Using Stem Cells to Cure Autism, Epilepsy & Schizophrenia | Dr. Sergiu Pașca

Andrew Huberman:
Welcome to the Huberman Lab podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Sergiu Pasca. Dr. Sergiu Pasca is a professor of psychiatry and behavioral sciences and the director of the Stanford Brain Organogenesis Program. During today's episode, we discuss autism, schizophrenia, and human brain development generally, both brain development during pregnancy as well as during childhood and leading all the way up to our third decade of life. During today's discussion, you will get the most up-to-date information about autism and its treatments. You'll learn why the prevalence of autism is rising, the role that genes play in autism, and the novel treatments that Dr. Pasca is developing to treat what is called profound autism, which are the most severe cases of autism. Dr. Pasca is one of a small handful of researchers that pioneered the discovery and development of what are called organoids and assembloids, which are essentially human brain circuits derived from stem cells that form in a dish, so that one can study them directly. And while that might sound artificial, today he explains why those organoids and assembloids are immensely powerful for understanding exactly what is wrong in psychiatric illnesses like profound autism, schizophrenia, and other psychiatric challenges, and for developing cures. So today, you're going to learn a lot about human brain development and about stem cells, which is going to be important for anyone interested in how the brain wires up, how to treat various diseases of the brain, but also for anyone who is considering stem cell therapies. As you'll soon learn, Sergiu is an extraordinary scientist, but also an extraordinary teacher. By the end of today's episode, you'll have the latest information on stem cells, organoids, autism, and what is being done to cure autism and other psychiatric conditions. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, today's episode does include sponsors. And now for my discussion with Dr. Sergiu Pasca. Dr. Sergiu Pasca, welcome.

Dr. Sergiu Pașca:
Thank you. It's great to be here.

Andrew Huberman:
We're old friends.

Dr. Sergiu Pașca:
Mm-hmm.

Andrew Huberman:
Shared a laboratory space years ago. We'll get back to that a little later. In the meantime, these days there's a ton of interest and I think misunderstanding about autism. As soon as the topic of autism comes up, immediately some people will say, "Why are we trying to cure this thing? I know autistic children and adults that are delightful people that lead functional lives."

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
"They might be a little bit different or a lot different than other people, but why are we trying to, quote unquote, 'cure autism?'" And then other people will say, "Well, there are people with autism who need constant care, who will never live independently." Tell us about autism, what this spectrum really is, and then we'll talk about what your laboratory is doing to try and literally find cures for the most debilitating forms of autism.

Dr. Sergiu Pașca:
Well, autism is a complex condition. It's a spectrum, as you said. In a way you could say autism and neurodevelopmental disorders. It's behaviorally defined. There's no biomarker, so in a way it's a condition that is defined exclusively by observing behavior.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
Which is actually the case for most psychiatric disorders. But it's essentially diagnosed by the presence and absence of certain behaviors in a certain period of time or up to a certain age. And of course, what triggered, I think, a lot of discussions in recent years is because the number or the prevalence of autism has increased. So now it's close to almost 3% of the general population, which of course it's a big number.

Andrew Huberman:
3%.

Dr. Sergiu Pașca:
Almost 3%, yes.

Andrew Huberman:
Wow.

Dr. Sergiu Pașca:
So it has increased even since I was in medical school. When I was in medical school, actually, it was considered a rare disease. The reason why I actually studied autism, because it was a very rare disease, and we had very few resources, so we thought studying a rare disease would be easier.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
But now we also know so much more about this condition. So we do know, for instance, that there is a strong genetic component to it, which for a while, obviously, we didn't. In fact, in early days, the psychoanalytic perspective dominated, especially in the '50s and '60s. So it was thought that it was resulting from having very cold parents, in particular a cold mother.

Andrew Huberman:
Emotionally cold?

Dr. Sergiu Pașca:
Yeah, emotionally cold.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
It was the so-called refrigerator mother hypothesis of autism. And then in the '70s, some of the first biological studies were done, primarily in twins, that show something quite remarkable, that if you have twins that are identical, genetically identical, and one has autism, then the probability that the other one has autism is very, very high.

Andrew Huberman:
Even with different mothers.

Dr. Sergiu Pașca:
Sure.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
Yes.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
But generally, we think that there is a strong heritable component to autism. So that was in the late '70s. And really just in the last 10, 15 years, we've learned actually that there are genes associated with autism and certainly with very specific forms of autism. So that's what we would call generally profound autism today, the conditions that are severe, that are causing an impairment, that are very often associated with other conditions such as intellectual disability, so low IQ, epilepsy. So because it is a spectrum, of course, it creates a lot of confusion, and certainly there's no doubt that there are individuals that have autistic traits that are fully functional in the general population. But the reality is also that there are kids that have autism who are very impaired and will require actually lifelong care of sorts. Another way of thinking about autism is that autism is not one disease, and I think no psychiatrist or even biologist who's studying autism would ever consider that this is one single disease. The way I look at it sometimes is think about the fever of the 19th century in medicine. So you see this very often in movies, right? They will say, "Oh, he has a fever, high fever. He's going to die from high fever." Well, that fever could have been a viral infection, a bacterial infection, could have been cancer, metastatic cancer. Could have been an autoimmune disease. The treatments are very different, but in that time, that's all we knew. It was we were observing that behavior, in which case, raising of the temperature, but we didn't know the biology. Today, we will use very different treatments for those conditions, and some of them, of course, we don't even treat. We just observe. So I think in autism research, as it is the case for many psychiatric conditions, they are defined behaviorally, but there is a disconnect with the biology. Very often we don't have biological markers by definition, and so that disconnect, I think, creates a lot of confusion.

Andrew Huberman:
I have a couple of questions. First of all, is the prevalence of autism higher in males? I've been told yes. If it's 3% overall, what's the distribution for males versus females?

Dr. Sergiu Pașca:
The ratio varies also based on severity, but generally it's been one to four, so more males than females.

Andrew Huberman:
And we just recently had our colleague, Nirao Shah, on the podcast, who basically said the difference between a biological male and female comes down to this SRY gene.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
Not even necessarily on the Y chromosome.

Dr. Sergiu Pașca:
Mm-hmm.

Andrew Huberman:
If a baby has the SRY gene, you're going to get a fully functional male.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
If not, you're essentially dealing with a female. So presumably, something about the SRY gene is conferring a vulnerability to autism. I think it's fascinating.

Dr. Sergiu Pașca:
Well, there are a lot of discussions, of course, like what causes this difference, and some discussions are just in terms of diagnosis that perhaps some of the girls are not getting diagnosed properly. We do know that some of them are very good at what we call masking the symptoms, so learning the social skills, and so covering for that diagnosis. But what we do know for sure is that there are differences in how the male and the female brain, especially around birth, can actually take up injury.

Andrew Huberman:
Hmm.

Dr. Sergiu Pașca:
So think, for instance, about premature birth. One of the best predictors for a premature baby in terms of outcomes, it's actually to be a female. Just in general, female preemies will do much better for whatever reasons. The way the nervous system is built, the resilience. We know that the maturation stage is also different for the male and the female. Think about acquisition of certain milestones that happen much faster in girls. They generally tend to speak a few months earlier, to walk a few months earlier. So just the nervous system is maturing at a different pace and can take injury differently. So it could be that that is certainly a cause, but at the same time, and as we were talking, since autism is not one single disease, it is very hard to point out to one specific factor that is behind it.

Andrew Huberman:
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Dr. Sergiu Pașca:
Mm-hmm.

Andrew Huberman:
Which can be confusing language because people think positive means good. No, positive is the presence, negative is the absence.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
I haven't looked at this literature in a while, but the last time I did, it seemed that babies or young children failing to Focus their own gaze on the eyes of other people is one of the major diagnostic criteria. It seems they look at the face more holistically, or they'll zoom in just on the nose, but they're not really making as much eye contact.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
Is that still a diagnostic criteria?

Dr. Sergiu Pașca:
It's not part of the diagnostic criteria.

Andrew Huberman:
Hmm. Interesting.

Dr. Sergiu Pașca:
But it is one of the features that has been observed.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
Of course, it also has to do with just in general, joint attention is one of the earlier, so if you just tell a child, "Oh, look here." So if they have that attention, if they engage in that attention, it's one of the features that is associated with autism. It's not certainly diagnostic. It's not pathognomonic, so to speak, so it's not specific to the disease in any way.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
But there are certainly many deficits, and some of them can actually be compensated later.

Andrew Huberman:
Interesting. There were some other things I've heard over the years, for instance, that when children with autism have a fever, that their symptoms improve.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
Is that still the case?

Dr. Sergiu Pașca:
Yeah. So those are mostly anecdotic reports-

Andrew Huberman:
Mm-hmm

Dr. Sergiu Pașca:
... of patients who would have a very high fever, and then, for instance, they were non-verbal. So many patients with autism, or individuals with autism, will be non-verbal. They have very few words, or they're not able to communicate. And so there are a few reports of parents saying that when they spike the very high fever, they'll start talking in sentences very briefly or engage. And in fact, that is known. Kids, in general, when they have a high fever, they tend to be more talkative. It activates somehow the nervous system. There have been a lot of hypotheses about this. Some of them having to do with how the noradrenergic system is activating during fever. Others saying that there are some of the cytokines, the immune molecules that are present during fever that are somehow getting into the brain, activating the nervous system. And others as simple as, oh, ion channels. Ion channels will open more when the temperature rises, so something about the circuits functioning differently during that. But it's mostly anecdotic at this point, and it's certainly, again, probably not present in all individuals with autism. Also because autism is, again, not one single disease, so we would not expect it to be present in all.

Andrew Huberman:
A few years ago, there was a lot of excitement about the idea that autism might somehow be related, perhaps even caused by deficits in the microbiome. There were some mouse experiments of doing-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... fecal transplants from what we call wild type or healthy mice into mice that had some symptoms that resemble autism, and there were improvements observed, to the point where I think there were some human clinical trials using fecal transplants.

Dr. Sergiu Pașca:
Sure.

Andrew Huberman:
Whatever became of that?

Dr. Sergiu Pașca:
I think, again, almost everything has been associated or thought to be causal. But generally, demonstrating this is very, very difficult. So we cannot deny that perhaps improving the microbiome will improve the quality of life of some of these individuals, but whether it's really causal, there's no clear evidence for it. Think about it, just to give you another example. Think about sleep. Many patients will report, especially the ones that are profoundly impaired, will have severe sleep disturbances. I mean, 70, 80% of them, they can have nights where they sleep very little. Then do that for a week. So just imagine even just improving the quality of sleep for those patients can do miracle. I mean, all of us, if we don't sleep for three, four days, our social skills, we become socially impaired. So I think, of course, correcting a lot of these issues. So for instance, many patients are picky eaters. They don't like certain textures, so they will never eat, for instance, veggies. So that creates, in the early days, for instance, we thought that there are dietary disturbances that really at the core. Of course, it remains to be seen whether just simply correcting those is going to be just improving or certainly reversing some of these forms. But again, most of the evidence points out towards a very strong genetic component behind it, and in fact, we now have hundreds of genes that we know when they are mutated, they are strongly associated with specific forms of autism.

Andrew Huberman:
I'm curious what sorts of proteins those genes are upstream of. And I ask because David Ginty at Harvard did these really beautiful experiments where he induced mutations just in the periphery, so outside the brain-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... of these mouse models for autism and saw a lot of the same symptomology.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
Raising the question of whether or not autism originates in the brain or whether or not the deficits in the brain are the byproduct of changes in the body. Yes, microbiome, but perhaps their skin, their hearing, et cetera, are more sensitive, and maybe that's why they-- You could imagine if you were ultrasensitive to an environment, that your brain would eventually wire differently according to-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... and overwhelmed by what was happening-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... in the sensory landscape.

Dr. Sergiu Pașca:
Yeah, absolutely. And those are really elegant experiments that he's done. Many of the genes fit in different categories. You would have genes that would produce proteins that sit at synapses, which was to be expected. Some of them are ion channels. They're proteins that would let ions inside or outside of a neuron. There are many of these conditions, so-called channelopathies. Then there are the ones that are synaptic-related, so synaptopathies. There are a lot of chromatin genes, so like proteins that pack the DNA in cells. Those are chromatinopathies. So there are really, again, many, many categories of genes. And then what is also interesting is that many of these genes are also expressed in the periphery. So I think the experiments that you are mentioning are really elegant because it showed that indeed that can perturb the development of the nervous system, even if they're affecting just the periphery. Of course, now in patients, they are present also in the central nervous system, so it's always difficult to distinguish. But just missing some of these critical periods or perturbing some of these critical periods of development can have certainly devastating effects later on.

Andrew Huberman:
So if a parent comes into the clinic nowadays with a child that's diagnosed with profound autism, what is the treatment? Let's set aside the potential for epilepsy, which hopefully they would treat as well, or other things that might be secondary. But what is the typical treatment? And let's assume infinite resources-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... which of course nobody has, most people don't have. But if one had infinite resources, what would be done? Would it be behavioral training? Would it be something to control the activation state of the brain? As far as I know, there's no single treatment for autism.

Dr. Sergiu Pașca:
No, there's no single treatment for autism. Again, in the context of this not being one single disease. What we can say today is that if a family walks into the clinic with the diagnosis of autism or perhaps they receive it into the clinic, there's still a 20% probability that they'll leave the clinic with a genetic diagnosis, meaning that it will be pointed out to them that this gene is mutated in your child. And it may be sometimes a mutation that was present in one of the parents and got transmitted, or maybe it was present in both and somehow the child got two copies that were modified now, or many of the genes are actually mutated de novo, meaning that the mutation was not present in either parents, but something went wrong during development, perhaps early in the sperm cell, in the egg cell, or perhaps in early stages of development, and a new mutation was acquired. We acquire a lot of mutations. All of us, we have a lot of new mutations. About 80 new mutations, 30 of them are protein truncating. So certainly the challenge very often is to, even when you see a gene that is mutated, to know whether that gene is truly causing the disease. So very often the way we know is that we find many patients that have a similar presentation clinically. Let's say maybe they'll have syndactyly, so they have webbing of the finger, and they have autism, and let's say epilepsy, and they all have a mutation in one single channel. Let's say in a calcium channel. So that would be Timothy syndrome, a genetic form of autism where the mutation is very clear. Actually, there's one single letter in the genome that is changed and causes a relatively similar presentation in all of these patients. So about 20% of the patients will get a genetic diagnosis. Now, sadly, that doesn't do that much today because we don't really have specific therapies for those forms. I think the hope is that perhaps we will have individual treatments, whether they're going to be genetic or otherwise. So being part of that community is generally useful. And then the rest of the patients will essentially fit into this larger category of idiopathic, meaning that we don't really know the precise cause.

