need to operate at the DNA level. So somehow you need to get into every single cell

00:35:33.260 | that is affected and correct that. And that's where CRISPR comes into play, where presumably you could,

00:35:41.660 | at one point, deliver, you know, the guides. So the tiny pieces of nucleic acid that tell you where to go

00:35:50.140 | on the DNA and then an enzyme that will do the cutting and then the putting back or various other

00:35:55.100 | versions of this that you would correct. Of course, there are challenges with that.

00:35:58.620 | Yeah. Where do you put it? I mean, so like for sickle cell anemia, I know they've essentially

00:36:02.620 | reversed sickle cell anemia using CRISPR technology. That's in the blood, right?

00:36:07.180 | It's in the blood.

00:36:07.740 | It's of the blood.

00:36:08.540 | Right.

00:36:08.860 | But if, for instance, we know about a genetic defect of, let's say, we'll talk more about this soon,

00:36:14.540 | but a mutated calcium channel that disrupts heart function and brain function,

00:36:17.900 | and you come in with CRISPR, you know what gene is mutated, you have the healthy gene that

00:36:23.660 | potentially you can put back, where do you put it?

00:36:25.260 | Right.

00:36:25.580 | Do you inject it? I mean, injecting into the heart is possible, into the blood supply,

00:36:31.260 | obviously easier, getting it directed to the bone marrow, but to the brain is hard.

00:36:37.100 | Yeah. Well, presumably you could inject into the brain as well, right? There are ways in which you

00:36:41.260 | can inject through either surgery or through an injection in the spinal canal, like intrathically.

00:36:45.900 | So that's certainly one way in which you can do it. It is very challenging though,

00:36:50.620 | because of course the brain has a lot of cell types and, you know, you very often,

00:36:55.100 | the way you deliver this, like through a virus or through other modalities, you know, there's only

00:36:59.340 | so much of that virus that you can actually put inside the nervous system. And the efficiency is not

00:37:05.820 | yet like very high. So another way is to go like one level down. So that gene will produce an RNA that

00:37:13.340 | will produce a protein. So perhaps we don't have to correct the DNA everywhere, but perhaps we can

00:37:18.380 | correct something that happens downstream. And that's sort of like being the strategy that we've

00:37:22.220 | been using primarily, just mostly because at this point, and probably in the future it will be possible,

00:37:27.100 | who knows, like in 10 years or maybe even earlier, we'll be able to deliver very effectively some of the

00:37:33.340 | genetic therapies using CRISPR. Because certainly in, um, non-human primate models, things like, um,

00:37:40.860 | color blindness have been rescued by introducing a gene through a, when we talk about viruses,

00:37:47.500 | people often will think, oh goodness, why would I want to get injected with a virus? But we should

00:37:51.100 | just mention there are things like adenoviruses, which cold viruses are adenoviruses that can be

00:37:56.540 | engineered so that they don't make you sick, but they can carry a cargo, like a gene you want to put into a

00:38:02.700 | nervous system or, or body that lacks that gene. So when we say using viruses to deliver genes,

00:38:07.900 | it's, uh, it's of the benevolent type or at least benevolent motivation. We think that, that those

00:38:13.020 | adenoviruses can live in our body for a long time without causing additional trouble. And they're very

00:38:17.820 | often modified to make sure that they don't cause disease. Of course, another limitation of that is

00:38:22.620 | that if the gene is really large, it simply won't fit in a virus. So for instance, that would be the case

00:38:28.780 | if you think about a calcium channel. Calcium channel is a gigantic gene.

00:38:31.900 | It would be very difficult to fit, uh, inside a virus. And then of course, the other thing is like with

00:38:36.620 | this virus is very often, especially with adenoviruses or AAVs, is that you will have one shot.

00:38:42.300 | Meaning that you have to inject once, uh, and hopefully would work because next time, you know,

00:38:49.100 | uh, you may have an immune reaction, right? You'll have, you'll produce antibodies and so you won't be able to

00:38:54.060 | deliver again. So there, again, there are all kinds of challenges that, uh, you know, people are working really hard to solve.

00:38:59.100 | And I have no doubt that in the next decade, we'll see, you know, therapies or, you know,

00:39:04.380 | perhaps even cures for some of these conditions. Of course. And I think you were bringing this up.

00:39:08.860 | One of the challenges is like when we do this, because especially for disorders of the brain,

00:39:14.620 | neurodevelopmental disorders, so autism and other neurodevelopmental disorders,

00:39:17.820 | disorders, the question is always how early it is too late. You know, how much damage has it done,

00:39:25.580 | has it been done and how much can I actually correct? And that's one of the things that,

00:39:29.420 | you know, we're only now starting to really explore as we're thinking about some of the first clinical

00:39:33.740 | trials in this space.

00:39:35.100 | - This might shock you a bit, but, um, folks in the quote unquote biohacking community,

00:39:40.380 | not me, um, are getting, I know some, they've gotten full of statin gene therapy as a body enhancement

00:39:48.620 | thing. Cause they're leaving the country cause you can't do it in the United States and literally

00:39:52.380 | getting injection of a, of a full of statin gene, uh, therapy, um, to, I guess, to have more muscle to,

00:40:00.940 | you know, improve that. Uh, I wouldn't do it personally. Um, I also, I like working out,

00:40:06.860 | so I don't need a full of statin gene therapy, but it's interesting to note that people are doing this

00:40:11.980 | and I'm raising this as a segue into a discussion about stem cells, um, because people around the

00:40:16.940 | world are getting injected with stem cells in the United States. It's still not allowed by

00:40:22.140 | FDA for most things. Um, but I think gene therapy has started. It's certainly begun. It's, but it's not

00:40:30.860 | the sort of thing that your physician offers up, uh, early. It's still very experimental for most things.

00:40:37.820 | - And then for gene therapies, again, in the context of what you're mentioning is some of this, again,

00:40:42.940 | they're irreversible. So once you put the gene in, you know, and it goes into a cell, let's say through

00:40:48.460 | a lentivirus that will integrate, you can't take it out anymore, right? That would be very difficult.

00:40:53.180 | It will get inactivated over time. But so that's what we have to be extra careful with some of these

00:40:57.820 | therapies and, you know, make sure that we don't do more harm, right? Which I guess it's always what we

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00:43:41.100 | Let's talk about stem cells, organoids and assembloids, and you'll explain what those are.

00:43:46.780 | But let's wade into this through the way it happened chronologically. Most people have heard of stem

00:43:55.900 | cells, cells that could become other things. When I was a postdoc, any laboratory that worked on human

00:44:05.100 | stem cells worked on human embryonic stem cells, literally cells that were collected from aborted

00:44:10.300 | fetuses and given for medical study. There was an incredible discovery, which you'll tell us about,

00:44:17.660 | which basically made that technology obsolete and also allowed scientists to bypass a lot of the

00:44:25.100 | ethical considerations, serious ethical considerations, regardless of where you sit on that debate. I mean,

00:44:30.300 | you're using the tissue from a human embryo to study things. You could say some people will support

00:44:37.340 | that, some people won't, but then a new technology comes along and basically makes that technology

00:44:42.620 | obsolete, allowing you and others to do the work on stem cells and assembloids and so forth without

00:44:47.820 | having to take cells from human embryos, which is spectacular. So could you please tell us about

00:44:52.860 | that discovery of the stem cell technology that really changed the entire game and did away with this

00:45:00.460 | ethical, serious ethical battle? Let's call it what it was. Sure. Let's start first with stem cells and what

00:45:06.540 | they are, because I think it's also important to define them. So stem cells are cells that have two properties.

00:45:14.540 | first of all, they in principle can become other cells. And if they are of the most potent type,

00:45:22.140 | they will be totally potent. So they can make everything. If they're pluripotent, they can make

00:45:26.940 | almost everything. And then of course there are, you know, lower levels of potency for the cells. So we all

00:45:33.020 | carry stem cells in us, right? Not in the brain or fewer in the brain for sure, but you know, in the liver and

00:45:38.540 | in other organs like in the gut, as we renew the gut, you know, every few weeks that is done primarily

00:45:44.300 | through the stem cells, but those are restricted. They can make everything. They can make mostly that

00:45:49.740 | specialized cell type for which they have been so like primed. Now the earliest, earliest of stem cells,

00:45:55.420 | like those pluripotent that are very important, those are present at early stages of development of

00:46:00.140 | the embryo. And of course that happens post-conception. So the challenge has been that you have to remove them

00:46:08.780 | from a fertilized egg. And if conception, if life starts at conception, then of course you're

00:46:14.620 | interfering. So I think a lot of the ethical debates have started because of that. But you know, in early

00:46:19.420 | days, even if you were to do that, you wouldn't be able to keep those cells. It turns out that the cells

00:46:24.860 | are very difficult to maintain. And this brings us actually to the second property of the cells,

00:46:29.820 | which is that in principle, they can be maintained forever. If you provide the right conditions,

00:46:35.580 | they will divide and stay the same forever. Those are the two properties. So, you know, you can keep

00:46:42.140 | them forever. You can freeze them down, put them in a, you know, liquid nitrogen, bring them out anytime,

00:46:47.340 | and they'll start exactly where they left. And then with the right guidance, they can become other cell

00:46:53.180 | cell types. So only around, you know, 1998, that was that when we could actually maintain some of the cells in a dish. So somebody figured out a soup of chemicals

00:47:05.820 | that you can add and this cells will survive because after that point, it was not possible. So that triggered,

00:47:12.380 | of course, the promise of this field that now would be able to take those cells and derive various organs,

00:47:18.860 | right? Perhaps transplant them, replace organs. Of course, that ended up being much more complicated.

00:47:24.140 | And of course, there were all these ethical debates related to the source of those cells and what does

00:47:29.820 | it actually mean to use this embryonic stem cells. And yet we've learned a lot about those cells in early days.

00:47:35.580 | What are the properties of those cells? And then almost 20 years ago, Shinya Yamanaka was a scientist

00:47:43.580 | in Japan at the UCSF, came up with an absolutely brilliant idea. You know, we were always thought

00:47:50.380 | that the development, the development of the human or of any, it's a one-way street. Once you go down

00:47:57.820 | development, you never come back. So once you start making, you know, a stem cell that is more restricted,

00:48:04.140 | and then at the end you make, let's say, a liver cell, you can never go back and become that pluripotent

00:48:09.740 | stem cell again. And that generally is thought to be useful to protect us from like cancer or like

00:48:15.740 | any others where we don't have, you know, parts of our hands like differentiating into something else.

00:48:20.380 | And he thought that maybe you could do that, not in a natural way, in an artificial way. And that,

00:48:27.980 | of course, would be very useful. So what he did is he went and he looked at the genes that are

00:48:33.260 | expressed in pluripotent stem cells at very, very high levels. So very, very high levels. And almost as

00:48:39.100 | gene therapy, because we were talking about gene therapy, he took like the top couple of dozens

00:48:44.060 | of these genes and then started adding them inside skin cells. So he took skin cells, initially from

00:48:50.460 | mice and then from human, and then started adding them one by one, two by two, three by three, four by

00:48:55.420 | four, five by five, six by six, to see whether any of those cells, once they have this combination of genes

00:49:02.060 | that are expressed in pluripotent stem cells, would somehow get confused and think that they're actually a

00:49:07.020 | pluripotent stem cell and then go back in time and actually become a pluripotent stem cells.

00:49:11.980 | And he showed indeed that a combination of four is enough. Of course, you can have six. And that ended

00:49:17.500 | up being what we today call the Yamanaka factor. In a way it was like, it was almost like alchemy,

00:49:24.620 | right? Where you sort of like, you know, transform something into something else, right? You make out of

00:49:29.900 | this metal, you make gold. It was pretty much like that. It was kind of like the essence of alchemy.

00:49:33.980 | Alchemy. And it turns out that that discovery was so profound because suddenly you could take a skin

00:49:40.620 | cell from anybody and put those genetic factors in, turn those cells into pluripotent stem cells

00:49:48.140 | that we'd later on learn. They're almost identical to those embryonic stem cells. And now have those

00:49:53.820 | cells from any of us and use them for various purposes, perhaps for, let's say, making blood cells

00:49:59.020 | in the future, or perhaps to, you know, model something else out of the body. And I was finishing

00:50:05.100 | my clinical training around that time. And I remember even seeing that paper. And of course,

00:50:11.260 | in my naivete at that time, I thought, wow, this is it. This is going to be, you know, the entry point for

00:50:18.540 | studying human neuroscience. I was doing experiments at that time, studying actually the cortex and recording

00:50:24.300 | from animals, electrical activity of those neurons. And always like thought, it's like this disconnect

00:50:30.460 | between what I was seeing in the clinic, which were these patients with severe, profound autism,

00:50:34.300 | and then recordings from the brain and thinking, we're never going to be able to do that. How are we

00:50:39.420 | going to understand this complex disorder of the brain if we cannot even listen to the activity of

00:50:44.780 | those cells alive? And then suddenly, like seeing that discovery, you know, again, naive at that time,

00:50:51.900 | thought, well, that could be perhaps the way in which we could make neurons from any patient. And so very

00:50:59.660 | soon after I came to Stanford, which I guess where we met with sort of like this idea in mind that we

00:51:06.300 | will be able to make neurons from this patients and rebuild maybe some of the cells or some of the circuits

00:51:13.340 | of the brain outside of the body without doing any harm because we're not doing a biopsy of the brain

00:51:17.900 | or anything invasive, just essentially creating a replica of some of those cells outside of the

00:51:22.940 | body, and then finally study them at will in a dish and do all kinds of experiments, whether you remove

00:51:27.660 | things and add things and perhaps that one day even develop therapeutics. And here we are 16 years later,

00:51:34.140 | since that process really started, took a long time. But now for the first time, we've gotten such a good

00:51:40.460 | understanding of some of these conditions and one of them in particular that actually a therapeutic is

00:51:46.540 | inside and we're preparing for the first clinical trial that is really arising exclusively through

00:51:52.140 | studies done with this human stem cell models without actually using any animal models, just essentially

00:51:57.980 | creating, recreating cells and circuits outside of the brain of those patients.

