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

The episode opens by deliberately staging the central tension around the word "cure." Huberman notes that whenever autism comes up, some people object that they know autistic children and adults who are "delightful people that lead functional lives," while others point to "people with autism who need constant care, who will never live independently." The stated target of the research is therefore not autism in general but the most debilitating forms: the introduction names "what is called profound autism, which are the most severe cases of autism." Pasca is introduced as a professor of psychiatry and behavioral sciences and director of the Stanford Brain Organogenesis Program, and as "one of a small handful of researchers that pioneered the discovery and development" of organoids and assembloids, described as "human brain circuits derived from stem cells that form in a dish, so that one can study them directly." Huberman frames these models as "immensely powerful" for understanding what is wrong in "profound autism, schizophrenia, and other psychiatric challenges, and for developing cures."

It's behaviorally defined. There's no biomarker, so in a way it's a condition that is defined exclusively by observing behavior.

Pasca's first substantive claim is that the condition is defined exclusively by behavior and "diagnosed by the presence and absence of certain behaviors in a certain period of time or up to a certain age," adding that this "is actually the case for most psychiatric disorders." The reported prevalence has risen to "close to almost 3% of the general population, which of course it's a big number" — a figure Huberman repeats back as "3%" and Pasca confirms as "Almost 3%, yes." Pasca adds that the number "has increased even since I was in medical school," where autism "was considered a rare disease," and that he originally chose to study it precisely because "we thought studying a rare disease would be easier" given "very few resources."

Pasca describes how the etiology was once misread through a psychoanalytic lens. In the 1950s and 1960s the dominant view blamed "very cold parents, in particular a cold mother" — a notion Huberman clarifies as "Emotionally cold?" and Pasca confirms as "Yeah, emotionally cold." Biological thinking arrived in the 1970s "with some of the first biological studies ... primarily in twins," which showed that for genetically identical twins "the probability that the other one has autism is very, very high" when one twin is affected.

It was the so-called refrigerator mother hypothesis of autism.

From those twin data Pasca says "generally, we think that there is a strong heritable component to autism," dating that shift to "the late '70s." Only "just in the last 10, 15 years" did the field learn "that there are genes associated with autism and certainly with very specific forms of autism." He labels the severe, impairing cases — "very often associated with other conditions such as intellectual disability, so low IQ, epilepsy" — as "what we would call generally profound autism today." He is careful to hold both ends of the spectrum at once: "there's no doubt that there are individuals that have autistic traits that are fully functional in the general population," yet "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

To explain why a single spectrum label misleads, Pasca compares autism to "the fever of the 19th century in medicine," when "he has a fever, high fever" might have been "a viral infection, a bacterial infection, could have been cancer, metastatic cancer" or "an autoimmune disease" — conditions with "very different" treatments that were lumped together because only the observable "raising of the temperature" was known and "we didn't know the biology." The parallel is explicit: in autism research "they are defined behaviorally, but there is a disconnect with the biology," and "very often we don't have biological markers by definition," a gap that "creates a lot of confusion." He insists "no psychiatrist or even biologist who's studying autism would ever consider that this is one single disease."

That framing drives the blunt clinical point. When Huberman asks what treatment a child would receive assuming "infinite resources" and notes "there's no single treatment for autism," Pasca answers, "No, there's no single treatment for autism. Again, in the context of this not being one single disease."

On the male skew, Pasca says "the ratio varies also based on severity, but generally it's been one to four, so more males than females." Huberman speculates the SRY gene — raised in a prior episode with their colleague Nirao Shah, where "the difference between a biological male and female comes down to this SRY gene" — could be "conferring a vulnerability to autism." Pasca offers competing explanations: possible under-diagnosis of girls, who "are very good at what we call masking the symptoms, so learning the social skills, and so covering for that diagnosis"; and sex differences in how "the male and the female brain, especially around birth, can actually take up injury." He cites premature birth, where "one of the best predictors for a premature baby in terms of outcomes, it's actually to be a female," faster milestone acquisition in girls ("tend to speak a few months earlier, to walk a few months earlier"), and a nervous system "maturing at a different pace and can take injury differently." He cautions that because "autism is not one single disease, it is very hard to point out to one specific factor that is behind it."