Andrew Huberman:
I want to talk about Timothy syndrome, and I also want to talk about genetic approaches for fixing genes-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... so-called gene therapy. Before we do that, would you be willing to just speculate on why you think there's this fairly dramatic increase in the incidence of autism? People will always say, well, maybe it's better detection, better diagnosis. So I'd like your thoughts on that, and if there are increases that can't be explained with that, I just would like your thoughts. I realize-

Dr. Sergiu Pașca:
Sure

Andrew Huberman:
... we're not talking formal biostatistics here.

Dr. Sergiu Pașca:
No.

Andrew Huberman:
Just in your experience, you're an MD, you think about autism a lot, you're working on potential cures for autism and other neurologic conditions. How do you think about this increased prevalence issue?

Dr. Sergiu Pașca:
Yeah. Well, certainly the increase is still puzzling. So I think on one hand, there's no doubt that the changes in diagnostic criteria, which have happened over time, we had to just refine what autism really is. That changed, to some extent, the prevalence. We've also seen a diagnostic migration, so to speak. So some children, for instance, 30 years ago would have been diagnosed with intellectual disability, and today they fit the criteria for autism. About a third of individuals with autism also have intellectual disability, so there is also a great overlap between the conditions. So there's been a move sometimes between the diagnosis over time. Of course, there are all kind of discussions about availability of services and to what extent that is also contributing. But we don't truly understand all the reasons behind this increase. There's no doubt. We know that it's highly heritable based on genetic studies.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
So we know the heritability is very high, one of the highest for psychiatric disorders that we know of. But of course, we don't have the genes for every single form, so it is likely that some of them are very rare. So essentially, just think of it as they're individually rare form, but collectively common. So it will take a while until we map all of them. And then, of course, there are environmental factors that we do know historically can contribute to this, so there are various exposures to environmental factors. Like in early days, thalidomide, for instance, was one of them that we know increases the risk for autism. So of course, those are contributing.

Andrew Huberman:
Thalidomide was a drug given to pregnant mothers to try and prevent miscarriage, right?

Dr. Sergiu Pașca:
Exactly.

Andrew Huberman:
It's no longer prescribed.

Dr. Sergiu Pașca:
It's no longer prescribed.

Andrew Huberman:
Because it caused major birth defects.

Dr. Sergiu Pașca:
Defects. Exactly.

Andrew Huberman:
Okay.

Dr. Sergiu Pașca:
Yeah. So certainly, it's quite complex because first of all, the definition of the condition is quite difficult. And I think that is in general the challenge with psychiatric disorders. And perhaps one of the reasons we've made such slow progress in understanding these conditions, because, of course, the power of modern medicine is in molecular biology. We deploy this remarkable force of an understanding. And in order to do that, you need two things. You need, first of all, to have a very clear definition of what that disease is, generally, biologically. Think about myocardial infarction, very clearly defined in terms of what it actually means. You immediately have biomarkers. The patient walks in, you take blood, you can immediately tell, yes, in 20 minutes, you can tell that they have a myocardial infarction based on a biomarker. And then the other one, which is certainly very important, which to a large extent is the source of all the work that we've done, is the unbearable inaccessibility of the human brain, so to speak. And to a large extent, the human brain is inaccessible for most of its development. And so if you look actually across branches of medicine, you can see that there is a very strong correlation between how accessible an organ is and how many cures or therapies we actually have. Think even just in cancer. Think about in cancer, which used to be, of course, an incurable disease a century ago. Think about leukemias in children. They were 90% lethal in the '50s and the '60s. Today, they are maybe 10% lethal. And that is because blood from these patients, it's very easy to collect. We've been bringing it to the lab, studying it, what goes wrong, and then deploying molecular biology to develop therapeutics. With the brain, sadly, there's no way of doing it. And so largely, what we've been trying to do is to find a way of shortcutting that process. But I do believe that the major challenges that we're facing in understanding brain disorders, whether they're neurological or psychiatric, are on one hand, the inaccessibility of the organ of interest, the brain, and on the other hand, our challenges are very often defining some of these conditions with biological markers because they're much more complex.

Andrew Huberman:
The degree to which correlation has been leveraged to try and understand neurologic disease is kind of staggering. I'll just share a couple, and I would love your reflections. 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.

Dr. Sergiu Pașca:
Mm-hmm.

Andrew Huberman:
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 toward the poles, where you have harsher winters as opposed to around the equator. But someone needs to check me on that because those statistics might have melted away with more careful analysis. I don't know. The other thing is that you'll nowadays hear a growing interest in populations for which a given disease is very rare. So one of the things that's circulating out there now that's related to the vaccine debate, and by the way, I'll myself go on record, I don't think there's any solid evidence that vaccines cause autism.

Dr. Sergiu Pașca:
And there's not. Epidemiologically, there's no evidence.

Andrew Huberman:
There's not. There's this open question as to whether or not vaccines of all kinds can increase inflammation, and there might be things downstream of inflammation. But for the record, right now there are no published papers that have not been retracted that support the vaccine-autism link. I think those papers are being reinvestigated under the new administration, but let's leave that aside for now. People will say, well, you have groups like Amish populations, where the incidence of autism is significantly lower. Turns out it does exist. I looked at these data, but it's significantly lower. And then people will say, well, it's the absence of food dyes, it's the absence of vaccines, perhaps, et cetera. But then as a genetic disease, we could say, well, there's a tendency for people in the Amish community to reproduce with other people in the Amish community, so it's a more restricted genetic pool.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
And so that could explain it as well. And I raise this not to create any additional arguments, there are enough out there-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... between people, but just because I think the correlative nature of all this is what kind of raises the opportunity for anything that's observed, like a fever, they get better.

Dr. Sergiu Pașca:
Sure.

Andrew Huberman:
But as you said, healthy kids without profound autism also talk more when they have a fever.

Dr. Sergiu Pașca:
Sure.

Andrew Huberman:
And so there's been so much made of autism and the various conditions that could create it.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
And I think it's been very confusing for the general public. Even as a trained scientist, it's been very confusing for me. I feel like every six months or so, every year, we have a new pet hypothesis.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
But except for these genetic data, nothing really is rock solid.

Dr. Sergiu Pașca:
Right. And then, of course, the other issue is also that these conditions are disorders of the human brain. So if you think about it, even talking about schizophrenia, hallucinations, or phenomena that are very difficult to study, and of course, we don't know this. We know that schizophrenia is present in almost every population that we know of, even isolated population at 1%. And again, it's a little bit easier because it's done in adults. I think in children, it's much more difficult. And in fact, many of the genes that were early on identified for autism were identified in these populations, in the Amish populations, for instance. There is a very classic example of a gene that is associated with severe epilepsy and autism that was identified there for the first time. It's present in other places as well. So, yeah, I think, of course, the complexity of the problem is that you also want to make sure that you don't just associate something, you also want to reverse it in a way. So you would want to do the other experiment where you change it and then it goes away. But you can never do that in the human brain. We can't just turn things on and off to see whether they're truly causal. And then, of course, human brain development also takes an incredibly long period of time. If anything, it seems that the human nervous system has done everything possible to slow down that process. We myelinate all the way to the third decade. Neurons are born and migrating through the nervous system into early postnatal years.

Andrew Huberman:
Wait, you're telling me that our neurons continue to get myelinated, which, of course, for those that don't know, is the building of the ensheathment that allows electrical signals to be passed down neurons more efficiently, until we're 30 years old?

Dr. Sergiu Pașca:
Yes. There's evidence that myelination, especially in the frontal areas of the brain, are continuing up to the third decade.

Andrew Huberman:
Our unfortunately now deceased former colleague, Ben Barris, he used to shout at people in lab meetings-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... when they'd say something he didn't like. He'd say, "What do you know? You're not even myelinated yet."

Dr. Sergiu Pașca:
Exactly.

Andrew Huberman:
So he was right.

Dr. Sergiu Pașca:
He was absolutely right.

Andrew Huberman:
Okay, so if you're in a disagreement with somebody younger than 30, and you happen to be older than 30, you can leverage the argument, what do you know? You're not even myelinated yet.

Dr. Sergiu Pașca:
Right.

Andrew Huberman:
Completely myelinated yet.

Dr. Sergiu Pașca:
Right.

Andrew Huberman:
All kidding aside, before we get into the incredible experiments that you're doing and the direction that you're taking to tackle these really hard diseases, I have to ask two questions. First, is the incidence of autism also increasing outside of the United States, or is this something unique to the United States and Northern Europe? I don't know why we always pair those two.

Dr. Sergiu Pașca:
Yes.

Andrew Huberman:
I should just be fair to the United States and Australia, or whatever. Or is there something going on in the United States in particular that autism is increasing faster here?

Dr. Sergiu Pașca:
Yeah, no. The prevalence for autism has been actually reported to be higher in other countries even before this. Some of the early reports many years ago show that in Korea, for instance, the prevalence was very high. Now that the studies are done, also in Scandinavian countries, it shows that it's probably around the same kind of rate, one in 30 to one in 40. So somewhere between.

Andrew Huberman:
Okay, so it can't be whatever is attached to United States specific conditions.

Dr. Sergiu Pașca:
Yeah, very unlikely.

Andrew Huberman:
Well, because you hear these arguments.

Dr. Sergiu Pașca:
Of course.

Andrew Huberman:
Oh, it's the glyphosates in the-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... the crops in the United States, and while I don't favor that argument, I do think we need to be cautious about what's in the food supply.

Dr. Sergiu Pașca:
Absolutely.

Andrew Huberman:
Those same people often will leverage the argument that, well, in Europe, they're not using these things. Well, if the incidence of autism is the same and rising-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... that sort of does away with at least the clean logic of that.

Dr. Sergiu Pașca:
And perhaps another argument which is very important to bring is that we find the same mutations. The same mutations, if we're talking, let's say, a mutation, a specific calcium channel, you'll find it in a patient in Denmark, as well as one in Africa or in, let's say, Australia. So I think some of these genetic mutations are sort of the same.

Andrew Huberman:
Yeah. Could we briefly talk about gene therapy and CRISPR? Just briefly.

Dr. Sergiu Pașca:
Sure.

Andrew Huberman:
Because I think in the context of a discussion about these neurologic diseases for which currently there aren't perfect cures, or even cures in many cases, gene therapy does hold some promise.

Dr. Sergiu Pașca:
Yeah, absolutely.

Andrew Huberman:
In simple terms that I and everyone else can understand, could you just explain what CRISPR allows physicians potentially to do?

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
In other words, can genes be fixed in adulthood? Do they have to be fixed in the embryo? Just give your thoughts generally about CRISPR and gene therapy, because I think most people have heard of it.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
But I think most people don't have an intuitive sense for how it works.

Dr. Sergiu Pașca:
So gene therapy is a rather broad term, and it covers many ways in which you can correct generally a gene or a genetic defect that we think it's causal. So on one extreme, for instance, you can 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 and deliver it to the patient.

Andrew Huberman:
An adult.

Dr. Sergiu Pașca:
In an adult or in a child, depending on the condition, with the idea is that the gene is not there, or there's not enough of it, so I'm just going to deliver more. That's one extreme.

Andrew Huberman:
Is it injected into the blood, or do you have to go into the specific cell type that's lacking the gene?

Dr. Sergiu Pașca:
Many of the studies were done for blood disorders, of course, because it was easier, so you would inject them. Of course, the other possibility is sometimes you don't want to put the gene, you want to put the protein already made. And that is the case for many conditions where an enzyme, so a protein that does some interesting chemical reactions that are essential to a cell is missing. So sometimes you just make that enzyme, and then you deliver that.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
It's not always working, but in some cases, it actually works really well. Now, the other thing that you can do is you can try to correct that defect directly. That means you need to operate at the DNA level. So somehow you need to get into every single cell that is affected, and correct that. And that's where CRISPR comes into play, where presumably you could at one point deliver the guides, so the tiny pieces of nucleic acid that tell you where to go on the DNA, and then an enzyme that will do the cutting and then the putting back, or various other versions of this that you would correct. Of course, there are challenges with that.

Andrew Huberman:
Yeah, where do you put it? So for sickle cell anemia, I know they've essentially reversed sickle cell anemia using CRISPR technology.

Dr. Sergiu Pașca:
Right.

Andrew Huberman:
That's in the blood, right?

Dr. Sergiu Pașca:
It's in the blood.

Andrew Huberman:
It's of the blood.

Dr. Sergiu Pașca:
Right.

Andrew Huberman:
But if, for instance, we know about a genetic defect of, let's say, we'll talk more about this soon, but a mutated calcium channel that disrupts heart function and brain function-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... and you come in with CRISPR, you know what gene is mutated. You have the healthy gene that potentially you can put back. Where do you put it?

Dr. Sergiu Pașca:
Right.

Andrew Huberman:
Do you inject it? Injecting into the heart is possible.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
Into the blood supply, obviously easier.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
Getting it directed to the bone marrow, but to the brain is hard.

Dr. Sergiu Pașca:
Yeah. Well, presumably you could inject into the brain as well, right? There are ways in which you can inject through either surgery or through an injection in the spinal canal, like intrathecally. So that's certainly one way in which we can do it. It is very challenging, though, because of course the brain has a lot of cell types. And very often the way you deliver this, like through a virus or through other modalities, there's only so much of that virus that you can actually put inside the nervous system. And the efficiency is not yet very high. So another way is to go one level down, so that gene will produce an RNA that will produce a protein. So perhaps we don't have to correct the DNA everywhere, but perhaps we can correct something that happens downstream. And that's been the strategy that we've been using primarily, just mostly because at this point, and probably in the future, it will be possible. Who knows, like in 10 years or maybe even earlier, we'll be able to deliver very effectively some of these genetic therapies using CRISPR.

Andrew Huberman:
Because certainly in non-human primate models, things like colorblindness-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... have been rescued by introducing a gene through a--

Dr. Sergiu Pașca:
Right.

Andrew Huberman:
When we talk about viruses, people often will think, "Oh goodness, why would I want to get injected with a virus?" But we should just mention there are things like adenoviruses, which cold viruses are adenoviruses-

Dr. Sergiu Pașca:
Yes

Andrew Huberman:
... that can be engineered so that they don't make you sick, but they can carry a cargo, like a gene you want to put into-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... a nervous system or body that lacks that gene. So when we say using viruses to deliver genes, it's of the benevolent type.

Dr. Sergiu Pașca:
Right.

Andrew Huberman:
Or at least benevolent motivation. We think that those adenoviruses can live in our body for a long time-

Dr. Sergiu Pașca:
Right

Andrew Huberman:
... without causing additional trouble.