00:52:02.620 | It's amazing because it allows you to study human cells, which has immense benefit. They're essentially

00:52:11.740 | limitless in number because all you need is one fibroblast, one skin cell or some cell that you can

00:52:18.780 | provide these Yamanaka factors to and essentially grow other cells. And we'll talk about what those cells that you

00:52:28.380 | create are capable of becoming not just cells, but circuits in a few moments.

00:52:34.460 | But I know it's going to be in the back of people's minds and certainly in the back of my mind.

00:52:38.860 | This idea that when one has a baby that you should keep the umbilical cord because the umbilical cord

00:52:46.140 | contains stem cells. Usually I think the umbilical cord is discarded. Maybe some people keep it. I don't know.

00:52:54.140 | What is the current thinking on stem cells that reside in the umbilical cord? People pay a lot of money to

00:52:59.740 | freeze those and most people don't have a minus 80 freezer around. So they pay to do that. What is

00:53:06.380 | the potential for umbilical stem cells in the future? Is it something that parents, I don't want to say

00:53:13.900 | should invest in, but if they have the disposable income that they would be wise to do that?

00:53:18.700 | So those cells that are collected from the umbilical cord are stem cells, but they're

00:53:24.460 | already quite restricted in what they can make. So their applications are also restricted mostly to

00:53:31.820 | blood disorders. So I think it's, it's important to keep in mind that they're not so like a universal

00:53:37.420 | uh, you know, solution to anything that would ever involve pluripotent stem cells in the future or stem

00:53:44.460 | cell therapies in the future. So again, I think it's important to know that while they have certain

00:53:49.100 | applications and there have been quite clear cases where the availability of those cells were useful in a

00:53:54.940 | blood disorder in that child later on. Um, they're certainly not, you know, they have this universal uses as

00:54:02.460 | maybe sometimes they're being advertised.

00:54:04.460 | when we hear about people typically leaving the U.S. uh, to get quote unquote stem cell injections,

00:54:11.180 | where are those stem cells coming from? Are they coming from those patients? And I should mention

00:54:14.940 | that there was a clinic down in Florida, um, that was offering stem cell injections into the eye for

00:54:21.340 | people with macular degeneration. And that clinic was shut down and all stem cell injections in the United

00:54:28.300 | States to my knowledge all were shut down because those patients, uh, not only did it fail to rescue

00:54:35.180 | their vision, it actually made them go blind very quickly. Uh, so the FDA shut down, uh, commercial

00:54:40.620 | stem cell injections. I think there's still places where they do a kind of a workaround. Yeah. Um, and

00:54:47.580 | it's worth mentioning that PRP, platelet rich plasma is FDA approved. It does not contain many, if any, stem

00:54:54.300 | cells, despite what you might read. Um, but what, what are your thoughts on like when people go down

00:54:59.340 | to Columbia, it seems like they go down to Columbia, uh, or elsewhere to get, or Mexico to get stem cell

00:55:04.700 | injections, assuming the conditions are, are clean. Um, and I, I say that because I know of at least one

00:55:10.940 | patient who was paralyzed from an injection of stem cells into their, uh, spinal disc, paralyzed, almost died.

00:55:18.540 | Yeah. Fortunately is doing better now. And it was because it went septic the way they got infected.

00:55:23.340 | Well, that's one of the problems. Very often we don't even know what is being injected.

00:55:27.260 | I think that is like a very important aspect. We don't know what is, sometimes are the cells from

00:55:32.540 | the patient that are being collected. Sometimes some of this umbilical cells, sometimes we don't

00:55:37.100 | even know what cells are being injected. Like it could be cells from somebody else.

00:55:40.460 | Yeah. They're incredibly risky procedures. Of course, they've never really been observed. There've been

00:55:44.940 | very few of any clinical trials trying to really address it in a very systematic way. And very often,

00:55:50.940 | that's also the case, you know, that's also because they're not really justified.

00:55:54.700 | So in the context of autism, this is very often like done, uh, you know, and it's not just in South

00:56:00.940 | America. Sometimes there are places in Europe where you can get an injection of some stem cells for

00:56:05.580 | autism. Wait, parents are taking their kids to these clinics and getting them injected with stem cells that

00:56:10.060 | come from some other patient. Some, some, some cells that are collected from the patient, you know,

00:56:14.380 | it depends a little bit on where it's done and how it's actually done. But again, even from a biological

00:56:19.740 | point of view, you know, what are those stem cells presumably doing? Let's say in autism, you know,

00:56:26.060 | we don't think that there is a cell type that is missing in the brain. So it's not like those cells can

00:56:29.900 | go. And I think, as I was mentioning before, most of the cells already restricted in their potential.

00:56:34.940 | They can no longer make any cell types. So, you know, the idea that you take this pluripotent stem cells, uh,

00:56:40.540 | and you just inject them, let's say in the knee and it will like miraculously grow, you know, cartilage.

00:56:46.620 | It's, uh, very often not really the case because those cells are not even capable of making cartilage.

00:56:51.900 | So I think there's, you know, very often, um, you know, a lack of understanding of what these therapies

00:56:58.140 | really are. And then of course, there is sadly a lack of understanding what, of what is actually being

00:57:03.740 | injected. So, uh, you know, for autism, this is unfortunately happening much more often than you

00:57:09.980 | would think. So I very often get like parents, uh, or families that are asking me desperately, you know,

00:57:16.780 | with like exhausted old resource. We don't know what else to do. We've tried behavioral therapy. We've tried

00:57:21.500 | this therapies, nothing works. And everybody's recommended that we should just go now to South

00:57:27.660 | America and do this injection. Should we do it or not? Right. And of course, my answer is always like,

00:57:32.060 | no, because again, there's no reason that that would work. Some parents come back and of course,

00:57:37.740 | they report an improvement and, uh, which is generally, uh, temporary, uh, to the extent that we know,

00:57:45.180 | of course, it's never really been studied in a very systematic way. Partly, it's, of course,

00:57:49.580 | there's a very strong placebo effect, uh, which you can, you know, especially in parents, like by proxy,

00:57:55.420 | when you have a child who's like very sick, those placebo effects are very, very strong.

00:58:00.700 | These parents really want those kids to improve. And so they will see things that are improving. Plus,

00:58:06.220 | those are still developing kids. So week by week, they may acquire new milestones. And then the other

00:58:13.100 | thing, uh, which of course could be part of this is that there is an inflammatory effect very often.

00:58:17.980 | And so that's almost like the fever in a way, right? Like would increase perhaps some of the

00:58:22.780 | cytokines will create a fever. Perhaps that is associated. We don't really know, but certainly

00:58:28.060 | there are dangers, uh, associated with, uh, you know, with like procedures like this that are,

00:58:33.100 | you know, lack the rationale, first of all. And then of course, then they lack any regulatory,

00:58:38.700 | uh, um, you know, uh, framework. Yeah. I mean, I think the, the concern is very real for stem cell

00:58:45.980 | injections into all tissues, but when it comes to eyes or brain, and of course, eyes are brain.

00:58:51.500 | Yes. Uh, that's where I just, you know, deep breath and hold it and like wide eye like, oh my goodness,

00:58:58.220 | no, because we don't get new neurons. Uh, you lose neurons, they're gone. I mean, we get a few

00:59:03.820 | in the olfactory bulb, in the dentate gyrus of the hippocampus, a few, but you know, once they're gone,

00:59:09.260 | that's it. Right. And, um, injecting something into the brain, the, the probability of tumor

00:59:14.380 | growth is, is incredibly high. Absolutely. And especially when it is in the brain where there's

00:59:19.340 | not enough space, right? So we know that anything that grows in the cranial cavity will actually push

00:59:25.900 | down, right? Vital centers. So there are certainly risks associated with that. So let's talk about the

00:59:31.900 | other approach, uh, which is the one that you are, uh, you've been embarking on. I'll never forget when we

00:59:37.820 | were postdocs. Folks, we were postdocs in the same room. It was D222. Yes. Uh, we had a lot of pride in

00:59:43.020 | that room. We had benches, uh, on opposite sides of the room and we sort of, uh, took over that room

00:59:49.100 | as an empty room. This is, you probably couldn't do this anymore, but it was like, there's an empty room.

00:59:52.380 | Let's bring some microscopes in there. We just started doing experiments there. And I'll never forget,

00:59:55.740 | um, when you started building organoids, you started building nervous systems in a dish and how excited you

01:00:06.300 | were. And, uh, and it's been remarkable to see your, your arc, uh, to, from that. Um, and it's not lost

01:00:14.300 | on me that you were working extremely hard then and continue to, to become what really one of the

01:00:18.300 | luminaries of this field. Um, tell us what organoids are, tell us why they're useful and

01:00:26.380 | what they're telling us already about how the brain develops and their therapeutic potential.

01:00:32.300 | Yeah. So let's start from the beginning. So around like, you know, 15, 16 years ago,

01:00:39.260 | we were able for the first time to get some of the cells that are now known as induced pluripotent

01:00:45.580 | stem cells. These are the Yamanaka. Yes. Or IPS cells. IPS. So induced because they've been induced to become

01:00:51.340 | pluripotent in an artificial way. But again, they stay like that. So you can share them with anybody

01:00:55.980 | else like afterwards. So we got some of those first cells in those early days. And now the question was,

01:01:02.220 | how do we make neurons? And what you do is you really kind of like leverage the, everything that

01:01:08.540 | is known in developmental biology. So we already know that there are certain molecules that are very

01:01:13.100 | important for making neurons. So all you do is you put those cells in a dish, right? In a plastic dish,

01:01:18.780 | in a Petri dish. And then you start almost like when you cook, you start adding various molecules on

01:01:24.620 | top and you see what happens. And we knew that it's actually quite easy to make neurons. That was already

01:01:31.020 | known. There've been a lot of experiments done the decade before that showed that even if you just

01:01:35.420 | remove some of the factors that maintain those cells pluripotent, those pluripotent stem cells will

01:01:41.260 | start out to differentiate and they like to become neural cells. By default. Almost by default. So it's

01:01:47.340 | actually not that difficult to make neurons. So in those early days, you know, you'll take those cells,

01:01:52.860 | play them nicely, those pluripotent stem cells in a dish, and then remove some of these factors. And then

01:01:57.580 | within a few days, you will see that they'll change shape. And within a few weeks, some of them will really

01:02:02.060 | look like neurons. And when you look at them, you can even sort of like look at proteins that only neurons

01:02:09.180 | will have, you can actually get an electrode inside a cell and listen to the electrical activity. So it

01:02:14.220 | was very exciting, as maybe you remember in those days. I mean, you know, this bursting curiosity is

01:02:20.700 | always sort of like, you know, the ATP of the life, the, you know, the life in the lab, so to speak.

01:02:26.060 | It is right. I mean, it's just like, I like want to wake up, right, and want to go see what happened to

01:02:31.020 | those cells. And it was clear in those days that, you know, we would be able to make those cells. But

01:02:37.580 | would we actually see any abnormalities in those cells? I think it was like the question, you know,

01:02:42.860 | how would you know if you derive cells from a patient with autism? How would you know that you found

01:02:48.380 | anything abnormal? I think that was like a question, you know, we didn't even know what would be abnormal

01:02:53.900 | in the brain. And so that's when we decided actually to focus on something that would be relatively

01:03:00.300 | predictable. And that was this mutation in a calcium channel, which was discovered just a few years before

01:03:05.660 | in very few patients that had essentially one single letter in their entire genome changed

01:03:12.140 | in a gene that makes a protein known as a calcium channel sits in excitable cells, meaning cardiac cells

01:03:19.900 | and brain cells. And every time a cell receives electrical input, this protein opens up and lets

01:03:27.500 | calcium go inside the cell. And that's very important because it couples electrical activity

01:03:32.460 | of the network with chemical activity inside the cells. And what we knew about that mutation at that

01:03:38.540 | point that that's pretty much all we knew in those early days is that it probably allows the channel

01:03:44.540 | to stay open slightly longer, just a little bit longer. So more calcium would go inside the cells.

01:03:49.500 | Of course, there will be no way to know because you can't get a neuron or a cardiac cell from those

01:03:54.380 | patients to actually test it. So what we did is essentially we made, we recruited some of these patients,

01:04:00.380 | we flew them to Stanford. Then we got a tiny skin biopsy, made this IPS cells. This takes months.