On observable features, Pasca clarifies that babies or young children failing to focus their gaze on others' eyes "is not part of the diagnostic criteria" but "is one of the features that has been observed." Joint attention — responding to "Oh, look here" — "is one of the earlier" features and "it's not pathognomonic, so to speak, so it's not specific to the disease in any way." Huberman raises the "positive and negative symptoms" terminology and clarifies that "positive is the presence, negative is the absence," because "people think positive means good." Pasca adds that "there are certainly many deficits, and some of them can actually be compensated later."

Huberman asks about reports that "when children with autism have a fever, that their symptoms improve." Pasca calls these "mostly anecdotic reports" of parents describing a non-verbal child who, during "a very high fever," will "start talking in sentences very briefly or engage," while noting "Kids, in general, when they have a high fever, they tend to be more talkative." He lists hypotheses — "how the noradrenergic system is activating during fever," cytokines and "immune molecules that are present during fever that are somehow getting into the brain," and ion channels that "will open more when the temperature rises" — but concludes "it's mostly anecdotic at this point" and "certainly, again, probably not present in all individuals with autism," precisely because "autism is, again, not one single disease."

On the microbiome, Huberman recalls mouse fecal-transplant experiments ("fecal transplants from what we call wild type or healthy mice into mice that had some symptoms that resemble autism") and "some human clinical trials using fecal transplants." Pasca replies that "almost everything has been associated or thought to be causal" but "demonstrating this is very, very difficult": "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." He uses sleep as a parallel — "70, 80% of them" among the profoundly impaired "will have severe sleep disturbances," where "just imagine even just improving the quality of sleep for those patients can do miracle" — and picky eating that "creates ... dietary disturbances" once thought "really at the core." Against all this, "most of the evidence points out towards a very strong genetic component behind it," with "hundreds of genes that we know when they are mutated, they are strongly associated with specific forms of autism."

Huberman then raises David Ginty's "really beautiful experiments" at Harvard, which "induced mutations just in the periphery, so outside the brain" of mouse models for autism and "saw a lot of the same symptomology," asking whether "autism originates in the brain or whether or not the deficits in the brain are the byproduct of changes in the body." Pasca calls these "really elegant experiments" and sorts the genes into categories: proteins "that sit at synapses"; ion channels, "so-called channelopathies"; synaptic-related genes, "synaptopathies"; and "chromatin genes, so like proteins that pack the DNA in cells," the "chromatinopathies." He stresses "many of these genes are also expressed in the periphery," so perturbing "some of these critical periods of development can have certainly devastating effects later on."

Asked about treatment, Pasca says a family presenting with an autism diagnosis has "still a 20% probability that they'll leave the clinic with a genetic diagnosis." The mutation "may be sometimes a mutation that was present in one of the parents and got transmitted," or "present in both," or "mutated de novo, meaning that the mutation was not present in either parents" but arose "perhaps early in the sperm cell, in the egg cell, or perhaps in early stages of development." Pasca notes "All of us, we have a lot of new mutations. About 80 new mutations, 30 of them are protein truncating," so even "when you see a gene that is mutated," the challenge is "to know whether that gene is truly causing the disease."

Causality is established clinically by finding "many patients that have a similar presentation clinically" — for example syndactyly ("they have webbing of the finger"), autism and epilepsy — who "all have a mutation in one single channel. Let's say in a calcium channel." That is "Timothy syndrome, a genetic form of autism where the mutation is very clear," where "there's one single letter in the genome that is changed and causes a relatively similar presentation in all of these patients." Yet "sadly, that doesn't do that much today because we don't really have specific therapies for those forms," and "the rest of the patients will essentially fit into this larger category of idiopathic, meaning that we don't really know the precise cause."

Asked to speculate on "this fairly dramatic increase in the incidence of autism" and the common refrain that "maybe it's better detection, better diagnosis," Pasca answers "certainly the increase is still puzzling." He credits "changes in diagnostic criteria, which have happened over time" that "changed, to some extent, the prevalence," and "a diagnostic migration, so to speak," in which "some children, for instance, 30 years ago would have been diagnosed with intellectual disability, and today they fit the criteria for autism," noting "About a third of individuals with autism also have intellectual disability." He also mentions "availability of services" but concludes "we don't truly understand all the reasons behind this increase."

So essentially, just think of it as they're individually rare form, but collectively common.