Dr. Sergiu Pașca:
And they're very often modified to make sure that they don't cause disease.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
Of course, another limitation of that is that if the gene is really large, it simply won't fit in a virus.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
So for instance, that would be the case if you think about a calcium channel. A calcium channel is a gigantic gene. It would be very difficult to fit inside a virus. Then, of course, the other thing is with these viruses, very often, especially with the adenoviruses or AAVs, is that you have one shot, meaning that you have to inject once-

Andrew Huberman:
Mm-hmm

Dr. Sergiu Pașca:
... and hopefully it would work, because next time you may have an immune reaction, right? You'll produce antibodies, and so you won't be able to deliver again. So again, there are all kinds of challenges that people are working really hard to solve, and I have no doubt that in the next decade we'll see therapies or perhaps even cures for some of these conditions. Of course, and I think you were bringing this up, one of the challenges is when we do this.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
Because especially for disorders of the brain, neurodevelopmental disorders, so autism and other neurodevelopmental disorders, the question is always how early it is too late.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
How much damage has been done, and how much can I actually correct? And that's one of the things that we're only now starting to really explore as we're thinking about some of the first clinical trials in this space.

Andrew Huberman:
This might shock you a bit, but folks in the quote-unquote biohacking community, not me I know some that have gotten follistatin gene therapy-

Dr. Sergiu Pașca:
Mm

Andrew Huberman:
... as a body enhancement thing.

Dr. Sergiu Pașca:
Mm.

Andrew Huberman:
So they're leaving the country because you can't do it in the United States, and literally getting an injection of a follistatin gene therapy to have more muscle to improve that. I wouldn't do it personally. Also, I like working out, so I don't need a follistatin gene therapy. But it's interesting to note that people are doing this, and I'm raising this as a segue into a discussion about stem cells-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... because people around the world are getting injected with stem cells. In the United States, it's-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... still not allowed by FDA for most things. But I think gene therapy has started. It's certainly begun. But it's not the sort of thing that your physician offers up early.

Dr. Sergiu Pașca:
Right.

Andrew Huberman:
It's still very experimental for most things.

Dr. Sergiu Pașca:
And then for gene therapies, again, in the context of what you're mentioning, is some of these, again, they are irreversible.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
So once you put the gene in, and it goes into a cell, let's say through a lentivirus that will integrate, you can't take it out anymore. Right? That would be very difficult. It would get inactivated over time, but so that's why we have to be extra careful with some of these therapies and make sure that we don't do more harm, right? Which I guess is always what we try.

Andrew Huberman:
Absolutely. I'd like to take a quick break and acknowledge our sponsor, AG1. AG1 is a vitamin mineral probiotic drink that also includes prebiotics and adaptogens. As many of you know, I've been taking AG1 for more than 13 years now. I discovered it way back in 2012, long before I ever had a podcast, and I've been drinking it every day since. For the past 13 years, AG1 has been the same original flavor. They've updated the formulation, but the flavor has always remained the same. And now for the first time, AG1 is available in three new flavors, berry, citrus, and tropical. All the flavors include the highest quality ingredients in exactly the right doses to together provide support for your gut microbiome, support for your immune health, and support for better energy and more. So now you can find the flavor of AG1 that you like the most. While I've always loved the AG1 original flavor, especially when I mix it with water and a little bit of lemon or lime juice, that's how I've been doing it for basically 13 years, now I really enjoy the new berry flavor in particular. It tastes great, and I don't have to add any lemon or lime juice. I just mix it up with water. If you'd like to try AG1 and these new flavors, you can go to drinkag1.com/huberman to claim a special offer. Right now, AG1 is giving away an AG1 welcome kit that includes five free travel packs and a free bottle of vitamin D3 K2. Again, go to drinkag1.com/huberman to claim the special welcome kit of five free travel packs and a free bottle of vitamin D3 K2. Today's episode is also brought to us by BetterHelp. BetterHelp offers professional therapy with a licensed therapist carried out entirely online. I personally have been doing therapy for well over 35 years. I find it to be an extremely important component to overall health. In fact, I consider doing regular therapy just as important as getting regular exercise, including cardiovascular exercise and resistance training, which of course, I also do every week. There are essentially three things that make up great therapy. First of all, it provides the opportunity to have a really good rapport with somebody that you can really trust and talk to about essentially any issue that you want. Second of all, it can provide support in the form of emotional support or directed guidance, or of course, both. And third, expert therapy should provide you useful insights, insights that can help you improve in your work life, your relationships, and in your relationship with yourself. With BetterHelp, they make it very easy for you to find an expert therapist who you resonate with, and that can provide those three benefits that come from expert therapy. Interestingly, in a recent survey, 72% of BetterHelp members reported a reduction in negative symptoms as a result of their BetterHelp therapy sessions. If you'd like to try BetterHelp, you can go to betterhelp.com/huberman to get 10% off your first month. Again, that's betterhelp.com/huberman. Let's talk about stem cells, organoids, and assembloids, and you'll explain what those are. But let's wade into this through the way it happened chronologically.

Dr. Sergiu Pașca:
Sure.

Andrew Huberman:
Most people have heard of stem cells, cells that can become other things. When I was a postdoc, any laboratory that worked on human stem cells worked on human embryonic stem cells.

Dr. Sergiu Pașca:
Mm-hmm.

Andrew Huberman:
Literally, cells that were-

Dr. Sergiu Pașca:
Mm-hmm

Andrew Huberman:
... collected from aborted fetuses, and given for medical study. There was an incredible discovery, which you'll tell us about, which basically made that technology obsolete and also allowed scientists to bypass a lot of the ethical considerations.

Dr. Sergiu Pașca:
Mm-hmm.

Andrew Huberman:
Serious ethical considerations.

Dr. Sergiu Pașca:
Mm-hmm.

Andrew Huberman:
Regardless of where you sit on that debate, you're using the tissue from a human embryo to study things. You could say some people will support that, some people won't, but then a new technology comes along-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... and basically makes that technology obsolete, allowing you and others to do the work on stem cells and assembloids and so forth without having to take cells from human embryos, which is spectacular. So could you please tell us about that discovery of the stem cell technology that really changed the entire game-

Dr. Sergiu Pașca:
Mm-hmm

Andrew Huberman:
... and did away with this serious ethical battle, let's call it what it was.

Dr. Sergiu Pașca:
Sure. Let's start first with stem cells and what they are because I think it's also important to define them. So stem cells are cells that have two properties. First of all, they in principle can become other cells, and if they are of the most potent type, they will be totipotent, so they can make everything. If they're pluripotent, they can make almost everything. And then of course there are lower levels of potency for the cells. So we all carry stem cells in us. Not in the brain, or fewer in the brain for sure, but in the liver and in other organs like in the gut, as we renew the gut every few weeks, that is done primarily through the stem cells. But those are restricted. They can't make everything. They can make mostly that specialized cell type for which they have been sort of primed. Now the earliest of stem cells, like those pluripotent that are very important, those are present at early stages of development of the embryo. And of course, that happens post-conception, so the challenge has been that you have to remove them from a fertilized egg, and if life starts at conception, then of course you're interfering. So I think a lot of the ethical debates have started because of that. But in the early days, even if you were to do that, you wouldn't be able to keep those cells. It turns out that the cells are very difficult to maintain. And this brings us actually to the second property of the cells, which is that in principle, they can be maintained forever. If you provide the right conditions, they will divide and stay the same forever. Those are the two properties. So you can keep them forever. You can freeze them down, put them in liquid nitrogen, bring them out any time, and they'll start exactly where they left. And then with the right guidance, they can become other cell types. So only around 1998, that was when we could actually maintain some of the cells in a dish. So somebody figured out a soup of chemicals that you can add, and the cells will survive. Because up to that point, it was not possible. So that triggered, of course, the promise of this field, that now we'd be able to take those cells and derive various organs. Perhaps transplant them, replace organs. Of course, that ended up being much more complicated, and of course, there were all these ethical debates related to the source of those cells and what does it actually mean to use these embryonic stem cells. And yet, we've learned a lot about those cells in early days. What are the properties of those cells? And then almost 20 years ago, Shinya Yamanaka, who's a scientist in Japan and at UCSF, came up with an absolutely brilliant idea. We always thought that the development of the human or of any, it's a one-way street. Once you go down development, you never come back. So once you start making a stem cell that is more restricted, and then at the end you make, let's say, a liver cell, you can never go back and become that pluripotent stem cell again. And that generally is thought to be useful to protect us from cancer or any other, so we don't have parts of our hands differentiating into something else. And he thought that maybe you could do that, not in a natural way, in an artificial way, and that, of course, would be very useful. So what he did is he went and he looked at the genes that are expressed in pluripotent stem cells at very high levels. So very high levels. And almost as gene therapy, because we were talking about gene therapy, he took the top couple of dozens of these genes and then started adding them inside skin cells. So he took skin cells initially from mice and then from human, and then started adding them one by one, two by two, three by three, four by four, five by five, six by six, to see whether any of those cells, once they have this combination of genes that are expressed in pluripotent stem cells, would somehow get confused and think that they're actually a pluripotent stem cell, and then go back in time and actually become a pluripotent stem cells. And he showed indeed that a combination of four is enough. Of course, you can have six. And that ended up being what we today call the Yamanaka factor. In a way, it was almost like alchemy, where you sort of transform something into something else. You make out of this metal, you make gold. It was pretty much like that. It was like the essence of alchemy. And it turns out that that discovery was so profound because suddenly you could take a skin cell from anybody and put those genetic factors in, turn those cells into pluripotent stem cells that we'd later on learn they're almost identical to those embryonic stem cells, and now have those cells from any of us and use them for various purposes, perhaps for, let's say, making blood cells in the future or perhaps to model something outside of the body. And I was finishing my clinical training around that time, and I remember even seeing that paper. And of course, in my naivete at that time, I thought, "Wow, this is it. This is going to be the entry point for studying human neuroscience." I was doing experiments at that time studying actually the cortex and recording from animals electrical activity of those neurons, and always thought this disconnect between what I was seeing in the clinic, which were these patients with severe profound autism, and then recordings from the brain and thinking, we're never going to be able to do that. How are we going to understand this complex disorder of the brain if we cannot even listen to the activity of those cells live? And then suddenly, seeing that discovery, again naive at that time, thought, well, that could be perhaps the way in which we could make neurons from any patient. And so very soon after I came to Stanford, which I guess where we met, with sort of this idea in mind that we will be able to make neurons from these patients and rebuild maybe some of the cells or some of the circuits of the brain outside of the body without doing any harm, because we're not doing a biopsy of the brain or anything invasive, just essentially creating a replica of some of those cells outside of the body, and then finally study them at will in a dish and do all kind of experiments where you remove things and add things and perhaps one day even develop therapeutics. And here we are 16 years later, since that process really started. It took a long time, but now for the first time, we've gotten such a good understanding of some of these conditions, and one of them in particular, that actually a therapeutic is in sight, and we're preparing for the first clinical trial that is really arising exclusively through studies done with these human stem cell models, without actually using any animal models, just essentially creating, recreating cells and circuits outside of the brain of those patients.

Andrew Huberman:
It's amazing because it allows you to study human cells, which has immense benefit. They're essentially limitless in number-

Dr. Sergiu Pașca:
Yes

Andrew Huberman:
... because all you need is one fibroblast-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... one skin cell-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... or some cell that you can provide these Yamanaka factors to and essentially grow other cells. And we'll talk about what those cells that you create are capable of becoming, not just cells, but circuits-

Dr. Sergiu Pașca:
Yes

Andrew Huberman:
... in a few moments. But I know it's going to be in the back of people's minds, and it's certainly in the back of my mind, this idea that when one has a baby, that you should keep the umbilical cord because the umbilical cord-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... contains stem cells. Usually, I think the umbilical cord is discarded.

Dr. Sergiu Pașca:
Mm-hmm.

Andrew Huberman:
Maybe some people keep it, I don't know. What is the current thinking on stem cells that reside in the umbilical cord? People pay a lot of money to freeze those, and most people don't have a minus 80 freezer-

Dr. Sergiu Pașca:
Right

Andrew Huberman:
... around, so they pay to do that. What is the potential for umbilical stem cells in the future? Is it something that parents, I don't want to say should invest in, but if they have the disposable income, that they would be wise to do that?

Dr. Sergiu Pașca:
So those cells that are collected from the umbilical cord are stem cells, but they're already quite restricted in what they can make.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
So their applications are also restricted, mostly to blood disorders. So I think it's important to keep in mind that they're not sort like a universal solution to anything that would ever involve pluripotent stem cells in the future or stem cell therapies in the future. So again, I think it's important to know that while they have certain applications, and there have been quite clear cases where the availability of those cells were useful in a blood disorder in that child later on, they're certainly not They have these universal uses as maybe sometimes they're being advertised.

Andrew Huberman:
When we hear about people typically leaving the US to get quote unquote stem cell injections-

Dr. Sergiu Pașca:
Yes

Andrew Huberman:
... where are those stem cells coming from? Are they coming from those patients? And I should mention that there was a clinic down in Florida that was offering stem cell injections into the eye for people with-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... macular degeneration, and that clinic was shut down, and all stem cell injections in the United States, to my knowledge all, were shut down because those patients, not only did it fail to rescue their vision, it actually made them go blind very quickly.

Dr. Sergiu Pașca:
Right.

Andrew Huberman:
So the FDA shut down commercial stem cell injections. I think there's still places where they do a kind of workaround.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
And it's worth mentioning that PRP, platelet-rich plasma, is FDA-approved. It does not contain many, if any, stem cells, despite what you might read. But what are your thoughts on when people go down to Colombia, it seems like they go down to Colombia-

Dr. Sergiu Pașca:
Oh, yeah

Andrew Huberman:
... or elsewhere, or Mexico, to get stem cell injections, assuming the conditions are clean?

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
And I say that because I know of at least one patient who was paralyzed from an injection of stem cells into their spinal disc.

Dr. Sergiu Pașca:
Mm-hmm.

Andrew Huberman:
Paralyzed, almost died.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
Fortunately, is doing better now, and it was because it went septic, it got infected.

Dr. Sergiu Pașca:
Well, that's one of the problems, is very often we don't even know what is being injected.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
I think that is a very important aspect. We don't know what is in-- Sometimes are the cells from the patient are being collected.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
Sometimes some of these umbilical cells, sometimes we don't even know what cells are being injected.

Andrew Huberman:
Like it could be cells from somebody else or-

Dr. Sergiu Pașca:
Yeah. They're incredibly risky procedures. Of course, they've never really been observed. There have been very few of any clinical trials trying to really address it in a very systematic way. And very often that's also because they're not really justified. So in the context of autism, this is very often done, and it's done not just in South America, sometimes there are places in Europe where you can get an injection of some stem cells for autism.