01:04:07.420 | This takes already like four or five months. And then we took those cells in a dish, started to

01:04:12.380 | deriving neurons. And after about five, six, seven weeks, then we put them under a microscope and we

01:04:18.700 | started looking at the calcium. You can measure calcium inside cells through a microscope and just

01:04:22.860 | literally look at it. And I'll never forget that day, you know, when we did that experiment, was looking

01:04:29.340 | down the microscope and we essentially stimulated the neurons. And you could just see how control cells

01:04:35.260 | will go . Calcium goes inside the cells and then it goes out. And then in patients that

01:04:40.220 | had Timothy syndrome, so in Timothy syndrome derived neurons, you could see how the calcium will go

01:04:44.620 | and then it will stay longer. It takes longer to go out. So it's like the first defect that we saw

01:04:52.220 | in patient derived neurons that were actually not coming from a biopsy. They were not coming. So that was

01:04:57.820 | incredibly exciting as you can imagine. But it was still relatively simplistic, just a few neurons at

01:05:03.580 | the bottom of a dish. And of course, for me, what was particularly frustrating was that we couldn't go

01:05:09.740 | very far in development. So think about the cerebral cortex, the outer layer of the brain that presumably

01:05:16.460 | makes us human, right? It has multiple layers, a large diversity of neurons. You know, it takes 27 weeks

01:05:22.860 | to make all those cells in the cortex, 27 weeks to make all those neurons. And we're not even talking

01:05:28.860 | about glial cells as supporting cells that are coming much later for several years afterwards.

01:05:33.420 | But just making those cells takes about 27 weeks. And it turns out something that we discovered in

01:05:39.900 | a three experiments done in a dish is that the timing of the development of those cells, it's actually

01:05:47.100 | recapitulated in a dish as well. So if you keep the cells in a dish, they'll actually essentially develop

01:05:54.460 | at the same pace. They're not like much faster. And it's very difficult to keep neurons in a dish for 27

01:06:01.100 | weeks to get all the neurons. Essentially, they peel off, you know, every time you start to move them to

01:06:05.980 | another plate and at one point they just die. And so then we thought, how about like never letting them

01:06:11.900 | to sit down on a surface? How about just essentially aggregating them as balls of cells and then letting

01:06:18.060 | those float? And in those early days, there was this amazing scientist from Japan, Yoshiki Sasai, who started

01:06:25.740 | doing really beautiful experiments where he was already moving some of these studies that he was doing of

01:06:32.780 | development in 3D cultures where he showed you can make an optic cup, a part of the eye. And so it was

01:06:38.620 | clear, it was in the air, this revolution of actually moving cells from 2D flat cultures to 3D self-organizing.

01:06:47.340 | And that actually unleashed amazing new properties of the cells. So essentially, all we did in those days is I

01:06:54.700 | ordered from Germany this plate that were counter-intuitively coated so the cells never stick, right? I mean, every time we

01:07:01.980 | keep cells in a dish, you want them to stick, that's the major problem. So they were actually coated so

01:07:05.980 | the cells will never stick. And then there were like this balls of cells, they were floating there.

01:07:10.780 | And of course, I remember talking in the lab and everybody was like, oh, they're not going to survive.

01:07:14.860 | It's going to be a couple of weeks and they're going to... And then a week passed and two weeks passed and

01:07:19.260 | then they kept growing and growing. And of course, the enthusiasm of every day to see, are they still alive?

01:07:24.940 | All right. And then we discovered that we can keep them for months. And this three-dimensional cultures

01:07:30.540 | are now known as organoids, which is perhaps not the most fortunate name because it suggests that it's

01:07:37.660 | organ-like. And of course, they're not an entire organ. So they're not a representation of the entire brain.

01:07:43.820 | But that's sort of like the term that we refer these days to anything that is so like three-dimensional

01:07:48.780 | and organizing in some way. And so we started keeping these cultures. And then at one point,

01:07:53.420 | actually, we discovered that we can pretty much keep them indefinitely. My lab maintained the longest

01:07:58.540 | cultures that have ever been reported, like literally going for years, for two, three years in a dish.

01:08:04.300 | And at one point in those early days, when I was running out of funds in the lab and I came one day in lab meeting,

01:08:10.780 | really, you know, determined for us to actually like cut costs. So I've told everybody, go into your incubators

01:08:19.580 | because we're spending so much money in feeding the cells and everybody throws out 20% of your cultures.

01:08:24.700 | And then people started saying, so should I throw the ones that are like 500 days old? And somebody was like,

01:08:30.060 | the ones that are 800 days old? And I said, what? You guys are keeping them for such a long?

01:08:33.180 | Yeah, they're just keep growing there in the incubator. So then we actually did the first study.

01:08:37.180 | And then we had a series of three studies done over the years of like trying to ask,

01:08:41.100 | how far do they go in development? So if you have a clump of human neurons that you've made from

01:08:46.140 | pluripotent stem cells and you keep feeding them in a dish, how far do they go in development? Do they

01:08:51.100 | move much faster? Do they move much slower? Are they stuck at one point in development? And it turns out

01:08:58.380 | that they actually keep track of development beautifully to such an extent that for instance,

01:09:04.300 | we discover when they reach nine months of keeping them in a dish. So about the time of birth,

01:09:09.340 | they literally switch to a postnatal signature really on their own.

01:09:14.220 | In a dish. In a dish. So, you know, there's this classic example in developmental neurobiology. There's

01:09:21.020 | this protein that usually changes around the time of birth. It's an NMDA receptor. So maybe some people

01:09:29.100 | know about NMDA receptors binding glutamate. They're very important, but they change a lot during development.

01:09:34.780 | They're made out of different units and the units change. And it was very well known that during

01:09:40.700 | early development, so prenatal, before birth, you primarily have 2B subunits. And then after birth,

01:09:47.100 | they're primarily 2A. So if you look in brain development, you just see how essentially 2B goes

01:09:52.780 | up and then it goes down and 2A goes up. And when you look, they meet around birth.

01:09:58.380 | So very often people thought that it's birth itself that triggers that switch. That canonical,

01:10:03.740 | it's called a canonical switch because we all thought that it was like so classic. And then you

01:10:08.780 | take an organoid that you maintain in the dish for 600 days. And of course, we're not inducing birth.

01:10:15.980 | We're not changing media. We're not doing anything special. And no hormones from mom. No hormones

01:10:19.740 | changes. Like, you know, we keep exactly the same media, which is certainly a very simplistic,

01:10:23.660 | uh, uh, you know, kind of like soup of chemicals, but we don't change it. And then you just look at

01:10:28.860 | this two subunits and you see how like 2B goes down and 2A goes up and they pretty much meet that

01:10:35.260 | nine months of keeping them in a dish. It's amazing. So that tells us that there's some sort of intrinsic

01:10:41.260 | clock. Once you start a development, the cells measure really, really well the time of development.

01:10:47.020 | That does not mean that all aspects of development are going to now be recapitulated in a dish,

01:10:51.740 | but it tells us that there is this incredible ability of cells, especially in the nervous

01:10:55.900 | system, because of course those cells will keep for the rest of our lives.

01:10:58.780 | We're not never going to renew neurons. It's going to be different for liver cells or gut cell,

01:11:03.340 | but for neurons, probably in particular, they'll need to keep track of time really, really well.

01:11:07.980 | So that was like the first discovery that we saw like made, which is still stunning today. We still

01:11:14.140 | don't know the mechanism. We're still working really hard on figuring out exactly how the cells are

01:11:18.220 | keeping track of time. Because as you can imagine, if we understand what that molecular machinery is,

01:11:24.220 | we used to call it the clock. We now call it a timer. We think it's more of a timer than an actual clock.

01:11:28.940 | But understanding what the molecular biology of that is will allow us actually to play with that clock.

01:11:34.620 | So if you want to make neurons that are, you know, 70 years old neuron from a patient with Parkinson,

01:11:41.900 | you know, I don't have to wait 70 years in a dish. Could I make it in like a few weeks?

01:11:45.820 | Or perhaps could I take an aging neuron and somehow, you know, rejuvenate it by playing with that with

01:11:52.940 | that timer. But just to make it clear, we still don't know that we have some clues about like what it

01:11:57.340 | may be, but I think it's still early days. And I think that was like one of the first things that this

01:12:02.060 | cultures allowed us to do. Just watch development, human brain development outside of the human body

01:12:11.260 | in a dish and actually witness that some fundamental aspects of brain development are actually

01:12:17.500 | recapitulated even outside of the uterus and of course of the brain. So that was like the first.

01:12:24.620 | And then of course, I guess I'm a developmental neurobiologist by training and, you know,

01:12:29.820 | I've done a lot of circuit work in early days. Of course, an obsession of mine was that especially

01:12:35.100 | for conditions as complex as autism and schizophrenia, we need to recapitulate some of the circuit

01:12:42.220 | properties of the brain, right? So we now know that, you know, probably both for schizophrenia and for

01:12:47.420 | autism, it is very unlikely based on the evidence that we have so far that there are cells really missing

01:12:52.620 | from the brain. You know, we thought for a while that maybe some cells are missing or maybe other

01:12:56.220 | cells are in, you know, in excess. But now the studies that have been done, especially with single cell

01:13:00.700 | profiling of brains of patients that have already died, showed us that the composition of the brain,

01:13:05.660 | of the cortex in particular, it's very, very similar. So it's unlikely that the cells are missing or like,

01:13:11.340 | but likely the way they're connected with each other is that makes a difference. And of course,

01:13:16.860 | in the beginning, we were just making this clump of cells. They're all for the cortex,

01:13:20.220 | but they're like not connected to anything else. So then came the idea of assembloids.

01:13:26.460 | Because most of the cells in the brain connect with cells across the nervous system. And in fact,

01:13:32.860 | even more interestingly, cells do not reside in the place in which they're born in the nervous system.

01:13:38.540 | We have the largest cell diversity of any other organ, almost 2000 cell types. By the end of the first

01:13:44.860 | trimester, there are about 600 cell types in the human brain. You know, think about the liver, right?

01:13:50.220 | Maybe a couple of dozens. The brain has to make, you know, hundreds of times more. So how do you do that?

01:13:56.540 | The only way is to actually make the cell types in different parts of the brain, provide local cues

01:14:02.300 | there. And then once the cells have been specified, let them move and find their final position. So the first

01:14:08.620 | assembloid that we've actually made were of a very stereotypical canonical movement of cells in the

01:14:15.740 | nervous system, which has to do again with the cortex. So the cortex, again, the outer layer of

01:14:20.540 | the brain has both excitatory and inhibitory neurons. It turns out that most inhibitory neurons are not born

01:14:26.460 | in the cortex, but they're born deep in the brain. So essentially, all we did is we made two brain regions,

01:14:33.180 | the ones that has excitatory neurons and the one that has inhibitory neurons. And the plan was to put them

01:14:38.540 | together, hoping that at one point, you know, the cells will like sort of like know what to do. And in fact, that was

01:14:44.060 | like one of the first projects in my lab, kind of like planning that. And I remember, gave to one of the students like

01:14:49.820 | this very difficult task of figuring out how we're going to fuse these two cultures. And they're about three millimeters in size.

01:14:55.660 | So you can see them by eye. And I thought it was going to be very difficult to put them together.

01:14:59.180 | So the student worked for months trying to figure out like biological glues, you know, kind of like

01:15:04.780 | using various electrodes and impaling them and everything else until somebody else came one day and said,

01:15:10.700 | like, it's very simple. You just put them at the bottom of a tiny eppendorf tube, which is the

01:15:17.100 | tiniest like of tubes that you get. You put them there overnight. And next day, they're completely fused.

01:15:22.300 | But they're not just fused. Because now if you look inside, within a few days,

01:15:25.820 | the cells that are supposed to move, start to actually point out towards the cortex. They

01:15:30.700 | literally smell the chemicals from the cortex. And they start to move in this very stereotypical way

01:15:37.420 | towards the cortex. And so that was the first assembloid made around 2015. And I still remember,

01:15:44.620 | it was Ben, actually, Ben was so excited. Ben Barris was so excited about like seeing the cells. He

01:15:50.460 | wanted to look at these movies every day. And then he said, I still have this email from him,

01:15:56.380 | where he was very preoccupied that he kept saying like, this new preparation is not an organite.

01:16:01.820 | It's not a steroid. It's something else. You have to find another name.

01:16:05.580 | He loved naming things. He loved naming things. Yeah. And he understood the importance of naming

01:16:09.500 | things, not just for like career reasons, although he understood a lot about how to build a career.

01:16:14.300 | Perhaps. But because naming like Yamanaka factors made sense to name it after Yamanaka. He got a Nobel

01:16:23.180 | and is immortalized that way, like stem cells immortalized. Yes. But I think the naming is

01:16:29.660 | essential because otherwise things can get lost in the technical details. Yes. So who came up with

01:16:36.460 | the name assembloid? So he kept insisting that I should find the name. So I made this long list.

01:16:41.580 | I still have like the, in my notebook, like I had a long list of about 20 and I would like keep sending

01:16:47.260 | Ben one. And you know, like Ben was always awake, like 24 hours. Yeah. He didn't sleep much.

01:16:51.420 | He never slept. So I remember after sending many emails going back and forth and he was just like,

01:16:56.460 | no, bad name, bad name. I don't like it. And then at one point I thought, well,

01:17:00.860 | OID because it's life and then assemble because we're assembled the circuits. So I thought assembloid.

01:17:06.460 | And I sent this and it says, perfect. I love it. So you named assembloids.

01:17:10.060 | I named assembloids and Ben sort of like blessed it, like one night at like 3:00 AM.

01:17:15.580 | And so that was the first assembloid. And the first assembloid was for cells migrating.

01:17:21.740 | But then the question was, cells have to find each other and form circuits.

01:17:26.140 | And so within a couple of years, we started making assembloids that will have exons. So the long

01:17:31.580 | projections of neurons finding other partners. And, uh, you know, how forgot who said this must have been

01:17:39.020 | Rodolfo Linas or, you know, who said that the brain is sort of, uh, you know, the next evolutionary

01:17:46.380 | step towards movement, you know, so like the nervous system has been this theories that has evolved as

01:17:53.100 | a way of like moving around. That was Sherrington. Sherrington said, uh, the final common path is

01:17:57.980 | movement. He was a physiologist. He was kind of vague in a statement, but I think it was Sherrington.

01:18:02.540 | And I don't doubt that Rodolfo said something about it too. I'm not going to try and take anything

01:18:06.540 | away from Rodolfo. Anyone that knows a Rodolfo, Luna says he's not somebody you want to piss off.

01:18:10.540 | Well, we should check it. Like who actually said it, give him credit. I like Rodolfo.

01:18:14.220 | But, but for us that became like the next objective, like, can we actually build a circuit

01:18:18.620 | that will have a very clear output? So we would know that we've actually built that circuit.

01:18:23.420 | So what we did is essentially, we thought about like the simplest circuit for movement,

01:18:27.820 | which is like the corticospinal tract, right? So that means that a neuron in deep layers of the cortex

01:18:34.620 | sends a long axons all the way to the spinal cord, finds a motor neuron, makes a connection,

01:18:40.540 | then the motor neuron leaves the spinal cord, goes to the muscle. And essentially you only have

01:18:45.820 | these two neurons, right? That are connecting with each other, with the muscle, two connections,

01:18:49.980 | one between the two of them and one with the muscle. So the simplest of circuits that you can have.

01:18:54.540 | Now lets me move my big toe. Right. Exactly.

01:18:57.260 | It's pretty, pretty long distance. It's a very simple. And of course, like in other species,

01:19:00.780 | a little bit more complicated. It turns out that in mice, there's an additional neuron there.

01:19:04.460 | So there are some changes that, you know, happened over evolution, but for us and in primates,

01:19:09.580 | it's, it's as, it's as simple as this. So what we did was we essentially made an organoid that

01:19:15.500 | resembles the cortex and has some of those neurons. And then we made an organoid that resembles the

01:19:21.420 | spinal cord and has some motor neurons in it. And then we made a ball of human muscle that you can

01:19:27.180 | make from a biopsy. You can literally biopsy a muscle, you get the myoblast, you grow them and you get a

01:19:32.620 | nice ball of muscle. And then of course the challenge was that, you know, the reality is

01:19:38.540 | that we don't know how those cells find each other. Like in development, we know some of the molecular

01:19:43.260 | cues that they use, but it's, we're far from having a comprehensive understanding of how they find each

01:19:49.180 | other. And I remember we were sitting down in the lab and kind of like thinking, I resisted actually

01:19:54.140 | doing this as the first assembloid in the lab for a while, because the probability was like against us.

01:19:59.740 | Like those cells in the cortical organoid that are less than 5%, the motor neurons are less than 10%.

01:20:04.700 | So the probability that they find each other perfectly and in enough numbers to trigger muscle

01:20:08.860 | contraction was close to zero. And yet you do it, you put the three parts together, you let them assemble.

01:20:15.660 | And within a few weeks, you can actually now stimulate the cortex with whatever you want to

01:20:21.660 | use, with an electrode, with light, and then the muscle starts to contract. And in fact, the more you

01:20:27.580 | do it, the more reliable the process is. And then of course we went on to like reverse engineering it and

01:20:33.180 | figure out that indeed the cells have connected in that precise way. So I think what we started actually

01:20:38.940 | to realize was that of course a lot of stem cell biology was, you know, I think a lot of biology

01:20:44.860 | was based on chemical and physical factors that we were leveraging, but we've never truly leveraged

01:20:50.620 | this kind of like next level of, um, law or power in biology, which is self-organization.

01:20:59.900 | The ability of a biological system will build it itself. If you think about it,

01:21:03.660 | the human brain builds itself, right? There's, of course there are instructions, but there's no blueprint.

01:21:08.780 | There's no plan that the brain constantly looks to make sure that it actually made all the connections

01:21:13.260 | properly, right? Instructions are sort of revealed at every step for kind of like the next step. Uh, and

01:21:18.940 | it mostly comes from the cells, uh, finding each other. So I think what we also started to learn from this

01:21:24.700 | was that all we need to do is make the parts. And if we make the parts right, then the parts will come

01:21:31.740 | with the instructions and then the circuits will assemble on their own. And so that has been really

01:21:36.860 | kind of like the, the beginning of it. And of course it became progressively more difficult to build circuits.

01:21:41.580 | And so of course, if you put two, you may think, oh, let's make three. And if you make three, can you make four?

01:21:47.580 | So actually we just published a few months ago, the first four part assembloid, uh, that actually now

01:21:53.180 | reconstitutes the pathway that processes sensory information in the nervous system. So you think

01:21:59.420 | about the cortex, you know, sends out, uh, to control movement and has an output, but it receives

01:22:05.580 | information from the outside constantly. And that happens through neurons that sit close to the spinal

01:22:10.540 | cord, have projections in the skin where they sense, uh, tactile vibrations or pain stimuli, send that

01:22:18.300 | information to the spinal cord. From the spinal cord, they cross, they go up to the thalamus in the middle

01:22:23.580 | of the brain. And from the thalamus, they go to the cortex. So this is a four part pathway. So it took us

01:22:28.940 | years, first of all, to make the parts, um, and then to put them together. And then again, the beautiful

01:22:35.180 | thing about it is that while we still don't know all the rules of assembly, you can make this four part,

01:22:40.460 | we call it a sensory assembloid or a somatosensory assembloid, because it turns out that the sensory

01:22:45.820 | neurons that we can make are mostly sensory neurons that sense pain stimuli. And so, uh, you can actually

01:22:51.740 | put the four parts together. So the sensory, the spinal cord, the thalamus and the cortex, and you have to

01:22:56.620 | put them in that order. If you change the order, the cells will not find each other. So you just

01:23:01.420 | have to create the minimal conditions for them, making the right cell types, putting them in the

01:23:05.020 | right order, and then they'll find each other. And within a few weeks, so it takes, you know, hundreds

01:23:10.140 | of days to build a circuit like this. But the beauty of it is that suddenly you look at it and you just

01:23:15.180 | see spontaneous activity that arises in the entire pathway, just starts to flicker all in sync.

01:23:21.500 | Can you use this assembloid to study the effects of different pain medications?

01:23:26.620 | Yes. So that is certainly one potential. The other thing that you can do in the first application

01:23:31.820 | that we've had was for genetic forms of pain conditions. So we very often think that genetic

01:23:37.580 | conditions where you have a very clear cause, or so like entry points, like Rosetta stones for

01:23:42.460 | understanding anything. So there are these interesting mutations in a sodium channel. So another channel,

01:23:48.140 | but the sodium channel turns out that if the channel is overactive because of a mutation,

01:23:53.100 | you'll have excessive pain. So this patients are highly sensitive, but then if the channel is

01:23:58.860 | essentially unable to function, then this pain that these patients have loss of pain. And that's equally

01:24:04.700 | bad. Many of these patients actually will die because they can't sense pain at all.

01:24:08.060 | Yeah. I think people don't realize that in mutations where people can't sense pain,

01:24:13.020 | people fail to make the postural adjustments. Exactly. That, um, allow you to stay alive

01:24:17.980 | and or to, because you, uh, they, unfortunately they can be resting a little bit too much on their

01:24:24.140 | right leg. We, we normally think, okay, no big deal, but you're constantly making these postural

01:24:28.140 | adjustments. If you don't do that, you actually, uh, can damage the legs that you're, you know,

01:24:33.580 | you're pushing down too hard on. It seems like a trivial amount of weight, right? It's your own body

01:24:37.340 | weight. Right. But we fail to recognize just how often we're redistributing our, uh, our position.

01:24:43.260 | No, no, no. And it's absolutely true. Like feedback in general is very important, including through like

01:24:47.660 | this, uh, painful stimuli through all stimuli in general. And it turns out that if you now make

01:24:53.740 | essentially a four part assembloid that carries the mutation that causes excessive pain. Now the sensor

01:24:59.900 | neurons are excessively active. So they keep bursting with activity throughout. And then we thought we're

01:25:05.020 | going to take it out. And of course, in this patients, they can fire. It turns out that it's not true that

01:25:09.260 | they can fire for some reason. They're probably other channels that are helping them compensate,

01:25:13.580 | but they fail to engage the rest of the pathway in a synchronized way. So that's why we need the four

01:25:20.220 | parts. And I think that's why assembloids generally are going to be very useful because there are emergent

01:25:25.100 | properties that are arising from the interactions of the cells at distance in the brain and likely many

01:25:29.820 | disorders. And of course, they're very far from understanding complex disorders such as autism.

01:25:34.220 | But certainly this interactions, fault interactions at a distance in the circuits

01:25:39.340 | are probably going to be, you know, key to understanding the biology of these conditions

01:25:42.780 | and hopefully at one point like reversing them.

01:25:44.780 | I'd like to take a quick break and acknowledge one of our sponsors, Function. Last year, I became

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01:27:31.420 | access to function. So I want to discuss an ethical consideration/concern, but before we do that,

01:27:38.540 | I want to take a step back and just have you reflect. I mean, I will never forget

01:27:45.420 | the first time I learned neural development, like sperm meets egg and then you get cell duplications

01:27:52.060 | and then the embryo figures out what's going to become muscle, what's going to become nervous system.

01:27:56.300 | And it's really a, it's a humbling thing to be able to realize that we understand even a small bit

01:28:03.420 | of that. Yeah. And very little was known until, you know, the sort of early parts of the last century

01:28:09.500 | really is where some of the defining tissues and interactions were first discovered. It was a

01:28:15.100 | relatively young science. Nowadays, I'm even more humbled by it because one only has to see a child that,

01:28:23.580 | you know, nine months ago didn't exist and you, and you really start, I mean, most people understand

01:28:28.620 | how babies are made. Um, and yet it just kind of, it's staggering. And I think what's so staggering

01:28:35.420 | about it, what's so miraculous that it really is, it's a miracle is the self-organizing aspect of it.

01:28:40.700 | Yes. And now I'm hearing that these self-organization knowledge of the cells own knowledge about what

01:28:48.220 | they should do and when is maintained. Uh, and I also have to just, um, both highlight again and, um,

01:28:57.900 | applaud the fact that regardless of where one stood on the, uh, embryonic stem cell debate,

01:29:04.220 | you're describing assembloids that were made from essentially taking a fibroblast, a skin cell

01:29:09.740 | Exactly. From a patient or from a non-patient, a healthy person that doesn't, at least doesn't

01:29:14.700 | have that mutation, putting them in a dish, reverting them to stemness through the Yamanaka factors,

01:29:20.140 | then giving them certain things to drive them towards neuronal fates and then other fates,

01:29:25.020 | putting them together. And none of this involves the use of aborted tissues. No. May I ask you this,

01:29:31.580 | if today you could bank your fibroblasts turned into a few neurons, um, would you do it? Um, knowing

01:29:41.660 | that those cells could eventually be used to create any tissue, like, I hope you live a very, very long

01:29:45.820 | life, Sergio. But let's say when you're a hundred, your heart has an issue. We humans can do heart

01:29:53.020 | transplants. Yeah. Um, from another human, their immune rejection issues, their, um, pig hearts have been

01:29:58.460 | transferred into humans, but we could potentially, you could potentially build a heart that is of your

01:30:05.100 | cells, no immune rejection. Why wouldn't you bank your cells? I think you, you can collect them at any

01:30:10.780 | time in principle, as long as you can get them on your 99th birthday. I think you can still get them.

01:30:15.260 | Okay. For sure. It could be an argument. So you have time folks. Right. So it could be an argument made

01:30:19.340 | that all the cells are going to be aging. So there are going to be some changes happening in those cells.

01:30:24.140 | Yeah. They'll accumulate mutations. Yeah. That could be an argument made about it. On the other hand,

01:30:29.100 | what we're also seeing with some of the cell therapies that are just being developed now more broadly,

01:30:34.700 | is that, um, they don't have to be necessarily personalized. So they don't have to be made from

01:30:39.900 | your own cells. Uh, because, uh, you know, you can use immunosuppression. That's one way in which you can do it.