Andrew Huberman:
Wait, parents are taking their kids to these clinics and getting them injected with stem cells-

Dr. Sergiu Pașca:
Yeah. They're getting-

Andrew Huberman:
... that come from some other patient.

Dr. Sergiu Pașca:
Some cells that are collected either from the patient. It depends a little bit on where it's done and how it's actually done.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
But again, even from a biological point of view, what are those stem cells presumably doing, let's say, in autism? We don't think that there is a cell type that is missing in the brain, so it's not like those cells can go. And I think as I was mentioning before, most of the cells already are restricted in their potential. They can no longer make any cell types. So, the idea that you take these pluripotent stem cells, and you just inject them, let's say, in the knee, and it will miraculously grow cartilage, it's very often not really the case because those cells are not even capable of making cartilage. So I think there's very often a lack of understanding of what these therapies really are, and then of course, there is sadly a lack of understanding of what is actually being injected. So, for autism, this is unfortunately happening much more often than you would think.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
So I very often get parents or families that are asking me desperately, "We've exhausted all resources. We don't know what else to do. We've tried behavioral therapy, we've tried these therapies. Nothing works, and everybody's recommended that we should just go now to South America and do this injection. Should we do it or not?" Right. Then, of course, my answer is always no, because again, there's no reason that that would work. Some parents come back and of course, they report an improvement, which is generally temporary to the extent that we know. Of course, it's never really been studied in a very systematic way. Partly, of course, there is a very strong placebo effect, especially in parents by proxy when you have a child who's very sick. Those placebo effects are very, very strong. These parents really want those kids to improve, and so they will see things that are improving. Plus, those are still developing kids, so week by week, they may acquire new milestones. And then the other thing, which of course could be part of this, is that there is an inflammatory effect very often. And so that's almost like the fever in a way, right? It would increase perhaps some of the cytokines, will create a fever, perhaps that is associated. We don't really know, but certainly there are dangers associated with procedures like this that lack the rationale, first of all, and then of course, then they lack any regulatory framework.

Andrew Huberman:
Yeah, I think the concern is very real for stem cell injections into all tissues, but when it comes to eyes or brain, and of course eyes are brain-

Dr. Sergiu Pașca:
Yes

Andrew Huberman:
... that's where I just take a big deep breath and hold it and wide-eyed like, "Oh my goodness, no," because we don't get new neurons.

Dr. Sergiu Pașca:
Right.

Andrew Huberman:
You lose neurons, they're gone. We get a few in the olfactory bulb, in the dentate gyrus of the hippocampus, a few. But once they're gone, that's it.

Dr. Sergiu Pașca:
Right.

Andrew Huberman:
And injecting something into the brain, the probability of tumor growth is incredibly high.

Dr. Sergiu Pașca:
Absolutely, and especially when it is in the brain where there's not enough space, right? So we know that anything that grows in the cranial cavity will actually push down vital centers. So there are certainly risks associated with that.

Andrew Huberman:
Mm-hmm. So let's talk about the other approach, which is the one that you've been embarking on. I'll never forget when we were postdocs. Folks, we were postdocs in the same room. It was D222.

Dr. Sergiu Pașca:
Yes.

Andrew Huberman:
We had a lot of pride in that room, where you had benches on opposite sides of the room, and we sort of took over that room as an empty room. You probably couldn't do this anymore, but it was like, "There's an empty room. Let's bring some microscopes in there." We just started doing experiments there. And I'll never forget when you started building organoids. You started building nervous systems in a dish and how excited you were.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
And it's been remarkable to see your arc from that, and it's not lost on me that you were working extremely hard then- ... and continue to, to become really one of the luminaries of this field. Tell us what organoids are, tell us why they're useful, and what they're telling us already about how the brain develops and their therapeutic potential.

Dr. Sergiu Pașca:
Yeah. So let's start from the beginning. So around 15, 16 years ago, we were able for the first time to get some of the cells that are now known as induced pluripotent stem cells.

Andrew Huberman:
These are the Yamanaka?

Dr. Sergiu Pașca:
Yes, or iPS cells.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
So induced because they've been induced to become pluripotent in an artificial way. But again, they stay like that, so you can share them with anybody else afterwards. So we got some of those first cells in those early days, and now the question was, how do we make neurons? And what you do is you really leverage everything that is known in developmental biology. So we already know that there are certain molecules that are very important for making neurons. So all you do is you put those cells in a dish, in a plastic dish, in a Petri dish, and then you start almost like when you cook, you start adding various molecules on top, and you see what happens. And we knew that it's actually quite easy to make neurons. That was already known. There have been a lot of experiments done the decade before that showed that even if you just remove some of the factors that maintain those cells pluripotent, those pluripotent stem cell will start now to differentiate, and they like to become neural cells.

Andrew Huberman:
By default.

Dr. Sergiu Pașca:
Almost by default. So it's actually not that difficult to make neurons. So in those early days, you would take those cells, play them nicely, those pluripotent stem cells in a dish, and then remove some of these factors, and then within a few days you will see that they'll change shape, and within a few weeks, some of them will really look like neurons. And when you look at them, you can even look at proteins that only neurons will have. You can actually get an electrode inside a cell and listen to the electrical activity. So it was very exciting, as maybe you remember in those days. This burst in curiosity is always sort of the ATP of the life in the lab, so to speak.

Andrew Huberman:
It is.

Dr. Sergiu Pașca:
Right? You just want to wake up and want to go see what happened to those cells. And it was clear in those days that we would be able to make those cells, but would we actually see any abnormalities in those cells, I think was the question. How would you know if you derive cells from a patient with autism, how would you know that you found anything abnormal? I think that was the question. We didn't even know what would be abnormal in the brain. And so that's when we decided actually to focus on something that would be relatively predictable. And that was this mutation in a calcium channel, which was discovered just a few years before in very few patients that had essentially one single letter in their entire genome changed in a gene that makes a protein known as a calcium channel, sits in excitable cells, meaning cardiac cells and brain cells. And every time a cell receives electrical input, this protein opens up and lets calcium go inside the cell. And that's very important because it couples electrical activity of the network with chemical activity inside the cells. And what we knew about that mutation at that point, that it's pretty much all we knew in those early days, is that it probably allows the channel to stay open slightly longer, just a little bit longer, so more calcium would go inside the cells. Of course, there will be no way to know because you can't get a neuron or a cardiac cell from those patients to actually test it. So what we did is essentially, we recruited some of these patients, we flew them to Stanford, then we got a tiny skin biopsy, made these iPS cells. This takes months. This takes already four or five months. And then we took those cells in a dish, started deriving neurons, and after about five, six, seven weeks, then we put them under a microscope, and we started looking at the calcium. You can measure calcium inside cells through a microscope and just literally look at it. And I'll never forget that day when we did that experiment, was looking down the microscope, and we essentially stimulated the neurons, and you could just see how control cells will go calcium goes inside the cells, and then it goes out. And then in patients that had Timothy syndrome, so in Timothy syndrome-derived neurons, you could see how the calcium will go and then it will stay longer. It takes longer to go out. So it's the first defect that we saw in patient-derived neurons that were actually not coming from a biopsy. They were not coming. So that was incredibly exciting, as you can imagine. But it was still relatively simplistic, just a few neurons at a bottom of a dish. And of course, for me, what was particularly frustrating was that we couldn't go very far in development. So think about the cerebral cortex, the outer layer of the brain that presumably makes us human. It has multiple layers, a large diversity of neurons. It takes 27 weeks to make all those cells in the cortex, 27 weeks to make all those neurons, and we're not even talking about glial cells, the supporting cells that are coming much later for several years afterwards. But just making those cells takes about 27 weeks. And it turns out, something that we discovered through experiments done in a dish, is that the timing of the development of those cells, it's actually recapitulated in a dish as well. So if you keep the cells in a dish, they'll actually essentially develop at the same pace. They're not much faster, and it's very difficult to keep neurons in a dish for 27 weeks to get all the neurons. Essentially, they peel off every time you start to move them to another plate, and at one point they just die. And so then we thought, how about never letting them just sit down on a surface? How about just essentially aggregating them as balls of cells and then letting those float? And in those early days, there was this amazing scientist from Japan, Yoshiki Sasai, who started doing really beautiful experiments where he was already moving some of these studies that he was doing of development in 3D cultures, where he show you can make an optic cup, a part of the eye. And so it was clear, it was in the air, this revolution of actually moving cells from 2D flat cultures to 3D self-organizing. And that actually unleashed amazing new properties of the cells. So essentially, all we did in those days is I ordered from Germany these plates that were counterintuitively coated, so the cells never stick. Right? Every time we keep cells in a dish, you want them to stick. That's the major problem. So they were actually coated, so the cells will never stick. And then there were these balls of cells, they were floating there. And of course, I remember talking in the lab, and everybody was like, "Oh, they're not going to survive. It's going to be a couple of weeks and they're going to..." And then a week passed, and two week passed, and then they kept growing and growing. And of course, the enthusiasm of every day to see, are they still alive? Right? And then we discovered that we can keep them for months. And these three-dimensional cultures are now known as organoids, which is perhaps not the most fortunate name because it suggests that it's organ-like, and of course, they're not an entire organ. So they're not a representation of the entire brain. But that's the term that we refer these days to anything that is three-dimensional and organizing in some way. And so we started keeping these cultures, and then at one point, actually, we discovered that we can pretty much keep them indefinitely. My lab maintained the longest cultures that have ever been reported, literally going for years, for two, three years in a dish. And at one point, in those early days when, actually, I was running out of funds in the lab, and I came one day in lab meeting really determined for us to actually cut cost. And so I've told everybody, "Go into your incubators, because we're spending so much money in feeding the cells, and everybody throws out 20% of your cultures." And then people started saying, "So should I throw the ones that are 500 days old?" And somebody else like, "The ones that are 800 days old?" Then I said, "What? You guys are keeping them for such a long..." "Yeah, they just keep growing. They're in the incubator." So then we actually did the first study, and then we had a series of three studies done over the years of trying to ask, how far do they go in development? So if you have a clump of human neurons that you've made from pluripotent stem cells, and you keep feeding them in a dish, how far do they go in development? Do they move much faster? Do they move much slower? Are they stuck at one point in development? And it turns out that they actually keep track of development beautifully. To such an extent that, for instance, we discover when they reach nine months of keeping them in a dish, so about the time of birth, they literally switch to a postnatal signature- Really? ... on their own. In a dish? In a dish. So there's this classic example in developmental neurobiology. There's this protein that usually changes around the time of birth. It's an NMDA receptor. So maybe some people know about NMDA receptors. They're binding glutamate. They're very important. But they change a lot during development. They're made out of different units, and the units change. And it was very well-known that during early development, so prenatal, before birth, you primarily have 2B subunits. And then after birth, they're primarily 2A. So if you look in brain development, you just see how essentially 2B goes up and then it goes down, and 2A goes up, and when you look, they meet around birth. So very often, people thought that it's birth itself that triggers that switch. That canonical, it's called a canonical switch because we all thought that it was so classic. And then you take an organoid that you maintain in the dish for 600 days. And of course, we're not inducing birth. We're not changing media. We're not doing anything special. Yeah, no hormones from mom. No hormones changes. Yeah. We keep exactly the same media, which is certainly a very simplistic kind of soup of chemicals, but we don't change it. And then you just look at these two subunits, and you see how 2B goes down and 2A goes up, and they pretty much meet that nine months of keeping them in a dish. It's amazing. So that tells us that there's some sort of intrinsic clock. Once you start a development, the cells measure really, really well the time of development. That does not mean that all aspects of development are going to now be recapitulated in a dish. But it tells us that there is this incredible ability of cells, especially in the nervous system, because, of course, those cells will keep for the rest of our lives. We're never going to renew neurons. It's going to be different for liver cells or gut cell. But for neurons, probably in particular, they'll need to keep track of time really, really well. So that was the first discovery that we've sort of made, which is still stunning today. We still don't know the mechanism. We're still working really hard on figuring out exactly how the cells are keeping track of time. Because as you can imagine, if we understand what that molecular machinery is, we used to call it a clock, we now call it a timer. We think it's more of a timer than an actual clock. But understanding what the molecular biology of that is will allow us actually to play with that clock. Right? So if you want to make neurons that are 70 years old neuron from a patient with Parkinson, I don't have to wait 70 years in a dish. Could I make it in a few weeks? Or perhaps could I take an aging neuron and somehow rejuvenate it by playing with that timer? But just to make it clear, we still don't know. We have some clues about what it may be, but I think it's still early days. And I think that was one of the first things that these cultures allowed us to do. Just watch development, human brain development, outside of the human body In a dish and actually witness that some fundamental aspects of brain development are actually recapitulated even outside of the uterus and, of course, of the brain. So that was the first. And then, of course, I guess I'm a developmental neurobiologist by training, and I've done a lot of circuit work in early days. Of course, an obsession of mine was that especially for conditions as complex as autism and schizophrenia, we need to recapitulate some of the circuit properties of the brain. So we now know that probably both for schizophrenia and for autism, it is very unlikely based on the evidence that we have so far, that there are cells really missing from the brain. We thought for a while that maybe some cells are missing or maybe other cells are in excess, but now the studies that have been done, especially with single-cell profiling of brains of patients that have already died, showed us that the composition of the brain, of the cortex in particular, it's very similar. So it's unlikely that the cells are missing, but likely the way they're connected with each other is what makes a difference. And of course, in the beginning, we were just making this clump of cells. They were all for the cortex, but they were not connected to anything else. So then came the idea of assembloids. Because most of the cells in the brain connect with cells across the nervous system, and in fact, even more interestingly, cells do not reside in the place in which they're born in the nervous system. We have the largest cell diversity of any other organ, almost 2,000 cell types. By the end of the first trimester, there are about 600 cell types in the human brain. Think about the liver, right? Maybe a couple of dozens. The brain has to make hundreds of times more. So how do you do that? The only way is to actually make the cell types in different parts of the brain, provide local cues there, and then once the cells have been specified, let them move and find their final position. So the first assembloid that we've actually made were of a very stereotypical canonical movement of cells in the nervous system, which has to do, again, with the cortex. So the cortex, again, the outer layer of the brain, has both excitatory and inhibitory neurons. It turns out that most inhibitory neurons are not born in the cortex, but they're born deep in the brain. So essentially, all we did is we made two brain regions, the ones that have excitatory neurons and the one that has inhibitory neurons, and the plan was to put them together, hoping that at one point, the cells will know what to do. And in fact, that was one of the first projects in my lab, planning that. I remember giving to one of the students this very difficult task of figuring out how we're going to fuse these two cultures, and they're about three millimeters in size, so you can see them by eye. And I thought it's going to be very difficult to put them together. So the student worked for months trying to figure out biological glues, using various electrodes and impaling them and everything else until somebody else came one day and said, "It's very simple. You just put them at the bottom of a tiny Eppendorf tube," which is the tiniest of tubes that you get. You put them there overnight, and the next day, they're completely fused. But they're not just fused because now if you look inside, within a few days, the cells that are supposed to move start to actually point out towards the cortex. They literally smell the chemicals from the cortex, and they start to move in this very stereotypical way towards the cortex. And so that was the first assembloid, made around 2015, and I still remember it was Ben, actually. Ben was so excited. Ben Barres was so excited about seeing the cells. He wanted to look at these movies every day. And then he said, I still have this email from him, where he was very preoccupied that he kept saying, "This new preparation is not an organoid. It's not a steroid. It's something else. You have to find another name."