01:30:47.660 | So you can transplant the cells from somebody else. Uh, of course that poses more challenges.

01:30:53.500 | If you think about the brain, um, replacing large parts of the brain, which certainly is like,

01:30:57.900 | yeah, you know, far to the future whose brain about about. Yeah, certainly. But in general, like,

01:31:02.540 | uh, you know, you can see how in the future we may have like off the shelf.

01:31:06.540 | Right. Uh, cells that have been made, uh, from a generic individual, uh, that you transplant with

01:31:13.820 | immunosuppression or cells that have been genetically modified so that they're not rejected by the

01:31:18.860 | immune system. So they're compatible with all of us now. It's much more likely to become a therapy

01:31:24.540 | that is broadly used. Uh, I think so that's why I'm not that worried about like harvesting my own cells

01:31:30.940 | like right now. Where do you sit on this idea that at some point in the not too distant future,

01:31:36.460 | we will be able to immortalize entire organs within our body, perhaps not ourselves, but our colleague,

01:31:43.420 | Michael Snyder chair of genetics at Stanford told me, um, that he thinks that at least in my lifetime,

01:31:49.420 | I'm a little bit younger than he is. Um, I'm almost 50. Uh, I forget how old Mike is almost 70,

01:31:55.660 | but he said at least in my lifetime, um, that immortalization of tissues, human tissues will be

01:32:03.340 | possible. He doesn't think that's a, a, a fantasy. Yeah. I think different people mean different things by

01:32:09.980 | immortalizing something. We generally, you know, think like for in vitro studies or for an additional

01:32:15.820 | study, when you immortalize something, it means that the cell is maintained forever, but it generally

01:32:19.900 | involves using a cancer like factor, giving them cancer properties. I mean, the cells that are immortalized,

01:32:24.860 | if you think about it, are either the stem cells that we talked about or the cancer cells. So we always

01:32:30.700 | have to be careful about like what it means to actually immortalized a cell. Rejuvenate cells.

01:32:36.860 | That's kind of like an interesting concept. Will we be able to actually rejuvenate ourselves even if they're

01:32:41.820 | aged? So a lot of discussions have been, um, happening lately, whether you can actually use the Yamanaka

01:32:48.700 | factors, not to the extent that you completely reprogram a cell, but that you just use them,

01:32:55.900 | you know, just a little bit so that you rejuvenate the cells, uh, not fully. But as you can imagine,

01:33:01.260 | those are complicated experiments, right? They're going to have to be tuned. You need to control very

01:33:06.060 | carefully the dial there. Microdosing Yamanaka factors, right? Because you would actually, you, you risk

01:33:11.500 | moving into another, uh, uh, state, uh, but, uh, you know, you know, that may be possible at one point.

01:33:17.900 | Yeah. I thought that at one point, one of the concerns of using Yamanaka factors and this whole

01:33:24.620 | technology therapeutically was that you could set the reversal and age of cells back to stemness,

01:33:33.180 | back to stem cells, but then how do you stop them there? Um, and also how do you send them? I mean,

01:33:40.300 | ultimately it's not a stem cell that you want. You want a fully differentiated heart cell or neuron,

01:33:44.700 | you want to stop there. Right. I mean, the idea being, uh, for anyone trying to reverse their age,

01:33:49.260 | I mean, how far back are you willing to go? Right. Right. And it's true when you use the Yamanaka

01:33:53.740 | factors or a combination of them, cause you know, we've discovered afterwards that it's not just those

01:33:58.380 | factors that can do that. There are combinations of other factors that can do the same. So there are

01:34:03.660 | various combinations. There is a lot of redundancy in that pathway. And if you hit the right combinations

01:34:08.700 | in a cell at the right time, you can push it back in time. Uh, now, of course, the challenge is that,

01:34:16.860 | uh, you know, that reprogramming is full in the sense that everything is going to be erased. If the

01:34:22.780 | reprogramming is done properly directly, all the methylation. So all this metal groups that you put across

01:34:30.060 | DNA that, you know, accumulate with age are going to be removed, uh, all the sort of like the, all the

01:34:36.140 | signatures of, you know, are essentially removed. So the cells truly rejuvenated as like in the beginning.

01:34:42.220 | And as you mentioned, you know, perhaps you don't want to do that, right. Fully. Uh, can you do it

01:34:46.540 | in a way that is a partial reprogramming as some people refer to? Um, but, but certainly that these

01:34:52.220 | are still like early days for that. Certainly it's a possibility.

01:34:55.260 | I think for most people, if I said, look, uh, scientists are developing, um, engineering eyes

01:35:04.460 | that can replace eyes for, uh, people that are blind, maybe one eye, maybe both. They'd say, great.

01:35:09.900 | Right. You're curing blindness effectively. Um, and people are trying to do this. Neuralink

01:35:15.180 | is doing this. E.J. Chichoniski and Dan Palenka at Stanford are trying to do this. Um, if I said,

01:35:22.300 | you know, there are, um, scientists and companies trying to develop chips so that, um, paralyzed people

01:35:28.860 | can walk again, or that people who have locked in syndrome can speak again, uh, through one modality

01:35:34.940 | or another, they'd say, great. But if I said,

01:35:39.500 | there are scientists who are building assembloids in a dish so that maybe you don't have like two

01:35:47.740 | hippocampi, you have three, you have a super memory. Yeah. I think most people be like, whoa, slow down.

01:35:54.460 | You're playing God. That's not okay. And as a parallel example, CRISPR gene therapy, which we talked

01:36:02.940 | about earlier. Yeah. Was employed by a Chinese scientist to, I think it was to mutate the HIV

01:36:09.420 | receptor. To modify, yeah, two individuals, two babies. Yeah. So there are at least two babies that

01:36:15.660 | we're aware of and probably more, uh, around the world, but not terribly many who, for whom CRISPR was

01:36:21.980 | used to make a genetic modification. Um, those babies were carried to term and it wasn't to fix any particular

01:36:28.860 | disease. It was to confer them with something additional. Yeah. To, to prevent, in this case,

01:36:33.340 | to prevent presumed transmission of HIV from the mother, which is not necessarily justified in that

01:36:39.980 | case. No. Right. Uh, did the mother have HIV? I think the idea was that, yeah, to avoid maternal

01:36:46.300 | transmission, uh, to the fetus, you would not not have that, but there are other ways in which that can

01:36:52.620 | actually be avoided. So in this case, it was not perhaps the best choice of a disease to correct.

01:36:58.300 | And I think that's why the scientific community has been quite outraged by both gets the rationale

01:37:05.020 | and the way the experiment was done, which was not following certainly. Yeah. Yeah. The, uh, the scientific

01:37:11.100 | community, as you, as you said, um, was very upset about that, which brings us to the question of ethics.

01:37:16.700 | Yes. So I'm sure being really familiar with this technology that you've thought about a number of

01:37:21.340 | ethical issues that aren't going to occur to me, or perhaps you've heard about things from the general

01:37:26.140 | public or from physicians and psychiatrists. What are some of the key ethical issues that come to mind

01:37:31.500 | when thinking about how assembloids are going to be implemented as eventually treatments for disease?

01:37:36.940 | Yeah. So we think a lot about like the ethical issues and we think this as a group at Stanford,

01:37:41.180 | that's part of like my center. Uh, we have like Ken Greeley who's a professor of law and an ethicist.

01:37:45.980 | Uh, but actually we've engaged, uh, many ethicists, sociologists or religions. We're actually going to have

01:37:51.020 | the first meeting at Asilomar this November on the ethics of neural organoids assembloids and their

01:37:56.940 | transplantation. And, uh, you know, there are various ways of classifying the ethical issues. The way I,

01:38:02.380 | so I think about it is that on one hand, there are ethical issues that are related to the cells.

01:38:08.380 | We are taking cells from a human. And so you expect that you have received proper consent, uh,

01:38:15.020 | for the use of those cells, whatever that is. On the other hand, if for instance, you put them into

01:38:19.980 | an animal, then there are ethical issues related to that animal. Are you doing any harm? How do we manage

01:38:26.220 | pain in the, in that animal that has been transplanted? And then there are sort of like issues that are at the

01:38:33.020 | interface between the two. So for instance, are there any emergent properties that are arising at one

01:38:39.260 | point, whether they're like in a dish or maybe perhaps in an animal, how complex can a circuit

01:38:45.100 | like this become? Is there any form of learning of computation? Of course, some people have raised the

01:38:51.100 | issue that perhaps there is sentience or awareness consciousness. Are they feeling pain? So for instance,

01:38:57.420 | that has been like one critique for one of the recent work that we've done. Of course, in that case,

01:39:01.820 | we know, you know, the emotional component of, uh, pain is processed in different brain regions. We don't

01:39:07.660 | have those, uh, in a dish. So we know that they're not really feeling pain. We have the pathway of pain,

01:39:11.980 | but also speaks to the fact that we need to be very careful about how we communicate this type of

01:39:18.540 | research. Even just using terms that are trivializing can actually create a lot of confusion. And the classic

01:39:24.540 | example in our field has been to call this preparations, this organotor assembloids, to call them

01:39:31.260 | mini brains, right? Then it may seem like as a trivial joke that it can do anything, uh, you know, any harm.

01:39:39.180 | But you hear that for the first time, scientists have made mini brains in a dish, right? And what do

01:39:45.180 | you think? You think, oh, it must be a miniature human brain that they're keeping in a dish, right?

01:39:50.860 | Isolated. And of course that's not true. We have not made the entire nervous system. We can make parts of

01:39:55.820 | the nervous system. We can put them in various combinations, but we've never made that entire brain.

01:40:00.700 | Actually, I don't know of any scientist who has as a goal to try to build the entire nervous system as

01:40:07.100 | an exact replica, uh, of the brain. So I think the words matter, uh, a lot. And in fact, that has been,

01:40:13.740 | uh, you know, one of the things that we've done over the years, uh, a few years ago,

01:40:18.620 | I thought it would be really important to get most of the scientists in the field

01:40:22.620 | together and start thinking about these terms really carefully. And so we got together, created,

01:40:27.980 | so like an ad hoc consortium and through many, many calls, one-on-one in various groups, we came up with

01:40:35.100 | one paper, which was published in nature a couple of years ago, which really comes as a nomenclature for

01:40:39.900 | the field. We, as scientists decided, this is also like the way we classify them. These are the terms

01:40:44.300 | that we all agreed should be used, uh, and not use, not for instance, um, you know, project, let's say,

01:40:52.540 | complex terms onto this. We'll never say that an organoid like sees just because there's a retina,

01:40:58.860 | right? We'll never say that a cortical organoid has intelligence because that's a property of an entire

01:41:03.980 | nervous system. So we think that this is actually quite important, especially in communicating with,

01:41:08.620 | uh, the public and that that consortium turned out to be an actually great exercise of getting

01:41:13.900 | everybody together and now thinking, what are some of the common practices that we should all use when

01:41:20.220 | we report this experiment? So we just had a few months ago, another paper, uh, that came also as a

01:41:25.100 | perspective in science where, in nature, where we also, uh, lay it out. So like the framework for the field,

01:41:31.260 | I think this also speaks to the fact that we're entering. So like a new era in science where I think,

01:41:36.060 | you know, you would say all these labs are working separately. They're competing with each other. And yet we

01:41:40.300 | all got together, you know, 25 or so labs discuss some of these issues, reach some consensus, you know,

01:41:47.260 | and I think that moves the field forward. And I think in general in science, we will need more and more of

01:41:53.180 | this collaborative efforts because the science is getting more complex. Biology is getting really, really

01:41:58.060 | complex and there's no one single lab that can solve all of that. Yeah, I completely agree. I think,

01:42:02.940 | uh, some years back collaboration became the norm as opposed to the, uh, occasional thing. And, uh,

01:42:08.860 | I always thought that laboratories should be named after projects, missions as opposed to individuals,

01:42:13.260 | but that's a, that's another story. Well, kudos to you for thinking about these issues so carefully

01:42:17.820 | and for gathering people around them, um, in order to come up with nomenclature, going back to this

01:42:23.740 | issue of naming, what things are called is so critical. It's so critical. And, and we see this

01:42:29.580 | in the public health sphere. Um, you know, when people talk about gain of function research now,

01:42:35.340 | you know, it's rarely mentioned that, you know, gain of function studies are critical for

01:42:38.860 | understanding things. It's not always the case. You're mutating a virus. It's like gain of function

01:42:42.940 | as a general technology, more specificity of language, I think is going to be immensely beneficial.

01:42:48.460 | So I appreciate you doing that. And, and these terms change with time. I think it's also important

01:42:53.100 | to like mention that our understanding evolves, science progresses, and sometimes there are things

01:42:59.100 | that we thought we understood and then new techniques come and change that. You know,

01:43:03.420 | I think it was Sydney Brenner who said that progress in science usually comes from a new technique

01:43:09.500 | that will yield new discoveries and that will create new ideas. So, you know, you think you

01:43:14.540 | understand something and suddenly you have a new machine that can measure it much better with more

01:43:18.940 | precision. Or let's say you have this technology when you can now recreate some of the circuits and

01:43:23.340 | suddenly new ideas come out of it, new discoveries. And then we rethink and we adjust. And I think

01:43:29.260 | that's the beauty of science that in a way it's self-correcting as we get a better and better

01:43:34.700 | understanding of the world around us. Also essential for people to hear, because I think whenever

01:43:39.020 | science or medicine comes out and tries to correct itself, often the general public, not all, but

01:43:46.940 | components of the general public will go up in arms as, you know, similar to like a teenager realizing

01:43:53.100 | that their parents also did some bad stuff when they were younger and they're like, see, I shouldn't

01:43:56.780 | believe anything you say. It turns out science as a whole, I think is a very well-intentioned

01:44:02.140 | endeavor. You get your occasional bad apples, but I think that this notion of self-correction is,

01:44:08.140 | it's fundamental. Just like engineering has gotten better. The phone you use now doesn't look anything

01:44:13.420 | like in terms of technology or speed of the phone you used 10 years ago, likewise with any technology.

01:44:19.180 | That's why it's so important that both when we communicate as scientists to the public,

01:44:22.620 | we use terms that are not trivializing. I think very often we're told like, you know,

01:44:27.020 | try to simplify so that the public understand. The public understands much more than we think.

01:44:31.420 | You know, there are always ways in which you can explain something without trivializing it,

01:44:35.500 | without using a new term or, you know, some comparison so that they understand that. Because

01:44:41.900 | very often analogies can also be dangerous, right? But I think, you know, I always sort of like assume,

01:44:49.180 | and that is sort of like being my, you know, my mantra, that somebody really has, when you explain

01:44:54.300 | even to the general public, that, you know, they have zero knowledge and yet, you know, infinite

01:44:59.500 | intelligence, right? I think as the saying goes in science. So I think there are always ways of

01:45:03.980 | explaining science very simply, but also communicating that science changes over time. There are new

01:45:10.380 | understandings that are correcting the science. And we've seen this, of course, in medicine. We've

01:45:14.780 | sadly seen it in psychiatry, right? Many, many times by labeling, relabeling, doing treatments that

01:45:21.100 | perhaps were like not the most, you know, fortunate, right? Over time. But I think it's important to tell

01:45:27.660 | the public that, you know, we're, you know, always trying to move towards. I think most physicians

01:45:31.500 | that I know, most psychiatrists that I know are really motivated by really trying to make their patient

01:45:37.500 | better. So let's play a, uh, a game where if I say, um, if you take two human cortical neurons,

01:45:50.620 | or three or five or 10 or a thousand that were developed from, uh, you know, one of my fibroblasts

01:45:58.220 | and you put it into a mouse or a non-human primate, like a macaque monkey,

01:46:02.220 | I think you've still got a mouse harboring a few of my neurons or a macaque monkey harboring

01:46:09.340 | a few of my neurons. At what point does that animal no longer, uh, become strictly a mouse or strictly a

01:46:15.740 | primate? Um, and then the parallel example, of course, is let's say I could get some neurons from

01:46:21.900 | fibroblasts that were made from you and those were put into my brain. Right. Um, at what point do I

01:46:28.300 | become more Sergio-like than, uh, Andrew-like? Yeah. So how do you think about those questions? And it,

01:46:34.380 | while it might seem too early to consider those, we've learned through history that it's never too early

01:46:40.300 | to start thinking about the ethical implications of a technology like this, where there's transplantation

01:46:45.420 | involved. No, it is absolutely not too early. Actually, it's, uh, the right time to think

01:46:49.420 | about this is as experiments are actually being planned, not when experiments have been done.

01:46:53.100 | Ah, good point. And that's what we've been, that's what we've been doing. And that's why actually,

01:46:56.380 | you know, all experiments that we do undergo ethical approval at Stanford. We, uh, you know, and I think

01:47:03.260 | most major institutions, right, and certainly in the United States, you have to first propose what you're

01:47:08.860 | going to do, uh, especially with pluripotent stem cells and especially with animals and a committee,

01:47:14.780 | you know, will decide whether that is acceptable or not. Now, of course there are experiments that

01:47:19.420 | perhaps are not necessarily illegal, but you know, when you try to break a new frontier, but I think what

01:47:25.020 | it's important to think about like this process of transplanting or transplantation that you take

01:47:29.500 | cells and you put them either in another individual or another species is that what really matters a lot,

01:47:36.140 | we've learned now, is the timing when you actually transplant those cells. So it turns out that the

01:47:42.460 | brain, the adult brain is not very permissive to forming new connections. We don't form them and we may

01:47:49.500 | form small connections. There's a lot of plasticity at the connections, but we don't have, let's say,

01:47:54.460 | in our adult brains, we don't have cells that are moving now across the nervous system. We don't have

01:47:59.100 | entire pathways that are being rewired. You know, you're never going to have a cortical neuron that

01:48:02.860 | just simply regrows and now connects to a spinal cord neurons, which is why injury to the nervous

01:48:07.820 | system is so devastating, right? There's so little recovery because the cells are usually not, um, you

01:48:14.460 | know, not essentially rejuvenating. There are no cells that are replenishing them. It's not just that

01:48:18.780 | there are no cells to actually replace them. It's also that the cells are just not that eager to connect

01:48:23.900 | with other cells as they are early in development. And so years ago, we've discovered that, you know,

01:48:30.700 | while we can keep some of these cultures in a dish for very long periods of time and connect them in

01:48:35.820 | ever more complex assembloids, and now they're like literally like dozens and hundreds of assemblies that

01:48:41.500 | people have made, and not just in the nervous system, actually even outside of the nervous system,

01:48:45.100 | because now they're assembloids of cardiac assembloids and endometrial assembloids. And so the

01:48:49.420 | concepts are like took over and I'm glad to talk about it. We're going to have the first conference

01:48:53.180 | on assembloids at Cold Spring Harbor this year, which is sort of like to bridge across

01:48:56.860 | fields and try to understand complex cell cell interactions. But even with this most complex

01:49:02.220 | assembloids, we realize that the cells are still missing cues that are present in vitro. So a few

01:49:07.420 | years ago, we were doing an experiment looking at some of the neurons that we made in a dish.

01:49:13.980 | And you know, these neurons in the cortex are very often called pyramidal because they look like a

01:49:19.180 | pyramid. They really have this beautiful triangular shape. And we're looking at the neuron, it looked

01:49:22.860 | beautiful, exactly like a pyramidal neuron. And then around that time, we got a piece of tissue that was

01:49:29.660 | removed from a child who underwent surgery for epilepsy. So when you sometimes have to undergo the

01:49:35.820 | surgeries, intractable epilepsy is really severe. Maybe you talked about this like previously, you have to

01:49:41.580 | remove some tissue. And when you remove some of that tissue, you also have to remove some healthy tissue.

01:49:45.180 | And so we got some of that healthy tissue. And of course, we're always like eager to understand how

01:49:51.100 | the cells that were made in a dish are similar or dissimilar to the ones in the actual brain. We still

01:49:55.740 | like need to benchmark before we use that for a therapy or for anything else. And we compare one day

01:50:00.700 | some of the cells and we realized to our amazement, I don't know how we'd never notice it or nobody has

01:50:07.020 | really like made a big deal out of it. But the neurons that we're making in the dish were about

01:50:12.060 | 10 times smaller than the ones in the cortex on average. I mean, there are kind of like miniature

01:50:18.300 | versions of what was happening. And so it was like, of course, immediately it was like, what is happening

01:50:22.860 | in vivo? You know, is there something, you know, as they say in vivo veritas very often, right? We know

01:50:29.580 | this has been the case for immunology, that many experiments in vitro have not always panned once

01:50:35.020 | you actually studied them in an actual patient. So that's when we actually started to also use

01:50:39.900 | transplantation. Meaning we started thinking, could we actually put some of the cells in an animal

01:50:44.460 | and see whether they acquire new properties or they look much more like this? And of course,

01:50:49.500 | transplantation has been used for 40 years. Many of these experiments were done before I was born,

01:50:54.700 | especially in Sweden, when scientists will actually take various cells and transplant them into animals.

01:51:01.900 | And so what we did, we started doing is like taking actual organoids, cortical organoids,

01:51:06.780 | organoids and then transplanting them into a rat, a early born rat in the somatosensory cortex. So

01:51:15.660 | the, so like the, the part of the brain that senses, uh, it receives information from whiskers.

01:51:20.860 | And done that, we've done that in the first few days after birth. And it turns out that that was key,

01:51:27.340 | because if you do it later, the cells don't really integrate that well. They integrate, but they don't

01:51:32.220 | fully integrate. And if you transplant that organoid into the somatosensory cortex of the rat, and then

01:51:38.380 | you wait for a few months, that graft starts to grow. The cells become vascularized by the rat.

01:51:44.380 | They will even receive microglia, the immune cells of the nervous system of the rat start to populate.

01:51:49.580 | And then when you use, look on an MRI, you now can see that about a third of one hemisphere of the rat is

01:51:56.140 | now made up of human cells. So you can see really from an MRI from the ventricle to the pia. Now you

01:52:02.620 | may think that that's like an inert piece of tissue that sits there, but it turns out that it is quite

01:52:07.420 | well connected to the host. And that happens because the brain is still eager to connect at that early

01:52:13.020 | stage of development, but later on is not. And so for instance, you can do experiments where you can

01:52:18.140 | actually record the activity of human neurons and at the same time move the whiskers of the rat. So if you

01:52:24.140 | move the whiskers of the rat onto the opposite side, obviously because the pathway is crossed,

01:52:28.220 | then human neurons now start to respond to that. And then the, I think probably the most important

01:52:34.860 | consequence of that is that they receive now input. They're now in an environment that is much more

01:52:39.900 | physiological. So when we now looked at the cells, it turned out that they're like six to eight fold

01:52:44.780 | larger than when we were making the dish. They're not yet identical replica, but they're very, very close.

01:52:51.180 | And that for us has actually been key and started to actually understand the biology of some of these

01:52:57.020 | conditions. So for instance, for Timothy syndrome, there is a very dramatic effect in the size of

01:53:04.700 | the neurons. They're almost twice as smaller than a control neuron.

01:53:09.260 | In the patient. Well, in the patient, only when you transplant the cells, we can see that defect.

01:53:15.020 | In a dish, you look at them and they're identical. And then you transplant them and some of them grow

01:53:19.740 | really large to control and the patients fail. And that phenotype can only really be seen properly in

01:53:25.420 | vivo. So that has been actually essential also, as we've been developing a therapeutic for this condition.

01:53:31.100 | And you start thinking like, how do you test a therapeutic? You know, if there's no animal model

01:53:36.060 | of the disease, you test everything in a dish. You do want to have some safety check, first of all,

01:53:43.180 | for making sure that there are no adverse effects, but also you want to make sure that it works in an

01:53:46.940 | in vivo environment. And actually it turns out that this model that we've built was essential

01:53:52.220 | because now we could take actually the animal and inject the therapeutic into the nervous system of

01:53:58.860 | the animal, but look at the effect on human neurons in an in vivo context. And, uh, you know, so I think

01:54:05.100 | that's one application for this, but if you do the transplantation at a later stage, like for instance,

01:54:10.140 | in an adult, that integration will probably not happen. I see. So it's quite dependent on the species.

01:54:15.900 | And there's another thing, the farther away the species are, the less likely it is, of course,

01:54:22.940 | that the cells will integrate. So, you know, think about it. It takes just a couple of weeks for the

01:54:28.700 | rats to make the cortex. It takes us 20 weeks to make most of the cortical cells. So the human cells

01:54:35.660 | are always behind. The rat is finishing development very quickly. The humans are trying, but they're keeping

01:54:41.580 | their pace. So the integration between the two species happens at some level, but it's not perfect.

01:54:46.780 | And that's actually not our goal. Our goal has never really been to have perfect integration. All we

01:54:51.500 | wanted to do is to have a better system where we can capture aspects of disease that we wouldn't be able

01:54:56.700 | to see in another way or test therapeutics that we wouldn't be able to test in any other way. And so that's

01:55:01.740 | where this actually comes in handy and it's been very useful. It's so interesting that for most people,

01:55:09.100 | again, I'm making a lot of assumptions here, but for most people, the idea of a chip of a, you know,

01:55:15.900 | electrode implanted into the brain of a patient or spinal cord of a patient, isn't that disturbing to them? I mean,

01:55:22.780 | no one would choose to do that in the absence of a clinical issue, but well, there are some people who are

01:55:28.140 | interested in brain augmentation through the implantation of chips to create super memory or to be able to, you know,

01:55:34.940 | process more bits of information in whatever, whatever capacity, but typically it's discussed

01:55:39.180 | in the therapeutic context. But as soon as we hear about, for instance, you know, a pig heart or baboon

01:55:45.020 | heart was, was transplanted into a human, you know, all of a sudden it's, it gets to some really core

01:55:50.220 | things about our humanness. Yeah. And then of course, I can't help but be reminded of all the

01:55:56.460 | anecdotes that you hear where, oh, you know, a patient died, had donated their heart to medicine.