Andrew Huberman:
He loved naming things.

Dr. Sergiu Pașca:
He loved naming things.

Andrew Huberman:
Yeah. And he understood the importance of naming things, not just for career reasons, although he understood a lot about how to build a career-

Dr. Sergiu Pașca:
Yeah, perhaps

Andrew Huberman:
... but because naming Yamanaka factors made sense-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... to name it after Yamanaka. He got a Nobel, and is immortalized that way, like stem cells, immortalized.

Dr. Sergiu Pașca:
Yes.

Andrew Huberman:
But I think the naming is essential because otherwise, things can get lost in the technical details.

Dr. Sergiu Pașca:
Yes.

Andrew Huberman:
So who came up with the name assembloid?

Dr. Sergiu Pașca:
So he kept insisting that I should find a name. So I made this long list I still have in my notebook. I had a long list of about 20, and I would keep sending Ben one, and Ben was always awake, like 24 hours.

Andrew Huberman:
Yeah, he didn't sleep much.

Dr. Sergiu Pașca:
He never slept.

Andrew Huberman:
No.

Dr. Sergiu Pașca:
So I remember after sending many emails going back and forth, and he was just like, "No, bad name. I don't like it." And then at one point, I thought, well, -oid because it's like, and then assemble because we assemble the circuits. So I thought assembloid, and I send this, and he says, "Perfect, I love it."

Andrew Huberman:
So you named assembloids.

Dr. Sergiu Pașca:
I named assembloids-

Andrew Huberman:
Mm-hmm

Dr. Sergiu Pașca:
... and Ben sort of blessed it one night at 3:00 a.m. And so that was the first assembloid. And the first assembloid was for cells migrating. But then the question was, cells have to find each other and form circuits. And so within a couple of years, we started making assembloids that will have axons, so the long projections of neurons finding other partners. And you know how-- I forgot who said this. Must have been Rodolfo Llinás or who said that the brain is sort of the next evolutionary step towards movement.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
So the nervous system has been this theory that has evolved as a way of moving around.

Andrew Huberman:
That was Sherrington.

Dr. Sergiu Pașca:
Was it Sherrington?

Andrew Huberman:
The final common path is movement. He was a physiologist. He was kind of vague in his statement, but I think-

Dr. Sergiu Pașca:
Perhaps that was

Andrew Huberman:
... that it was Sherrington. And I don't doubt that Rodolfo said something about it, too. I'm not going to try and take anything away from Rodolfo. Anyone that knows who Rodolfo Llinás is, he's not somebody you want to piss off.

Dr. Sergiu Pașca:
Well, we should check it, who actually said it.

Andrew Huberman:
No, give him credit.

Dr. Sergiu Pașca:
But-

Andrew Huberman:
I like Rodolfo

Dr. Sergiu Pașca:
... but for us, that became the next objective. Can we actually build a circuit That will have a very clear output. So we would know that we've actually built that circuit. So what we did is essentially, we thought about like the simplest circuit for movement, which is like the corticospinal tract. Okay, so that means that a neuron in deep layers of the cortex sends along axons all the way to the spinal cord, finds a motor neuron, makes a connection, then the motor neuron leaves the spinal cord, goes to the muscle. And essentially, you only have these two neurons, right? That are connecting with each other, with the muscle, two connections, one between the two of them and one with the muscle. So the simplest of circuits that you can have.

Andrew Huberman:
Now lets me move my big toe.

Dr. Sergiu Pașca:
Right. Exactly.

Andrew Huberman:
It's pretty long distance, if you think about it.

Dr. Sergiu Pașca:
It's a very simple, and of course, like in other species, a little bit more complicated. It turns out that in mice, there's an additional neuron there. So there are some changes that happened over evolution. But for us and in primates, it's as simple as this. So what we did was we essentially made an organoid that resembles the cortex and has some of those neurons, and then we made an organoid that resembles the spinal cord and has some motor neurons in it, and then we made a ball of human muscle that you can make from a biopsy. You can literally biopsy a muscle, you get the myoblast, you grow them, and you get a nice ball of muscle. And then, of course, the challenge was that the reality is that we don't know how those cells find each other. Like in development, we know some of the molecular cues that they use, but we're far from having a comprehensive understanding of how they find each other. And I remember we were sitting down in the lab and kind of like thinking, I resisted actually doing this as the first assembloid in the lab for a while because the probability was against us. Like those cells in the cortical organoid that are less than 5%, the motor neurons are less than 10%. The probability that they find each other perfectly and in enough numbers to trigger muscle contraction was close to zero. And yet you do it, you put the three parts together, you let them assemble, and within a few weeks, you can actually now stimulate the cortex with whatever you want to use, with an electrode, with light, and then the muscle starts to contract. And in fact, the more you do it, the more reliable the process is. And then, of course, we went on, so like reverse engineering it, and figure out that indeed the cells have connected in that precise way. So I think what we started actually to realize was that, of course, a lot of stem cell biology was-- I think a lot of biology was based on chemical and physical factors that we were leveraging, but we've never truly leveraged this next level of law or power in biology, which is self-organization, the ability of a biological system of build it itself. If you think about it, the human brain builds itself. Of course, there are instructions, but there's no blueprint. There's no plan that the brain constantly looks to make sure that it actually made all the connections properly, right? Instructions are sort of revealed at every step for the next step. And it mostly comes from the cells finding each other. So I think what we also started to learn from this was that all we need to do is make the parts. And if we make the parts right, then the parts will come with the instructions, and then the circuits will assemble on their own. And so that has been really the beginning of it. And of course, it became progressively more difficult to build circuits. 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? So actually, we just published a few months ago, the first four-part assembloid, that actually now reconstitutes the pathway that processes sensory information in the nervous system. So you think about the cortex, sends out to control movement and has an output, but it receives information from the outside constantly. And that happens through neurons that sit close to the spinal cord, have projections in the skin where they sense tactile vibrations or pain stimuli, send that information to the spinal cord, from the spinal cord they cross, they go up to the thalamus in the middle of the brain, and from the thalamus, they go to the cortex. So this is a four-part pathway. So it took us years, first of all, to make the parts, and then to put them together. And then again, the beautiful thing about it is that while we still don't know all the rules of assembly, you can make this four-part, we call it the sensory assembloid or a somatosensory assembloid. Because it turns out that the sensory neurons that we can make are mostly sensory neurons that sense pain stimuli. And so you can actually put the four parts together, so the sensory, the spinal cord, the thalamus, and the cortex, and you have to put them in that order. If you change the order, the cells will not find each other. So you just have to create the minimal conditions for them, making the right cell types, putting them in the right order, and then they'll find each other. And within a few weeks-- So it takes hundreds of days to build a circuit like this. But the beauty of it is that suddenly you look at it, and you just see spontaneous activity that arises in the entire pathway, just starts to flicker all in sync.

Andrew Huberman:
Can you use this assembloid to study the effects of different pain medications?

Dr. Sergiu Pașca:
Yes. So that is certainly one potential. The other thing that you can do, and the first application that we've had was for genetic forms of pain conditions. So we very often think that genetic conditions where you have a very clear cause, so like entry points, like Rosetta Stones for understanding anything. So there are these interesting mutations in a sodium channel, so another channel. But the sodium channel turns out that if the channel is overactive because of a mutation, you'll have excessive pain. So these patients are highly sensitive. But then if the channel is essentially unable to function, then these patients have loss of pain. And that's equally bad. Many of these patients actually will die because they can't sense pain at all.

Andrew Huberman:
Yeah, I think people don't realize that in mutations where people can't sense pain, people fail to make the postural adjustments-

Dr. Sergiu Pașca:
Exactly

Andrew Huberman:
... that allow you to stay alive, or because they, unfortunately, they can be resting a little bit too much on their right leg. We normally think, "Okay, no big deal," but-

Dr. Sergiu Pașca:
Right

Andrew Huberman:
... you're constantly making these postural adjustments. If you don't do that, you actually can damage-

Dr. Sergiu Pașca:
Right

Andrew Huberman:
The legs that you're pushing down too hard on. Seems like a trivial amount of weight, right, to your own body weight.

Dr. Sergiu Pașca:
Right.

Andrew Huberman:
But we fail to recognize just how often we're redistributing our-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... our position.

Dr. Sergiu Pașca:
No, no, no. And it's absolutely true. Like feedback in general is very important, including through this painful stimuli, through all stimuli in general. And it turns out that if you now make essentially a four-part assembloid that carries the mutation that causes excessive pain, now the sensor neurons are excessively active, so they keep bursting with activity throughout. And then we thought we're going to take it out, and of course, in these patients, they can fire. It turns out that it's not true, that they can fire. For some reason, there are probably other channels that are helping them compensate, but they fail to engage the rest of the pathway in a synchronized way.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
So that's why we need the four parts, and I think that's why assembloids generally are going to be very useful because there are emergent properties that are arising from the interactions of the cells at distance in the brain, and likely many disorders, and of course, we're very far from understanding complex disorders such as autism. But certainly, these fault interactions at a distance in the circuits are probably going to be key to understanding the biology of these conditions and hopefully at one point, reversing them.

Andrew Huberman:
I'd like to take a quick break and acknowledge one of our sponsors, Function. Last year, I became a Function member after searching for the most comprehensive approach to lab testing. Function provides over 100 advanced lab tests that give you a key snapshot of your entire bodily health. This snapshot offers you with insights on your heart health, hormone health, immune functioning, nutrient levels, and much more. They've also recently added tests for toxins such as BPA exposure from harmful plastics and tests for PFAS or forever chemicals. Function not only provides testing of over 100 biomarkers key to your physical and mental health, but it also analyzes these results and provides insights from top doctors who are expert in the relevant areas. For example, in one of my first tests with Function, I learned that I had elevated levels of mercury in my blood. Function not only helped me detect that, but offered insights into how best to reduce my mercury levels, which included limiting my tuna consumption, I'd been eating a lot of tuna, while also making an effort to eat more leafy greens and supplementing with NAC, N-acetylcysteine, both of which can support glutathione production and detoxification. And I should say, by taking a second Function test, that approach worked. Comprehensive blood testing is vitally important. There are so many things related to your mental and physical health that can only be detected in a blood test. The problem is blood testing has always been very expensive and complicated. In contrast, I've been super impressed by Function's simplicity and at the level of cost. It is very affordable. As a consequence, I decided to join their scientific advisory board, and I'm thrilled that they're sponsoring the podcast. If you'd like to try Function, you can go to functionhealth.com/huberman. Function currently has a wait list of over 250,000 people, but they're offering early access to Huberman podcast listeners. Again, that's functionhealth.com/huberman to get early access to Function. So I want to discuss an ethical consideration/concern, but before we do that, I want to take a step back and just have you reflect. I will never forget the first time I learned neural development, like sperm meets egg, and then you get cell duplications, and then the embryo figures out what's going to become muscle, what's going to become nervous system, and it's a humbling thing-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... to be able to realize that we understand even a small bit of that.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
And very little was known until the sort of early parts of the last century really is where some of the defining tissues and interactions were first discovered, so it was a relatively young science.

Dr. Sergiu Pașca:
Mm-hmm.

Andrew Huberman:
Nowadays, I'm even more humbled by it because one only has to see a child that-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... nine months ago didn't exist, and you really start-- Most people understand how babies are made, and yet it's staggering, and I think what's so staggering about it, what's so miraculous, it's a miracle, is the self-organizing aspect of it.

Dr. Sergiu Pașca:
Yes.

Andrew Huberman:
And now I'm hearing that these self-organization, the cell's own knowledge about what they should do and when is maintained. And I also have to just both highlight again and applaud the fact that regardless of where one stood on the embryonic stem cell debate, you're describing assembloids that were made from essentially taking a fibroblast, a skin cell-

Dr. Sergiu Pașca:
Exactly

Andrew Huberman:
... from a patient or from a non-patient, a healthy person that at least doesn't have that mutation, putting them in a dish, reverting them to stemness through the Yamanaka factors, then giving them certain things to drive them towards neuronal fates and then other fates, putting them together, and none of this involves the use of aborted tissues.

Dr. Sergiu Pașca:
No.

Andrew Huberman:
May I ask you this? If today you could bank your fibroblasts turned into a few neurons-

Dr. Sergiu Pașca:
Mm-hmm

Andrew Huberman:
... would you do it? Knowing that those cells could eventually be used to create any tissue, like I hope you live a very, very long life, Sergio. But let's say when you're 100, your heart has an issue. Humans can do heart transplants-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... from another human. There are immune rejection issues there. Pig hearts have been transferred into humans.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
But you could potentially build a heart that is of your cells, no immune rejection. Why wouldn't you bank your cells?

Dr. Sergiu Pașca:
I think you can collect them at any time, in principle. As long as you can-

Andrew Huberman:
Okay, so you can get them on your 99th birthday.

Dr. Sergiu Pașca:
I think you can still get them.

Andrew Huberman:
Okay.

Dr. Sergiu Pașca:
For sure, it could be an argument-

Andrew Huberman:
So you have time, folks.

Dr. Sergiu Pașca:
Right. So it could be an argument made that all the cells are going to be aging, so there are going to be some changes happening in those cells that maybe they have some mutated-

Andrew Huberman:
Yeah, they'll accumulate mutations.

Dr. Sergiu Pașca:
Yeah, that could be an argument made about it. On the other hand, what we're also seeing with some of the cell therapies that are just being developed now more broadly is that they don't have to be necessarily personalized. So they don't have to be made from your own cells. Because you can use immunosuppression, that's one way in which you can do it. So you can transplant the cells from somebody else. Of course, that poses more challenges if you think about the brain, replacing large parts of the brain, which certainly is like-

Andrew Huberman:
Yeah

Dr. Sergiu Pașca:
... far into the future.

Andrew Huberman:
You want to be very careful whose brain you're taking about.

Dr. Sergiu Pașca:
Yeah, certainly. But in general, you can see how in the future we may have off-the-shelf cells that have been made from a generic individual that you transplant with immunosuppression, or cells that have been genetically modified so that they're not rejected by the immune system, so they're compatible with all of us. Now it's much more likely to become a therapy that is broadly used, I think. So that's why I'm not that worried about harvesting my own cells right now.

Andrew Huberman:
Where do you sit on this idea that at some point in the not too distant future we will be able to immortalize entire organs within our body? Perhaps not ourselves, but our colleague Michael Snyder, Chair of Genetics at Stanford-

Dr. Sergiu Pașca:
Mm-hmm

Andrew Huberman:
... told me that he thinks that at least in my lifetime, I'm a little bit younger than he is, I'm almost 50, I forget how old Mike is, almost 70, but he said at least in my lifetime that immortalization of human tissues will be possible. He doesn't think that's a fantasy.

Dr. Sergiu Pașca:
Yeah, I think different people mean different things by immortalizing something. We generally think like for in vitro studies or for in a dish study, when you immortalize something, it means that the cell is maintained forever, but it generally involves using a cancer-like factor, giving them cancer properties. The cells that are immortalized, if you think about it, are either the stem cells that we talked about or the cancer cells.

Andrew Huberman:
Okay.

Dr. Sergiu Pașca:
So we always have to be careful about what it means to actually immortalize a cell. Rejuvenate cells, that's an interesting concept. Will we be able to actually rejuvenate our cells even if they're aged? So a lot of discussions have been happening lately whether you can actually use the Yamanaka factors, not to the extent that you completely reprogram a cell, but that you just use them just a little bit so that you rejuvenate the cells, not fully. But as you can imagine, those are complicated experiments. They're going to have to be tuned.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
You need to control very carefully the dial there.

Andrew Huberman:
Microdosing Yamanaka factors.

Dr. Sergiu Pașca:
Right. Because you would actually risk moving into another state. But that may be possible at one point.

Andrew Huberman:
Yeah. I thought that at one point one of the concerns of using Yamanaka factors and this whole technology therapeutically was that you could set the reversal in age of cells back to stemness, back to stem cells.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
But then how do you stop them there? And also how do you send them-- Ultimately it's not a stem cell that you want, you want a fully differentiated heart cell or neuron, and you want to stop there.

Dr. Sergiu Pașca:
Right.

Andrew Huberman:
The idea being for anyone trying to reverse their age, how far back are you willing to go?

Dr. Sergiu Pașca:
Right. And it's true when you use the Yamanaka factors or a combination of them, because we've discovered afterwards that it's not just those factors that can do that. There are combinations of other factors that can do the same.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
So there are various combinations. There is a lot of redundancy in that pathway, and if you hit the right combinations in a cell at the right time, you can push it back in time.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
Now, of course, the challenge is that reprogramming is full in the sense that everything is going to be erased. If the reprogramming is done properly, theoretically all the methylation, so all these methyl groups that you put across DNA that accumulate with age are going to be removed. All the signatures are essentially removed, so the cell is truly rejuvenated as in the beginning.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
And as you mentioned, perhaps you don't want to do that fully.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
Can you do it in a way that is partial reprogramming, as some people refer to? But certainly these are still early days for that, but certainly it's a possibility.

Andrew Huberman:
I think for most people if I said, "Look, scientists are developing engineering eyes that can replace eyes for people that are blind, maybe one eye, maybe both," they'd say, "Great."

Dr. Sergiu Pașca:
Right.

Andrew Huberman:
You're curing blindness effectively.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
And people are trying to do this. Neuralink is doing this. Ejieshe Oniski and Dan Palanker at Stanford are trying to do this.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
If I said there are scientists and companies trying to develop chips so that paralyzed people can walk again, or that people who have locked-in syndrome can speak again-

Dr. Sergiu Pașca:
Mm-hmm

Andrew Huberman:
... through one modality or another, they'd say, "Great." But if I said there are scientists who are building assembloids in a dish so that maybe you don't have two hippocampi, you have three. You have a super memory.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
I think most people would be like, "Whoa, slow down. You're playing God. That's not okay." And as a parallel example, CRISPR gene therapy, which we talked about earlier-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... was employed by a Chinese scientist to, I think it was to mutate the HIV receptor.

Dr. Sergiu Pașca:
To modify two individuals.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
Two babies.

Andrew Huberman:
Yeah. So there are at least two babies that we're aware of, and probably more around the world, but not terribly many, for whom CRISPR was used to make a genetic modification. Those babies were carried to term, and it wasn't to fix any particular disease, it was to confer them with something additional.

Dr. Sergiu Pașca:
Yeah. In this case, to prevent presumed transmission of HIV from the mother.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
Which is not necessarily justified in that case, though.

Andrew Huberman:
Right. Did the mother have HIV?

Dr. Sergiu Pașca:
I think the idea was that to avoid maternal transmission to the fetus You would not have that. But there are other ways in which that can actually be avoided. So in this case, it was not perhaps the best choice of a disease to correct. And I think that's why the scientific community has been quite outraged by both, I guess, the rationale and the way the experiment was done, which was not following certainly-

Andrew Huberman:
Mm-hmm. Yeah. The scientific community, as you said, was very upset about that, which brings us to the question of ethics.

Dr. Sergiu Pașca:
Yes.

Andrew Huberman:
So I'm sure being really familiar with this technology, that you've thought about a number of ethical issues that aren't going to occur to me, or perhaps you've heard about things from the general public or from physicians and psychiatrists. What are some of the key ethical issues that come to mind when thinking about how assembloids are going to be implemented as eventually treatments for disease?

Dr. Sergiu Pașca:
Yeah. So we think a lot about the ethical issues, and we think this as a group at Stanford that's part of my center. We have Hank Greely, who's a professor of law and an ethicist. But actually, we've engaged many ethicists, sociologists of religions. We're actually going to have the first meeting at Asilomar this November on the ethics of neural organoids, assembloids, and their transplantation. And there are various ways of classifying the ethical issues. The way I think about it is that on one hand, there are ethical issues that are related to the cells. We are taking cells from a human, and so you expect that you have received proper consent for the use of those cells, whatever that is. On the other hand, if, for instance, you put them into an animal, then there are ethical issues related to that animal. Are you doing any harm? How do we manage pain in that animal that has been transplanted? And then there are issues that are at the interface between the two. So for instance, are there any emergent properties that are arising at one point, whether they're in a dish or maybe perhaps in an animal? How complex can a circuit like this become? Is there any form of learning, of computation? Of course, some people have raised the issue that perhaps there is sentience or awareness, consciousness. Are they feeling pain? So for instance, that has been one critique for one of the recent work that we've done. Of course, in that case, we know the emotional component of pain is processed in different brain regions. We don't have those in a dish, so we know that they're not really feeling pain. We have the pathway of pain. But it also speaks to the fact that we need to be very careful about how we communicate this type of research. Even just using terms that are trivializing can actually create a lot of confusion. And the classic example in our field has been to call these preparations, these organoids or assembloids, to call them mini brains. Right? Then it may seem like as a trivial joke that it can't do anything, any harm. But you hear that for the first time, scientists have made mini brains in a dish. Right? And what do you think? You think, "Oh, it must be a miniature human brain that they're keeping in a dish." Right? Isolated. And of course, that's not true. We have not made the entire nervous system. We can make parts of the nervous system. We can put them in various combinations, but we've never made an entire brain. Actually, I don't know of any scientist who has as a goal to try to build the entire nervous system as an exact replica of the brain. So I think the words matter a lot, and in fact, that has been one of the things that we've done over the years. A few years ago, I thought it would be really important to get most of the scientists in the field together and start thinking about these terms really carefully. And so we got together, created an ad hoc consortium, and through many calls, one-on-one, in various groups, we came up with one paper, which was published in "Nature" a couple of years ago, which really comes as a nomenclature for the field. We, as scientists, decided this are the way we classify them. These are the terms that we all agreed should be used, and not use, for instance, project, let's say, complex terms onto this. We'll never say that an organoid sees just because there is a retina. Right? We'll never say that a cortical organoid has intelligence because that's a property of an entire nervous system. So we think that this is actually quite important, especially in communicating with the public. And that consortium turned out to be an actually great exercise of getting everybody together and now thinking, what are some of the common practices that we should all use when we report this experiment? So we just had a few months ago, another paper that came also as a perspective in "Nature," where we also laid out the framework for the field. I think this also speaks to the fact that we're entering a new era in science, where I think you would say all these labs are working separately, they're competing with each other, and yet we all got together, 25 or so labs, discussed some of these issues, reached some consensus, and I think that moves the field forward. And I think in general, in science, we will need more and more of these collaborative efforts because the science is getting more complex, biology is getting really complex, and there's no one single lab that can solve all of that.

Andrew Huberman:
Yeah, I completely agree. I think some years back, collaboration became the norm as opposed to the occasional thing, and I always thought that laboratories should be named after projects, missions-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... as opposed to individuals, but that's a-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... that's another story. Well, kudos to you for thinking about these issues so carefully and for gathering people around them in order to come up with nomenclature. Going back to this issue of naming, what things are called is so critical. It's so critical, and we see this in the public health sphere when people talk about gain-of-function research now.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
It's rarely mentioned that gain-of-function studies are critical for understanding things. It's not always the case you're mutating a virus. Gain-of-function is a general technology. More specificity of language, I think, is going to be immensely beneficial. So-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... appreciate you doing that.

Dr. Sergiu Pașca:
And these terms change with time. I think it's also important to mention that our understanding evolves. Science progresses, and sometimes there are things that we thought we understood, and then new techniques come and change that. I think it was Sydney Brenner who said that progress in science usually comes from a new technique that will yield new discoveries and that will create new ideas. So you think you understand something, and suddenly you have a new machine that can measure it much better with more precision, or let's say you have this technology when you can now recreate some of the circuits, and suddenly new ideas come out of it, new discoveries, and then we rethink and we adjust. And I think that's the beauty of science, that in a way, it's self-correcting as we get a better and better understanding of the world around us.

Andrew Huberman:
Also essential for people to hear, because I think whenever science or medicine comes out and tries to correct itself, often the general public, not all, but components of the general public will go up in arms as similar to a teenager realizing that their parents also did some bad stuff when they were younger, and they're like, "See? I shouldn't believe anything you say." It turns out science as a whole, I think, is a very well-intentioned endeavor. You get your occasional bad apples, but I think that this notion of self-correction, it's fundamental.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
Just like engineering's gotten better.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
The phone you use now doesn't look anything like-

Dr. Sergiu Pașca:
Right

Andrew Huberman:
... in terms of technology or speed of the phone you used 10 years ago, likewise with any technology.

Dr. Sergiu Pașca:
That's why it's so important that both when we communicate as scientists to the public, we use terms that are not trivializing. I think very often we're told, "Try to simplify so that the public understand." The public understands much more than we think.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
There are always ways in which you can explain something without trivializing it, without using a new term or some comparison so that they understand that. Because very often, analogies can also be dangerous. But I always assume, and that has being my mantra, that when you explain even to the general public, that they have zero knowledge and yet infinite intelligence. I think as the saying goes in science. So I think there are always ways of explaining science very simply, but also communicating that science changes over time, that there are new understandings that are correcting the science, and we've seen this, of course, in medicine. We've sadly seen it in psychiatry many times by labeling, relabeling, doing treatments that perhaps were not the most fortunate over time. But I think it's important to tell the public that we're always trying to move towards. I think most physicians that I know, most psychiatrists that I know, are really motivated by really trying to make their patient better.

Andrew Huberman:
So let's play a game where if I say, if you take two human cortical neurons-

Dr. Sergiu Pașca:
Mm-hmm

Andrew Huberman:
... or three or five or 10 or 1,000 that were developed from one of my fibroblasts, and you put it into a mouse or a non-human primate, like a macaque monkey, I think you've still got a mouse harboring a few of my neurons or a macaque monkey harboring a few of my neurons. At what point does that animal no longer become strictly a mouse or strictly a primate? And then the parallel example, of course, is let's say I could get some neurons from fibroblasts that were made from you and those were put into my brain.

Dr. Sergiu Pașca:
Right.

Andrew Huberman:
At what point do I become more Serguei-like than Andrew-like?

Dr. Sergiu Pașca:
Sure. Yeah.

Andrew Huberman:
So how do you think about those questions? And while it might seem too early to consider those, we've learned through history that it's never too early to start-

Dr. Sergiu Pașca:
It is

Andrew Huberman:
... thinking about the ethical implications-

Dr. Sergiu Pașca:
It is

Andrew Huberman:
... of a technology like this where there's transplantation involved.

Dr. Sergiu Pașca:
No, it is absolutely not too early, actually. The right time to think about this is as experiments are actually being planned, not when experiments have been done.

Andrew Huberman:
Ah, good point .

Dr. Sergiu Pașca:
And that's what we've been doing. And that's why, actually, all experiments that we do undergo ethical approval at Stanford. And I think at most major institutions, and certainly in the United States, you have to first propose what you're going to do, especially with pluripotent stem cells and especially with animals, and a committee will decide whether that is acceptable or not. Now, of course, there are experiments that perhaps are not necessarily illegal, but when you try to break a new frontier. But I think what it's important to think about this process of transplanting or transplantation, that you take cells and you put them either in another individual or another species, is that what really matters a lot, we've learned now, is the timing, when you actually transplant those cells. So it turns out that the brain, the adult brain, is not very permissive to forming new connections. We may form small connections. There's a lot of plasticity of the connections, but we don't have, let's say in our adult brains, we don't have cells that are moving now across the nervous system. We don't have entire pathways that are being rewired. You're never going to have a cortical neuron that just simply regrows and now connects to spinal cord neurons, which is why injury to the nervous system is so devastating. There's so little recovery because the cells are usually not essentially rejuvenating. There are no cells that are replenishing them. And it's not just that there are no cells to actually replace them, it's also that the cells are just not that eager to connect with other cells as they are early in development. And so years ago, we've discovered that while we can keep some of these cultures in a dish for very long periods of time and connect them in ever more complex assembloids, and now there are literally dozens and hundreds of assembloids that people have made, and not just in the nervous system, actually even outside of the nervous system, because now there are cardiac assembloids and endometrial assembloids. And so the concept took over, and I'm glad to talk about it. We're going to have the first conference on assembloids at Cold Spring Harbor this year, which is to bridge across fields and try to understand complex cell-cell interactions. But even with these most complex assembloids, we realize that the cells are still missing cues that are present in vitro. So a few years ago We were doing an experiment looking at some of the neurons that we made in a dish. And these neurons in the cortex are very often called pyramidal because they look like a pyramid. They really have this beautiful triangular shape. And we were looking at the neuron, it looked beautiful, exactly like a pyramidal neuron. And then around that time, we got a piece of tissue that was removed from a child who underwent surgery for epilepsy. So when you sometimes have to undergo the surgeries, intractable epilepsy is really severe, maybe you talked about this previously, you have to remove some tissue. And when you remove some of that tissue, you also have to remove some healthy tissue. And so we got some of that healthy tissue, and of course, we're always eager to understand how the cells that were made in a dish are similar or dissimilar to the ones in the actual brain. We still need to benchmark before we use that for a therapy or for anything else. And we compare one day some of the cells, and we realized, to our amazement, I don't know how we'd never noticed it, or nobody has really made a big deal out of it, but the neurons that we were making in a dish were about 10 times smaller than the ones in the cortex on average.