01:56:02.700 | The heart was transferred. And then the person who received it thought that maybe they had adopted

01:56:06.460 | some features of a person's experience. And there's a, you know, you can't really do the control

01:56:11.340 | experiment, but there's a lot of interesting questions that, that border on mystical, but that,

01:56:16.940 | you know, given that experience is mapped into the nervous system, it's not inconceivable that you

01:56:21.900 | would have memory traces, at least of bodily experiences built into the organ system. Although

01:56:26.860 | typically we think of that stuff as in the brain. So, you know, as I hear and learn more about these

01:56:31.900 | incredible assembloids, I'm very enthusiastic about where this is headed. I also, of course,

01:56:39.420 | think that treatment of diseases that is like the primary entry point. This is what, you know, as opposed to

01:56:44.780 | building, you know, superhumans, which is, I think, why that CRISPR experiment mutating the HIV receptor

01:56:51.100 | was also disparaged. There was this idea that maybe the HIV receptor in the absence of HIV is

01:56:56.220 | performing other roles related to learning and memory. And so there was this, there were kind of hints of

01:57:00.140 | eugenic type approaches. And that raises a question for me. You mentioned that there are many genes that

01:57:07.180 | are associated with autism. Yeah. I think most parents or parents-to-be don't take a test for those

01:57:14.620 | genes. There are companies like ORCID in the Bay Area now that will do deep sequencing of embryos in

01:57:20.620 | IVF. You know, they'll do, depending on how much you pay, they'll sequence more. This was in the news

01:57:24.700 | a few weeks or months ago. Yeah. And then people, people start thinking, oh, this is like eugenics,

01:57:29.180 | right? On the other hand, partner selection, who one chooses to have children with, is its own form of

01:57:34.380 | genetic selection. Yeah. They'll say, oh, you know, he's very kind. She's very kind. She's very smart. You know,

01:57:40.700 | that there are people are basing their decisions, hopefully according to features that they would

01:57:45.340 | like to create in the offspring. It's not always the case, but so I think sometimes the boundary

01:57:50.940 | between, you know, what we call eugenics and mate selection and creating offspring in the purely old

01:57:59.820 | fashion way, it's blurry. It becomes a continuum. How far off are we from genetic testing of parents

01:58:08.060 | as a kind of obligatory thing? Now that we know some of the genes associated with autism,

01:58:15.100 | we test parents for things like Tay-Sachs, sickle cell anemia, congenital adrenal hyperplasia,

01:58:24.780 | things that are almost deterministic. Down syndrome, right? Trisomy. And in some countries,

01:58:32.940 | they'll implant embryos that are not, as we say, eucloid, you know, the proper assortment of

01:58:39.340 | chromosomes. But in the U.S., typically that's discouraged. So how do you think about all this?

01:58:46.220 | Like, I mean, you're not responsible for deciding for everyone, but you're right at the kind of leading

01:58:52.460 | edge of what's possible and you can kind of sniff what's going to be possible. I mean,

01:58:57.980 | how much information should a person thinking about having a child have in order to make the best

01:59:04.140 | informed decisions? So for some of these conditions, you know, it's more straightforward than for others.

01:59:11.500 | You know, as you were saying, some of them are very deterministic. So if you have like 321 chromosomes,

01:59:17.900 | you're going to have Down syndrome and that's going to be associated with the very classic presentation,

01:59:22.700 | you know. But for others, it turns out, and I think that's where it's much more complicated than just

01:59:28.540 | testing and making a decision, is that the, what we call in genetics, the penetrance of the genetic

01:59:35.180 | mutations is variable. Meaning that you could have a genetic mutation that in one patient could cause a

01:59:42.780 | very severe presentation or phenotype and another would be very mild. It's not the case for Timothy

01:59:48.780 | syndrome, where actually it's quite predictable. Most of the patients that we know, we've never

01:59:53.580 | identified a patient who is non-affected and they're very severely affected. But there are other conditions

02:00:00.140 | that are much more common. I think the classic one is a deletion that is happening on chromosome 22,

02:00:07.420 | the so-called 22Q11.2 deletion syndrome, known by many, many names. Velocardiofacial syndrome,

02:00:14.780 | Dijors syndrome, known by many names because it's been, it's so common. It's actually the most common

02:00:19.580 | micro deletion in humans. About one in 3,000 births. Now, the condition is associated with cardiac issues,

02:00:30.540 | immune conditions, you know, many of which can actually be addressed medically. But it also comes

02:00:36.620 | with a 30% risk for schizophrenia. 30%? Yeah. So you think the general population is 1%. So this is

02:00:44.940 | about 30 times higher. It also comes with the 30% risk of autism. But you could also not have any of this.

02:00:53.580 | There are individuals who are carrying the 22Q11.2 deletion, which is a large deletion, by the way,

02:01:00.460 | there's 60 genes that are gone in the classic deletion. And yet, still carry it around and have

02:01:06.540 | minimal defects or phenotypes. Do we test for this 22Q? This is tested generally these days, yes,

02:01:13.100 | because it's so common. But I think that the challenge is this problem of penetrance. And in

02:01:20.700 | some patients, and we don't know what the context is, each of us has a very complex genetic background.

02:01:25.580 | So it could be that, you know, the same mutation, two different individuals will have different

02:01:31.580 | levels of severity, because one of them perhaps compensates much better, for whatever reason,

02:01:36.700 | there's a lot of stochastic forces in development. And if a cell, it's much faster at opening the other

02:01:42.220 | gene, you know, like the similar gene that is unmutated, and in the other case, it wasn't and,

02:01:46.620 | or maybe there are other environmental factors that are, you know, interacting. But the other

02:01:51.260 | possibility is that the genetic background that we have is very different. And so we're still like in

02:01:55.980 | early days of truly understanding what are the effects of the genetic backgrounds in modulating

02:02:01.340 | the severity of these conditions. But in itself, it's a very interesting question, why some individuals

02:02:07.100 | can have, you know, a massive deletion, right, of 60 genes, and yet still move around.

02:02:12.940 | So I think that that that's going to be a lot of interesting biology to discover behind this. And

02:02:18.220 | then of course, we know that there are differences between animals and humans, right, that we already

02:02:22.140 | know, that very often, a mutation that would be very severe in a human has almost no, you know,

02:02:29.020 | defect in an animal model, partly because that gene maybe plays a different role or perhaps the genetic

02:02:34.060 | background is very different. Speaking of which, what are some of the other diseases that are being

02:02:40.140 | modeled and studied with assembloids? So Timothy syndrome has sort of like been the first example,

02:02:47.420 | because partly because it was some of the first neurons that were derived from iPS cells, and from

02:02:53.100 | patients with neurodevelopmental disorders in those early days. And also partly because it's the disease that

02:02:59.100 | we studied so much on all possible angles, first with 2D neurons, then with 3D organoids, then with

02:03:04.860 | the assembloids, that at one point, and I like to say that it kind of like a therapy became self-evident,

02:03:12.060 | so to speak. I mean, we were honestly not, I was not thinking that we would develop a therapy for

02:03:17.260 | Timothy syndrome, like not in the near future. But at one point, we just accumulated enough biological

02:03:24.540 | information that you just look at it and you say, oh, this is exactly what we need to do.

02:03:27.820 | And it turns out that, and this we did about like five years ago, that we understood so well how this

02:03:34.380 | channel is processed in the cells and what it causes that at one point we realized that all we need to do

02:03:39.180 | is generate this tiny piece of nucleic acid that we can get inside the cells, it will go in, switch the way

02:03:48.540 | the channel is actually processed and rescue or reverse the phenotypes. And it turns out that every

02:03:54.060 | single defect that we've described over the past 15 years in the studies can be rescued by just adding

02:03:59.340 | the tiny piece of nucleic acid. It's almost like a gene therapy in a way, it just doesn't involve a virus.

02:04:05.740 | And so this is the first disease and we're preparing for a clinical trial. These patients are very rare.

02:04:09.900 | So I've been traveling around the world trying to find most patients with Timothy syndrome, even try to

02:04:13.660 | understand the complexity of the disease, the severity of the disease. And so we now have a large cohort of

02:04:19.260 | the patients ready and we're preparing for the first clinical trial. We already started producing the drug.

02:04:24.300 | So it's druggable. We think that it's druggable, but this will be the first therapeutic

02:04:29.100 | for a psychiatric disease that has been exclusively developed with human stem cell models without

02:04:34.460 | anything else, you know. I like to joke about probably you knew very well Luber's dryer. He developed the

02:04:39.420 | so-called gene chip, the early days of evaluating genes in different cells. He passed away recently.

02:04:45.420 | He passed away recently. He also, um, yeah, he would bring coffee by. He would bring coffee by.

02:04:50.140 | He had our office across our D222, right? So he would come at nine.

02:04:54.700 | Anyone who's ever taken biochemistry, the big red biochemistry book, Stryer.

02:04:58.860 | It's Stryer. That's what it is. I mean, he was an amazing communicator. I think above anything,

02:05:03.500 | he was just a larger than life figure who like be able to like go with you in a conversation from like

02:05:08.780 | a deep molecular mechanism to what does it actually mean?

02:05:11.420 | Yeah. Very kind person too.

02:05:12.860 | So my last conversation with Lubert, which happened, I think a month before he passed away,

02:05:18.460 | he came to my office at Stanford. We would meet like every few months. He was just like so interested

02:05:22.700 | about like how this is evolving. And I remember he was sitting in my office and then he wanted to

02:05:27.580 | know, where are you with Timothy syndrome? The paper was still under revision at nature was coming in

02:05:31.500 | the next few months. And, uh, and then he said like, you know, like the saddest thing is like,

02:05:36.700 | I'm not going to see this paper published.

02:05:38.060 | Like, I want to see this paper published. And I said, like, why?

02:05:42.300 | And he goes, do you know what you've done? You know, cause he would usually use with that intensity.

02:05:46.860 | And I thought like, oh my God, maybe, you know, he realized some, you know,

02:05:50.620 | we've made the mistake somewhere in the paper or like, you know, it's going to point out to some flaw.

02:05:54.220 | And then he says, no, you've demystified the psychiatric disease.

02:05:58.780 | I said, what do you mean?

02:06:00.060 | I said, well, you think about psychiatric disorders.

02:06:02.460 | They're so esoteric, so complex mental processes in, you know, that are arising behavioral changes.

02:06:08.700 | And yet you went all the way down to like a molecular defect, a point mutation, figure out the rest.

02:06:15.340 | And now you're on a verge of potentially, you know, perhaps not reversing, but at least improving some.

02:06:19.980 | So he was so excited about this. I think I never kind of like think enough perhaps about it,

02:06:24.940 | but he was the last one who's like reminded about like how important it is actually to

02:06:30.460 | focus on these genetic disorders of which we know more.

02:06:33.820 | Of course, this is just one form of disease. There's so many more afterwards.

02:06:38.700 | But our hope is that just by understanding and learning from this, we're going to be able

02:06:43.020 | to apply to other disorders. So another one that we're studying now, there are forms of epilepsy,

02:06:47.500 | which are very difficult to study. There are intractable forms of epilepsy.

02:06:51.420 | Patients who have some of these genetic mutations, whether they're in an ion channel or in molecules

02:06:56.220 | that are important for cells to stick with each other,

02:06:58.460 | they can cause 60 seizures a day. So there are really devastating conditions that are actually

02:07:03.820 | causing impairment just by having those seizures every single day for 10, 15 years.

02:07:08.620 | And so those are a really big issue right now. So we've been focusing a lot on trying to build our

02:07:14.940 | models for this epileptic seizures, either through in vitro studies or after we transplant. And then we study

02:07:21.500 | more complex networks in patients. And then of course, intellectual disability, so severe intellectual

02:07:27.260 | disability, schizophrenia, forms of schizophrenia. So we've been studying now for almost 12, 13 years,

02:07:33.820 | 22Q11 deletion syndrome. We think it's like an entry point. It's the highest genetic risk factor

02:07:40.860 | that we know of for schizophrenia. So we think it may give us some windows into how molecular defects

02:07:47.580 | arise. So I think you can think of most psychiatric and neurological conditions that you can study now,

02:07:54.060 | as long as they have a strong biological genetic component. So I think those that have a social

02:08:00.540 | component, those that are triggered by social stress, let's say, right, like forms of anxiety,

02:08:05.980 | you know, depression, those are much more challenging to study because of course we can mimic that social environment.

02:08:13.580 | Can I make a request?

02:08:15.260 | - Please. - That someone in your lab tried to tackle dystonia.

02:08:19.580 | - Yes. - I had the experience last year of somebody contacting me. I get contacted a lot, you know,

02:08:25.820 | for requests to help with horribly sad situations, right, as one does if you're in the neuroscience field.