Andrew Huberman:
Hmm.

Dr. Sergiu Pașca:
There are kind of miniature versions of what was happening. And so it was like, of course, immediately it was like, what is happening in vivo? Is there something, as they say, in vivo veritas very often, right? We know this has been the case for immunology, that many experiments in vitro have not always panned once you actually study them in an actual patient. So that's when we actually started to also use transplantation, meaning we started thinking, could we actually put some of the cells in an animal and see whether they acquire new properties or they look much more like this? And of course, transplantation has been used for 40 years. Many of these experiments were done before I was born, especially in Sweden, when scientists will actually take various cells and transplant them into animals. And so what we started doing is taking actual organoids, cortical organoids, and then transplanting them into a rat, an early-born rat, in the somatosensory cortex, so the part of the brain that receives information from whiskers. And we've done that in the first few days after birth. And it turned out that that was key because if you do it later, the cells don't really integrate that well. They integrate, but they don't fully integrate. And if you transplant that organoid into the somatosensory cortex of the rat, and then you wait for a few months, that graft starts to grow. The cells become vascularized by the rat. They will even receive microglia. The immune cells of the nervous system of the rat start to populate. And then when you look on an MRI, you now can see that about a third of one hemisphere of the rat is now made up of human cells. So you can see really on an MRI from the ventricle to the pia. Now, you may think that that's like an inert piece of tissue that sits there, but it turns out that it is quite well connected to the host, and that happens because the brain is still eager to connect at that early stage of development, but later on is not. And so, for instance, you can do experiments where you can actually record the activity of human neurons and at the same time move the whiskers of the rat. So if you move the whiskers of the rat onto the opposite side, obviously because the pathway is crossed, then human neurons now start to respond to that. And then I think probably the most important consequence of that is that they receive now input. They're now in an environment that is much more physiological. So when we now looked at the cells, it turned out that they're like six to eightfold larger than when we were making the dish. They're not yet identical replica, but they're very, very close. And that for us has actually been key and started to actually understand the biology of some of these conditions. So, for instance, for Timothy syndrome, there is a very dramatic effect in the size of the neurons. They're almost twice as smaller than a control neuron.

Andrew Huberman:
In the patient.

Dr. Sergiu Pașca:
Well, in the patient. Only when you transplant the cells, we can see that defect. In a dish, you look at them and they're identical.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
And then you transplant them, and some of them grow really large to control, and the patients fail. And that phenotype can only really be seen properly in vivo. So that has been actually essential also as we've been developing a therapeutic for this condition, and you start thinking like, how do you test a therapeutic? If there's no animal model of the disease, you test everything in a dish. You do want to have some safety check, first of all, for making sure that there are no adverse effects, but also you want to make sure that it works in an in vivo environment. And actually, it turns out that this model that we've built was essential because now we could take actually the animal and inject the therapeutic into the nervous system of the animal, but look at the effect on human neurons in an in vivo context. And so I think that's one application for this, but if you do the transplantation at a later stage, like for instance in an adult, that integration will probably not happen.

Andrew Huberman:
I see.

Dr. Sergiu Pașca:
So it's quite dependent on the species. And there's another thing. The farther away the species are, the less likely it is, of course, that the cells will integrate.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
So think about it. It takes just a couple of weeks for the rat to make the cortex. It takes us 20 weeks to make most of the cortical cells. So the human cells are always behind. The rat is finishing development very quickly. The humans are trying, but they're keeping their pace. So the integration between the two species happens at some level, but it's not perfect. And that's actually not our goal. Our goal has never really been to have perfect integration. All we wanted to do is to have a better system where we can capture aspects of disease that we wouldn't be able to see in another way, or test therapeutics that we wouldn't be able to test in any other way. And so that's where this actually comes in handy, and it's been very useful.

Andrew Huberman:
It's so interesting that for most people Again, I'm making a lot of assumptions here, but for most people, the idea of a chip, of an electrode implanted into the brain of a patient or spinal cord of a patient isn't that disturbing to them. No one would choose to do that in the absence of a clinical issue. But, well, there are some people who are interested in brain augmentation through the implantation of chips to create super memory or to be able to process more bits of information in whatever capacity. But typically, it's discussed in the therapeutic context. But as soon as we hear about, for instance, a pig heart or baboon heart was transplanted into a human, all of a sudden it gets to some really core things about our humanness.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
And then, of course, I can't help but be reminded of all the anecdotes that you hear where, oh, a patient died, had donated their heart to medicine, the heart was transferred, and then the person who received it thought that maybe they had adopted some features of-

Dr. Sergiu Pașca:
Sure

Andrew Huberman:
... the person's experience, and you can't really do the control experiment. But there's a lot of interesting questions that border on mystical.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
But given that experience is mapped into the nervous system, it's not inconceivable that you would have memory traces, at least of bodily experiences, built into the organ system. Although typically we think of that stuff as in the brain. So, as I hear and learn more about these incredible assembloids, I'm very enthusiastic about where this is headed. I also, of course, think that treatment of disease is the primary entry point. This is what-

Dr. Sergiu Pașca:
Yes

Andrew Huberman:
... as opposed to building superhumans. Which is, I think, why that CRISPR experiment, mutating the HIV receptor, was also disparaged. There was this idea that maybe the HIV receptor, in the absence of HIV, is performing other roles related to learning and memory.

Dr. Sergiu Pașca:
Right.

Andrew Huberman:
And so there were hints of eugenic-type approaches. And that raises a question for me. You mentioned that there are many genes that are associated with autism.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
I think most parents or parents-to-be don't take a test for those genes. There are companies like Orchid in the Bay Area now that will do deep sequencing of embryos in IVF. Depending on how much you pay, they'll sequence more. This was in the news a few weeks or months ago.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
And people start thinking, oh, this is like eugenics, right? On the other hand, partner selection, who one chooses to have children with, is its own form of genetic selection.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
They'll say, "Oh, he's very kind. She's very kind. She's very smart." People are basing their decisions, hopefully according to features that they would like to create in the offspring. It's not always the case. So I think sometimes the boundary between what we call eugenics and mate selection and creating offspring in the purely old-fashioned way, it's blurry. It becomes a continuum. How far off are we from genetic testing of parents as a kind of obligatory thing-

Dr. Sergiu Pașca:
Mm-hmm

Andrew Huberman:
... now that we know some of the genes associated with autism? We test parents for things like Tay-Sachs, sickle cell anemia-

Dr. Sergiu Pașca:
Down syndrome

Andrew Huberman:
... congenital adrenal hyperplasia, things that are almost deterministic.

Dr. Sergiu Pașca:
Yes.

Andrew Huberman:
Down syndrome, trisomy.

Dr. Sergiu Pașca:
Mm-hmm.

Andrew Huberman:
And in some countries, they'll implant embryos that are not, as we say, euploid, the proper assortment of chromosomes. But in the US, typically that's discouraged.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
So how do you think about all this? You're not responsible for deciding for everyone, but you're right at the leading edge of what's possible, and you can sniff what's going to be possible. How much information should a person thinking about having a child have in order to make the best-informed decisions?

Dr. Sergiu Pașca:
So for some of these conditions, it's more straightforward than for others. As you were saying, some of them are very deterministic. So if you have three 21 chromosomes, you're going to have Down syndrome, and that's going to be associated with a very classic presentation. But for others, it turns out, and I think that's where it's much more complicated than just testing and making a decision, is that what we call in genetics the penetrance of the genetic mutations is variable. Meaning that you could have a genetic mutation that in one patient could cause a very severe presentation or phenotype, and another would be very mild. It's not the case for Timothy syndrome, where actually it's quite predictable. Most of the patients that we know, we've never identified a patient who is non-affected, and they're very severely affected. But there are other conditions that are much more common. I think the classic one is a deletion that is happening on chromosome 22, the so-called 22q11.2 deletion syndrome, known by many names, velocardiofacial syndrome, DiGeorge syndrome, known by many names because it's so common. It's actually the most common microdeletion in humans, about one in 3,000 births. Now, the condition is associated with cardiac issues, immune conditions, many of which can actually be addressed medically. But it also comes with a 30% risk for schizophrenia.

Andrew Huberman:
30%?

Dr. Sergiu Pașca:
Yeah. So you think the general population is 1%, so this is about 30 times higher. It also comes with a 30% risk of autism. But you could also not have any of this. There are individuals who are carrying the 22q11.2 deletion, which is a large deletion, by the way. There's 60 genes that are gone in the classic deletion, and yet still carry it around and have minimal defect or phenotypes.

Andrew Huberman:
Do we test for this 22q?

Dr. Sergiu Pașca:
This is tested generally these days, yes, because it's so common. But I think that the challenge is this problem of penetrance, and in some patients, and we don't know what the context is. Each of us has a very complex genetic background. So it could be that the same mutation, two different individuals will have different levels of severity because one of them perhaps compensates much better for whatever reason. There is a lot of stochastic forces in development, and if a cell is much faster at opening the other gene, like the similar gene that is unmutated, and in the other case it wasn't, or maybe there are other environmental factors that are interacting. But the other possibility is that the genetic background that we have is very different. And so we're still in early days of truly understanding what are the effects of the genetic backgrounds in modulating the severity of these conditions. But in itself, it's a very interesting question, why some individuals can have a massive deletion of 60 genes and yet still move around. So I think that's going to be a lot of interesting biology to discover behind this. And then, of course, we know that there are differences between animals and humans. That we already know, that very often a mutation that would be very severe in a human has almost no defect in an animal model, partly because that gene maybe plays a different role, or perhaps the genetic background is very different.

Andrew Huberman:
Speaking of which, what are some of the other diseases that are being modeled and studied with assembloids?

Dr. Sergiu Pașca:
So Timothy syndrome has sort of been the first example, partly because it was some of the first neurons that were derived from iPS cells and from patients with neurodevelopmental disorders in those early days, and also partly because it's the disease that we studied so much on all possible angles. First with 2D neurons, then with 3D organoids, then with assembloids. Then at one point, and I like to say that a therapy became self-evident, so to speak. I was not thinking that we would develop a therapy for Timothy syndrome, not in the near future. But at one point, we just accumulated enough biological information that you just look at it and you say, "Oh, this is exactly what we need to do." And it turns out that, and this we did about five years ago, that we understood so well how this channel is processed in the cells and what it causes, that at one point, we realized that all we need to do is generate this tiny piece of nucleic acid that we can get inside the cells. It will go in, switch the way the channel is actually processed, and rescue or reverse the phenotypes. And it turns out that every single defect that we've described over the past 15 years in the studies can be rescued by just adding the tiny piece of nucleic acid. It's almost like a gene therapy in a way.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
It just doesn't involve a virus. And so this is the first disease, and we're preparing for a clinical trial. These patients are very rare, so I've been traveling around the world trying to find most patients with Timothy syndrome, even try to understand the complexity of the disease, the severity of the disease. And so we now have a large cohort of the patients ready, and we're preparing for the first clinical trial. We already started producing the drug.

Andrew Huberman:
So it's druggable.

Dr. Sergiu Pașca:
We think that it's druggable, but this will be the first therapeutic for a psychiatric disease that has been exclusively developed with human stem cell models without anything else. And I actually joke about it. Probably you knew very well Lubert Stryer.

Andrew Huberman:
He developed the so-called gene chip, early days of evaluating genes in different cells. He passed away recently.

Dr. Sergiu Pașca:
He passed away recently.

Andrew Huberman:
Sadly. He would bring coffee by.

Dr. Sergiu Pașca:
He would bring coffee by.

Andrew Huberman:
Yeah.

Dr. Sergiu Pașca:
He had their office across our D222, so he would come at 9:00.

Andrew Huberman:
Anyone who's ever taken biochemistry, the big red biochemistry book, Stryer-

Dr. Sergiu Pașca:
It's Stryer

Andrew Huberman:
... that's Lubert.

Dr. Sergiu Pașca:
That's what it is.

Andrew Huberman:
Yeah.

Dr. Sergiu Pașca:
He was an amazing communicator.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
I think above anything, he was just a larger-than-life figure who able to go with you in a conversation from a deep molecular mechanism to what does it actually mean?

Andrew Huberman:
Yeah, a very kind person, too.

Dr. Sergiu Pașca:
So my last conversation with Lubert, which happened I think a month before he passed away, he came to my office at Stanford. We would meet every few months. He was just so interested about how this is evolving. And I remember he was sitting in my office, and then he wanted to know, "Where are you with Timothy syndrome?" The paper was still under revision at Nature. It was coming in the next few months. And then he said, "The saddest thing is I'm not going to see this paper published. I want to see this paper published." And I said, "Why?" And he goes, "Do you know what you've done?" Because he would usually use with that intensity, and I thought, "Oh my God, maybe he realized we've made the mistake somewhere in the paper, or it's going to point out to some flaw." And then he says, "No, you've demystified the psychiatric disease." I said, "What do you mean?" He said, "Well, you think about psychiatric disorders. They're so esoteric, so complex, mental processes that are arising, behavioral changes, and yet you went all the way down to a molecular defect, a point mutation, figure out the rest, and now you're on a verge of potentially perhaps not reversing, but at least improving some." So he was so excited about this, and I think I never think enough perhaps about it. But he was the last one who sort of reminded about how important it is actually to focus on these genetic disorders of which we know more. Of course, this is just one form of disease. There are so many more afterwards. But our hope is that just by understanding and learning from this, we're going to be able to apply to other disorders. So another one that we're studying now, there are forms of epilepsy which are very difficult to study. There are intractable forms of epilepsies. Patients who have some of these genetic mutations, whether they're in an ion channel or in molecules that are important for cells to stick with each other, they can cause 60 seizures a day. So they're really devastating conditions that are actually causing impairment just by having those seizures every single day for 10, 15 years. And so those are a really big issue right now. So we've been focusing a lot on trying to build now models for these epileptic seizures. Either through in vitro studies or after we transplant, and then we study more complex networks in patients. And then, of course, intellectual disability, so severe intellectual disability, schizophrenia, forms of schizophrenia. So we've been studying now for almost 12, 13 years, 22q11 deletion syndrome. We think it's so like an entry point. It's the highest genetic risk factor that we know of for schizophrenia, so we think it may give us some windows into how molecular defects arise. So I think you can think of most psychiatric and neurological conditions that you can study now, as long as they have a strong biological genetic component.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
So I think those that have a social component, those that are triggered by social stress, let's say, right, like forms of anxiety, depression, those are much more challenging to study because, of course, we can mimic that social environment.