02:08:34.220 | Typically it's people with visual deficits who've gone blind or losing their vision. This time it was a

02:08:40.860 | mother of a young kid who had a form of dystonia where he was essentially just going from a, by all accounts,

02:08:47.100 | normal appearing and acting kid to having basically no ability to move or do anything. Couldn't go to

02:08:53.180 | camp, couldn't go to school. And just, it was just a very, very tragic situation. He had a neurosurgery. I

02:09:00.620 | will know soon how, how he's doing, but I learned that these dystonias are not super uncommon. I mean,

02:09:06.940 | fortunately they're, they're uncommon enough, but you just have to witness one of these stories and, and

02:09:13.100 | turns out there, there is a genetic basis for these. So I'm putting in a vote for dystonia for the parent

02:09:19.260 | and for the child. It's, it's devastating. Um, and we don't hear from these people very often. Um, and

02:09:25.420 | they're, they're sociological reasons for that. Um, certain diseases are underrepresented in the public

02:09:31.020 | sphere. Autism we hear a lot about, not just because of the prevalence, but because, um, there's a,

02:09:36.620 | we have a certain affinity to, uh, kids, um, and that, that explains that discussion for another time.

02:09:44.540 | But these dystonias are very hard to witness in a way that, um, has made them kind of, um, uh, veiled.

02:09:51.980 | Yeah. To, to the public and that, but they're very, very detrimental and it would be amazing. I know you

02:09:57.820 | already have a lot on your plate. Um, but I'm putting in a strong vote for, but we are, we are

02:10:02.380 | actually working on, on dystonias because there are devastating conditions and there are now genetic

02:10:06.940 | mutations that cause really severe forms of dyskinesia and dystonia. So really uncontrollable movements

02:10:12.380 | in these kids that are really devastating for social, uh, functioning and in general, in general for

02:10:17.180 | development. And so we do know a little bit about the biology behind it. We do know that the basal

02:10:23.420 | ganglia, this deep structure into the brain is very important for movements. You know, we very often

02:10:28.700 | stimulate that brain region for Parkinson's disease or parts, you know, of those circuitry. So we know

02:10:34.060 | it's very important. So we've been trying to rebuild it in a dish. So we now can build some of the circuits,

02:10:39.340 | we call them loop assembloids, where essentially you can put a cortex and we've made the striatum and

02:10:44.300 | then you put parts of the mesencephalon and the midbrain and the thalamus and the cells connect in a

02:10:48.780 | loop and now they have activity. So you can now induce mutations at various levels of the circuit and see

02:10:55.260 | where is that mutation most important. So let's say if you were to develop a gene therapy, where would you

02:11:00.620 | deliver that gene, right? If you were to choose, if you can deliver it in the entire brain. So these are

02:11:05.820 | really, so like early days, but I think the, uh, it can be applied. And I think in general, you know, you're

02:11:11.900 | mentioning this before about autism, right? And this, you know, even the ability of sort of like

02:11:16.380 | communicating, uh, these disorders or how much awareness there is, right? I think when I refer

02:11:23.420 | to autism, I generally refer to the severe forms and profound autism. And as we discussed earlier,

02:11:30.700 | there's certainly a continuum and there are many individuals that are high functioning, right? There are,

02:11:37.100 | uh, uh, uh, they have high skills. Uh, they may lack certain social skills, but they have other skills.

02:11:44.780 | They're different. They're productive in society. I am not talking about discovering or developing a

02:11:51.580 | therapeutic for any of these individuals. We are talking about the profound forms of autism. The ones

02:11:57.980 | that actually the parents are still struggling to even communicate about, right? The kids who may never go to

02:12:02.940 | school may, uh, never be able to actually live on their own. The same is the case for many of these

02:12:08.860 | patients with severe dystonias. So I think it's very important because, uh, I think in the case of autism,

02:12:15.020 | partly because it's being talked about and I can, because it is a, a spectrum is, uh, you know,

02:12:20.540 | it's also part of the identity, right? Of a part of the population. And that's absolutely fine. I think

02:12:26.140 | perhaps like at one point having different terms. Yeah, that would be useful. It may be useful because

02:12:30.380 | we were talking before about terminology, which is so important. Um, so perhaps that would be so like

02:12:35.820 | useful at one point to define, um, you know, the border between, uh, profound forms of autism and forms

02:12:42.460 | of autism that are, are not really a disease. Yeah. As well-meaning as the psychiatric community is,

02:12:47.740 | it's bound by this, you know, DSM, whatever number it happens to be on for, for understandable reasons.

02:12:53.180 | But I think, uh, better, um, nomenclature would really help that has societal implications. It has

02:12:59.500 | to do with how we treat people generally. Um, actually just as a quick reflection years ago,

02:13:04.780 | I sat down with Bob Desimone who, you know, world-class neuroscientist, as you know, but he was the head of the

02:13:11.500 | national institutes of mental health at that time. And he said to me directly, it was over lunch. He

02:13:16.300 | said, um, do you know why there's so much more money spent trying to understand autism as opposed

02:13:21.020 | to schizophrenia? At least that was the case at the time. And I think it is still now. I said, no. And

02:13:25.340 | he said, because the, uh, strong genetic link in schizophrenia means that, um, oftentimes the parents

02:13:31.900 | are struggling as well. They're not bringing their children in and with severe, uh, nowadays it's not

02:13:38.860 | politically correct to call them schizophrenics for people with severe schizophrenia. Uh, it's scary

02:13:44.620 | to be around. Yeah. It's really scary. Whereas with autism, um, even in the profound cases, these are

02:13:50.620 | children and as a human species, we, we naturally have this, we want to care for our young and it just,

02:13:56.940 | it just pulls on us. And he said, you know, so there's been this incredible lobby, uh, of the

02:14:01.820 | government and therefore pressure on NIH to, um, direct funds towards studying autism far, far less

02:14:10.380 | for schizophrenia. That's interesting. You know, in light of the homeless problem in California and

02:14:15.500 | elsewhere and the huge amount of mental disease and drug addiction, I think nowadays there's a kind

02:14:20.060 | of a broader understanding of brain diseases as diseases that people suffer from as opposed to

02:14:26.380 | cold mothering or something, you know, like ridiculous theories like that. I definitely

02:14:31.100 | want to talk a little bit about, um, you, um, not getting too personal here, but, um, I've known you

02:14:37.340 | for some years and, um, from the first time I met you, it was clear you were going to work on something

02:14:42.860 | important. You were going to figure it out and your, your work ethic is like something to behold,

02:14:48.220 | uh, without inflating numbers. Um, uh, how much time are you, are you spending these days either

02:14:54.380 | at the computer working on things related to your science or in the lab or thinking about your science?

02:15:00.380 | I mean, of, of your waking hours, what percentage? Well, I've never seen this at work. So probably all

02:15:05.900 | the time, I think about this all the time. I mean, luckily now, of course I have a lab of incredible

02:15:10.060 | scientists and many of them now have their own labs. And, uh, we've been teaching so many people

02:15:16.300 | around the world now, like more than 350 labs around the world to just implement this technology very

02:15:21.260 | systematically through courses that we do at Stanford. So I feel we've kind of like amplified

02:15:25.500 | so much. So there's always something happening, uh, but I've never seen it honestly at work. I mean,

02:15:29.900 | I think it's, it's, it's so fun to think about, you know, the human brain. It's certainly fascinating

02:15:35.260 | to think about the biology of these conditions. And of course, for me training as a physician,

02:15:39.740 | I think seeing firsthand some of the devastating effects of, of psychiatric disorders,

02:15:44.380 | which it was a very strong, um, you know, motivation to actually go into neuroscience.

02:15:49.740 | I'll never forget when the org, when your first paper was published as a postdoc.

02:15:55.340 | Yes. You brought in, um, a cake for everyone else.

02:15:59.420 | I don't know if you remember that. You brought in cake for everyone else.

02:16:03.100 | I don't remember. And I was like, this is the first time I've ever observed this. This is awesome.

02:16:06.220 | At the time I was eating cake. I don't eat cake anymore. With each successive decade, I, I get stricter and

02:16:12.460 | stricter with my eating. I still enjoy food very much, but, um, it's, it really speaks to your,

02:16:17.660 | your spirit and your generosity. I feel so blessed that someday I'll be able to say,

02:16:21.900 | I can tell you stories from way back when D two, two, two, when we took over that room without

02:16:27.020 | permission, I think we just did it. I think we just took it. Which is the way to,

02:16:29.900 | which is the way to do it. It's unincorporated.

02:16:31.820 | Ben was the one who always said, you know, ask for forgiveness, not permission within the proper

02:16:36.780 | context, uh, of doing science. Um, he, he, uh, was famous for bringing his experiments to talks

02:16:43.660 | as a postdoc, so he wouldn't lose time on his experiments. He, and then I think at one point,

02:16:48.940 | there's a story where somebody called it out, him out and said, Hey, you know, like, why are you

02:16:52.860 | bringing your experiments to seminars? Everyone else is drinking coffee and doing stuff. And he said,

02:16:56.460 | because I don't know if your seminar is going to be any good and I don't want to waste the time on

02:16:59.820 | my experiments. You know, he had such a, an incredible spirit about just ceaseless pursuit

02:17:05.900 | of knowledge, uh, which clearly you do as well. Um, Sergio, I am so grateful for you taking time out of

02:17:13.420 | your immensely busy schedule to come here and educate us all on this incredible technology that you've

02:17:18.460 | developed and that other laboratories are now using. I realize it's a field, um, but clearly a field that

02:17:24.060 | you've been seminal in launching. And, you know, I think for a lot of people, if they were to just

02:17:29.020 | hear about organoids in the news or hear, okay, we took these neurons and we were able to grow them

02:17:34.540 | in a dish and they formed some, uh, things that resemble circuits and we're putting them into mice,

02:17:39.100 | they'd say, you know, this sounds a lot like a parlor trick or something that scientists do to keep

02:17:42.780 | themselves busy with our tax dollars. But I just want to thank you because you've beautifully illustrated

02:17:48.220 | the linear fashion in which you've gone from human disease to building up technologies, one cell type

02:17:55.580 | in a dish, two cell types, circuits in a dish, three synapses, modeling, using drugs and other

02:18:02.300 | approaches, genetic therapies to figure out what actually needs to be fixed, going back into patients,

02:18:07.900 | which is super exciting. I'm absolutely convinced this is the way science is going to be done on the

02:18:12.700 | brain to cure neurologic and psychiatric diseases. I'm absolutely convinced because animal models,

02:18:19.100 | while they have their place, they just can't recapitulate everything we're interested in.

02:18:23.660 | And we know that as you mentioned from other fields. So, uh, whatever we have to do to keep

02:18:28.620 | you going, uh, you look younger than the last time I saw you, which was a while ago. So, uh,

02:18:33.020 | you told me before we started, you walk a lot. How many steps a day are you doing?

02:18:36.060 | I do more than 12, 15,000 for sure. So you're walking to and from work?

02:18:40.460 | Yeah. And I walk all the time. I like to walk, especially when I travel. I, you know, I visit a

02:18:46.300 | lot Europe and parts of the world and I love to just walk and art is the only other thing that I do.

02:18:51.980 | Oh yeah. Other than science. I love art.

02:18:53.740 | You paint?

02:18:54.700 | I used to paint right now is mostly thinking about art and like what, you know, I've, I've seen most

02:18:59.500 | museums in Europe at this point, like several times.

02:19:01.820 | Whose art is exciting? You know, I'm fascinated by, I love art, but whose art are you, um, intrigued by

02:19:07.980 | lately?

02:19:08.300 | Well, I mean, I've, my favorites have always been impressionist. Uh, but then I go through phases

02:19:13.260 | and, uh, so I, I love all art as an expression. And I think that's sort of like, uh, you know,

02:19:18.540 | I walk a lot in museums. I think you could, you could probably trace like where I've done most

02:19:23.180 | of the walking and it's probably done in museums or in California walking at night. And so like

02:19:27.340 | discussing science with students or others.

02:19:29.580 | Fantastic. And none of this biohacking nonsense, you eat one meal a day. That's how you stay so fit.

02:19:34.460 | I generally eat one meal a day. Yeah.

02:19:36.620 | How long have you been doing that?

02:19:37.660 | Uh, years, I think, uh, years. I mean, I think in medical school, uh, initially as a necessity,

02:19:43.180 | because, uh, uh, I grew up in Romania and I went to medical school there and there wasn't really

02:19:48.780 | dedicated time for research. So I had no option, but to do my experiments either very early in the

02:19:54.620 | morning or very late at night. So there'll be very little time, um, to actually like eat to be

02:20:00.620 | honest at that time. So I felt that was like running all the time doing experiments or clinical work.

02:20:05.660 | Well, like I said, your, your vigor seems to be just increasing with time as it's really wonderful.

02:20:11.100 | Clearly you've found the career path for you and it's going to benefit us all. It already has. So

02:20:16.540 | so please come back and tell us about your progress, um, in six months, a year, uh, whenever the time is

02:20:23.180 | right, we'll have you back. And once again, thanks for doing everything you do. You're, uh, in this time

02:20:27.500 | of hearing so much negative news and like thinking like science is so, you know, hobbled and all this

02:20:33.020 | stuff, science needs support obviously, but, um, you know, what's that saying you see on the internet?

02:20:38.700 | Uh, you know, not all superheroes wear capes here. You're, you're doing God's work. So thank you.

02:20:42.620 | Thank you so much. Thank you. Thank you for joining me for today's discussion with Dr. Sergio Pasca.

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Curing Autism, Epilepsy & Schizophrenia with Stem Cells | Dr. Sergiu Pașca

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