Andrew Huberman:
Can I make a request?

Dr. Sergiu Pașca:
Please.

Andrew Huberman:
That someone in your lab try to tackle dystonia.

Dr. Sergiu Pașca:
Mm-hmm. Yes.

Andrew Huberman:
I had the experience last year of somebody contacting me. I get contacted a lot for requests to help with horribly sad situations, right-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... as one does if you're in the neuroscience field. Typically, it's people with visual deficits who've gone blind or are losing their vision. This time it was a mother of a young kid who had a form of dystonia, where he was essentially just going from a, by all accounts, normal-appearing and acting kid to having basically no ability to move or do anything.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
Couldn't go to camp, couldn't go to school, and it was just a very tragic situation. He had a neurosurgery. I will know soon how he's doing. But I learned that these dystonias are not super uncommon.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
I mean, fortunately, they're uncommon enough, but you just have to witness one of these stories.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
And it turns out there is a genetic basis for these.

Dr. Sergiu Pașca:
Yes. Yeah.

Andrew Huberman:
So I'm putting in a vote for dystonia.

Dr. Sergiu Pașca:
No.

Andrew Huberman:
For the parent and for the child, it's devastating. And we don't hear from these people very often, and there are sociological reasons for that. Certain diseases are underrepresented in the public sphere.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
Autism we hear a lot about, not just because of the prevalence, but because we have a certain affinity to kids, and that explains that. A discussion for another time. But these dystonias are very hard to witness in a way that has made them kind of veiled-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... to the public, but they're very, very detrimental, and it would be amazing-- I know you already have a lot on your plate, but I'm putting in a strong vote for dystonia.

Dr. Sergiu Pașca:
But we are actually working on dystonias-

Andrew Huberman:
Great

Dr. Sergiu Pașca:
... because they are devastating conditions, and there are now genetic mutations that cause really severe forms of dyskinesia and dystonia, so really uncontrollable movements in these kids that are really devastating for social functioning and, in general, for development.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
And so we do know a little bit about the biology behind it. We do know that the basal ganglia, this deep structure into the brain, is very important for movement. We very often stimulate that brain region for Parkinson's disease or parts of that circuitry, so we know it's very important. So we've been trying to rebuild it-

Andrew Huberman:
Mm-hmm

Dr. Sergiu Pașca:
... in a dish. So we now can build some of the circuits. We call them loop assemblies, where essentially you can put a cortex, and we've made the striatum.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
And then you put parts of the mesencephalon in the midbrain and the thalamus.

Andrew Huberman:
Awesome.

Dr. Sergiu Pașca:
And the cells connect in a loop-

Andrew Huberman:
Mm-hmm

Dr. Sergiu Pașca:
... and now they have activity. So you can now induce mutations at various levels of the circuit and see where is that mutation most important. So let's say if you were to develop a gene therapy-

Andrew Huberman:
Mm-hmm

Dr. Sergiu Pașca:
... where would you deliver that gene? If you were to choose, if you can't deliver it in the entire brain. So these are really early days, but I think it can be applied. And I think in general, you were mentioning this before about autism, right, and even the ability of communicating these disorders or how much awareness there is, right? I think when I refer to autism, I generally refer to the severe forms and profound autism.

Andrew Huberman:
Yes.

Dr. Sergiu Pașca:
And as we discussed earlier, there's certainly a continuum, and there are many individuals that are high-functioning, right? They have high skills. They may lack certain social skills, but they have other skills. They're different. They're productive in society. I am not talking about discovering or developing a therapeutic for any of these individuals. We are talking about the profound forms of autism, the ones that actually the parents are still struggling to even communicate about, right? The kids who may never go to school, may never be able to actually live on their own. The same is the case for many of these patients with severe dystonias. So I think it's very important because I think in the case of autism, partly because it's being talked about, and again, because it is a spectrum, it's also part of the identity, right, of a part of the population.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
And that's absolutely fine. I think perhaps at one point having different terms-

Andrew Huberman:
Yeah, that would be useful

Dr. Sergiu Pașca:
... it may be useful because we were talking before about terminology, which is so important. So perhaps that would be useful at one point to define the border between profound forms of autism and forms of autism that are not really a disease.

Andrew Huberman:
Yeah. As well-meaning as the psychiatric community is, it's bound by this DSM whatever number-

Dr. Sergiu Pașca:
Yes

Andrew Huberman:
... it happens to be on.

Dr. Sergiu Pașca:
Five.

Andrew Huberman:
For understandable reasons, but I think better nomenclature-

Dr. Sergiu Pașca:
Absolutely

Andrew Huberman:
... would really help. It has societal implications. It has to do with how we treat people generally. Actually, just as a quick reflection, years ago, I sat down with Bob Desimone who-

Dr. Sergiu Pașca:
Mm

Andrew Huberman:
... a world-class neuroscientist, as you know, but he was the head of the National Institutes of Mental Health at that time, and he said to me directly, it was over lunch, he said, "Do you know why there's so much more money spent trying to understand autism as opposed to schizophrenia?" At least that was the case at the time, and I think it is still now. I said, "No." And he said, "Because the strong genetic link in schizophrenia means that oftentimes the parents are struggling as well. They're not bringing their children in." And with severe-- nowadays it's not politically correct to call them schizophrenics. For people with severe schizophrenia, it's scary to be around.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
It's really scary, whereas with autism, even in the profound cases, these are children, and as a human species, we naturally have this, we want to care for our young. And it just pulls on us. And he said, "So there's been this incredible lobby of the government, and therefore pressure on NIH to direct funds towards studying autism far, far less for schizophrenia." It's interesting in light of the homeless problem in California and elsewhere, and the huge-

Dr. Sergiu Pașca:
Yeah

Andrew Huberman:
... amount of mental disease and drug addiction. I think nowadays there's a kind of a broader understanding of brain diseases as diseases that people suffer from, as opposed to-

Dr. Sergiu Pașca:
Right

Andrew Huberman:
... cold mothering or something-

Dr. Sergiu Pașca:
Right

Andrew Huberman:
... like ridiculous theories like that.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
I definitely want to talk a little bit about you. Not getting too personal here, but I've known you for some years, and from the first time I met you, it was clear you were going to work on something important, you were going to figure it out, and your work ethic is something to behold. Without inflating numbers how much time are you spending these days either at the computer working on things related to your science, or in the lab, or thinking about your science? Of your waking hours, what percentage?

Dr. Sergiu Pașca:
Well, I've never seen this as work, so probably all the time. I think about this all the time. Luckily now, of course, I have a lab of incredible scientists, and many of them now have their own labs.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
And we've been teaching so many people around the world now, more than 350 labs around the world to just implement this technology very systematically through courses that we do at Stanford. So I feel we've amplified so much that there's always something happening.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
But I've never seen it, honestly, as work. I think it's so fun to think about the human brain. It's certainly fascinating to think about the biology of these conditions, and of course for me, training as a physician, I think seeing firsthand some of the devastating effects of psychiatric disorders, which it was a very strong motivation to actually go into neuroscience.

Andrew Huberman:
I'll never forget when your first paper was published as a postdoc.

Dr. Sergiu Pașca:
Yes.

Andrew Huberman:
You brought in a cake for everyone else. I don't know if you remember that.

Dr. Sergiu Pașca:
No, I don't.

Andrew Huberman:
You brought in cake for everyone else.

Dr. Sergiu Pașca:
I don't remember that.

Andrew Huberman:
And I was like, "This is the first time I've ever observed this. This is awesome." At the time, I was eating cake. I don't eat cake anymore. With each successive decade, I get stricter and stricter with my eating. I still enjoy food very much. But it really speaks to your spirit and your generosity. I feel so blessed that someday I'll be able to say "I can tell you stories from way back when, D222, when we took over that room without permission." I think we just did it.

Dr. Sergiu Pașca:
I think we just took it, yeah.

Andrew Huberman:
Which is the way to do it.

Dr. Sergiu Pașca:
It's unincorporated.

Andrew Huberman:
Well, Ben was the one who always said, "Ask for forgiveness, not permission," within the proper context of doing science. He was famous for bringing his experiments to talks as a postdoc so he wouldn't lose time on his experiments. And then I think at one point, there's a story where someone had called him out and said, "Hey, why are you bringing your experiments to seminars? Everyone else is drinking coffee and doing stuff." And he said, "Because I don't know if your seminar is going to be any good, and I don't want to waste the time on my experiments." He had such an incredible spirit about just ceaseless pursuit of knowledge, which clearly you do as well. Sergiu, I am so grateful for you taking time out of your immensely busy schedule to come here and educate us all on this incredible technology that you've developed and that other laboratories are now using. I realize it's a field, but clearly a field that you've been seminal in launching, and I think for a lot of people, if they were to just hear about organoids in the news or hear, okay, we took these neurons, and we were able to grow them in a dish, and they formed some things that resemble circuits, and we're putting them into mice, they'd say, "This sounds a lot like a parlor trick or something that scientists do to keep themselves busy with our tax dollars." But I just want to thank you because you've beautifully illustrated the linear fashion in which you've gone from human disease to building up technologies, one cell type in a dish, two cell types, circuits in a dish, three synapses, modeling, using drugs and other approaches, genetic therapies, to figure out what actually needs to be fixed, going back into patients, which is super exciting. I'm absolutely convinced this is the way science is going to be done on the brain to cure neurologic and psychiatric diseases. I'm absolutely convinced because animal models, while they have their place, they just can't recapitulate everything we're interested in, and we know that, as you mentioned, from other fields. So whatever we have to do to keep you going. You look younger than the last time I saw you which was a while ago. So you told me before we started, you walk a lot. How many steps a day are you doing?

Dr. Sergiu Pașca:
I do more than 12,000, 15,000, for sure.

Andrew Huberman:
So you're walking to and from work?

Dr. Sergiu Pașca:
Yeah, and I walk all the time. I like to walk, especially when I travel. I visit a lot, Europe and parts of the world, and I love to just walk, and art is the only other thing that I do-

Andrew Huberman:
Oh, yeah?

Dr. Sergiu Pașca:
... other than science.

Andrew Huberman:
Really?

Dr. Sergiu Pașca:
I love art.

Andrew Huberman:
Do you paint?

Dr. Sergiu Pașca:
I used to paint. Right now, it's mostly thinking about art and like-

Andrew Huberman:
Okay

Dr. Sergiu Pașca:
... I've seen most museums in Europe at this point several times.

Andrew Huberman:
Whose art is exciting you now? I'm fascinated by it. I love art, but whose art are you intrigued by lately?

Dr. Sergiu Pașca:
Well, my favorites have always been Impressionists, but then I go through phases and so I love all art as an expression, and I think that's sort of like a-- I walk a lot, museums. I think you could probably trace Where I've done most of the walking, and it's probably done in museums or in California walking at night and so like discussing science with students or others.

Andrew Huberman:
Fantastic. And none of this biohacking nonsense. You eat one meal a day. That's how you stay so fit.

Dr. Sergiu Pașca:
I generally eat one meal a day, yeah.

Andrew Huberman:
How long have you been doing that?

Dr. Sergiu Pașca:
Years, I think. Years. I think in medical school initially as a necessity because I grew up in Romania, and I went to medical school there, and there wasn't really dedicated time for research. So I had no option but to do my experiments either very early in the morning or very late at night.

Andrew Huberman:
Mm-hmm.

Dr. Sergiu Pașca:
So there would be very little time to actually eat, to be honest, at that time. So I felt I was running all the time doing experiments or clinical work.

Andrew Huberman:
Oh, like I said, your vigor seems to be just increasing with time. It's really wonderful. Clearly, you've found the career path for you, and it's going to benefit us all. It already has. So please come back and tell us about your progress-

Dr. Sergiu Pașca:
Absolutely

Andrew Huberman:
... in six months, a year, whenever the time is right, we'll have you back. And once again, thanks for doing everything you do. In this time of hearing so much negative news and thinking science is so hobbled and all this stuff, science needs support, obviously.

Dr. Sergiu Pașca:
Yeah.

Andrew Huberman:
But what's that saying you see on the internet? "Not all superheroes wear capes." You're doing God's work, so thank you.

Dr. Sergiu Pașca:
Thank you so much. Thank you.

Andrew Huberman:
Thank you for joining me for today's discussion with Dr. Sergiu Pasca. To learn more about his work, please see the links in the show note captions. If you're learning from and/or enjoying this podcast, please subscribe to our YouTube channel. That's a terrific zero-cost way to support us. In addition, please follow the podcast by clicking the follow button on both Spotify and Apple. And on both Spotify and Apple, you can leave us up to a five-star review, and you can now leave us comments at both Spotify and Apple. Please also check out the sponsors mentioned at the beginning and throughout today's episode. That's the best way to support this podcast. If you have questions for me or comments about the podcast or guests or topics that you'd like me to consider for the Huberman Lab podcast, please put those in the comments section on YouTube. I do read all the comments. For those of you that haven't heard, I have a new book coming out. It's my very first book. It's entitled "Protocols: An Operating Manual for the Human Body." This is a book that I've been working on for more than five years, and that's based on more than 30 years of research and experience, and it covers protocols for everything from sleep to exercise to stress control, protocols related to focus and motivation, and of course, I provide the scientific substantiation for the protocols that are included. The book is now available by presale at protocolsbook.com. There you can find links to various vendors. You can pick the one that you like best. Again, the book is called "Protocols: An Operating Manual for the Human Body." And if you're not already following me on social media, I am hubermanlab on all social media platforms. So that's Instagram, X, Threads, Facebook, and LinkedIn. And on all those platforms, I discuss science and science-related tools, some of which overlaps with the content of the Huberman Lab podcast, but much of which is distinct from the information on the Huberman Lab podcast. Again, it's hubermanlab on all social media platforms. And if you haven't already subscribed to our Neural Network Newsletter, the Neural Network Newsletter is a zero-cost monthly newsletter that includes podcast summaries as well as what we call protocols in the form of one to three-page PDFs that cover everything from how to optimize your sleep, how to optimize dopamine, deliberate cold exposure. We have a foundational fitness protocol that covers cardiovascular training and resistance training. All of that is available completely zero cost. You simply go to hubermanlab.com, go to the Menu tab in the top right corner, scroll down to Newsletter, and enter your email. And I should emphasize that we do not share your email with anybody. Thank you once again for joining me for today's discussion with Dr. Sergiu Pasca. And last but certainly not least, thank you for your interest in science.

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