a16z Podcast - The Story of Schizophrenia

Episode Date: April 7, 2020

Descriptions of the mental illness we today call schizophrenia are as old as humankind itself. And more than likely, we are are all familiar with this disease in some way, as it touches 1% of us—millions of lives—and of course, their families. In this episode, we dive into the remarkable story of one such American family, the Galvins: Mimi, Don, and their 12 children, 6 of whom were afflicted with schizophrenia.In his new book, Hidden Valley Road: Inside the Mind of an American Family, Robert Kolker follows the family from the 1950s to today, through, he writes, "the eras of institutionalization and shock therapy, the debates between psycho-therapy versus medication, the needle-in-a-haystack search for genetic markers for the disease, and the profound disagreements about the cause and origin of the illness itself." Because of that, this is really more than just a portrait of one family; it’s a portrait of how we have struggled over the last decades to understand this mysterious and devastating mental illness: the biology of it, the drivers, the behaviors and pathology, the genomics, and of course the search for treatments that might help, from lobotomies to ECT to thorazine.Also joining Robert Kolker and a16z's Hanne Tidnam in this conversation is Stefan McDonough, Executive Director of Genetics at Pfizer World R&D, one of the genetic researchers who worked closely with the Galvins. The conversation follows the key moments where our understanding of this disease began to shift, especially with new technologies and the advent of the Human Genome Project—and finally where we are today, and where our next big break might come from.

Hi, and welcome to the A16Z podcast. I'm Hannah, and in this episode we talk all about the remarkable story of one American family, the Galvins, Mimi, Don, their 10 sons, and two girls, out of whom six sons were afflicted with schizophrenia, following them from the 1950s to today. Robert Colker, author of the book and previous author of Lost Girls, writes, They lived through the eras of institutionalization and shock therapy, the debates between psychotherapy versus medication, the needle in a haystack search for genetic markers for the disease, and the profound disagreements about the cause and origin of the illness itself. And because of that, this story is really more than just a portrait of one family. It's a portrait of how we have struggled to understand this mental illness, the biology of it, the drivers, the behaviors and pathology, the genomics of it, and a humanics of it,

of course, the search for treatments that might help. Also joining Robert Kolker and myself for this conversation is Stefan McDonough, Executive Director of Genetics at Pfizer World R&D, who is one of the genetic researchers who worked closely with the Galvins. We start by talking about our attempts to understand and treat schizophrenia from Freud to lobotomies to the entrance of Thorzine onto the scene, where that understanding of the disease finally began to shift, especially with new technologies and the advent of the human genome project and where we are today in our understanding of the disease, how to treat it,

and where our next big break might come from. What really struck me about this book was that it was this huge story, not just about one family and this particular disease of schizophrenia, but also kind of a portrait of our entire effort to understand mental illness, period. and not just how we understand it, but how we experience it and how we try to treat it. So let's go back a little bit and talk about schizophrenia itself. I'd love to hear where you think our modern understanding of the disease really began. You describe a key moment in 1903 where we shift from thinking of it as a religious ailment into something else. Or where would you begin that story?

That's around the time of the dawn of psychiatry as we understand it. today. Obviously, there are glimmers beforehand of people believing that mental illness is physical and not spiritual or religious. But by the turn of the century, there was an entire field emerging, and there was a nature-nurture debate over what schizophrenia was that really, in many ways, continues today in a different form. Back then, the debate was between Freud, who believed that therapy could cure schizophrenia, that schizophrenia was something that happened in the nurture side of things, something that happened in your childhood, it, perhaps bad parenting. And then on the other side were a lot of other psychiatrists,

including the ones who named schizophrenia, who believed it had some sort of physical property but could never put their finger on what it was. And into this debate come the Galvins, who by the 1950s and 60s are starting to become mentally ill at a time where most psychotherapy believes it's the parent's fault. And medical psychiatry is sure that drugs can hit whatever is happening genetically, but they really have no. clue how those drugs work or what genes are really at play. And this continues for decades. The story of the family starts in the 1950s, but you describe some developments before you get to this with Dr. Frome Reikman and Gregory Bateson and a couple of other characters that to me felt

like kind of key points as our understanding of the disease was developing. In 1948, Frieda Fromm Reikman, who was a psychoanalyst then living in America, came up with a term called the schizophrenogenic mother, which she believed was a certain type of mother or father in some cases who was so bad at parenting, was so torturous in the way that they dealt with their children, that the child then would somehow create their own imaginary reality in order to escape from that parent and become schizophrenic. And that was the split. The split was from internal to external. Exactly. You know, when sometimes people think schizophrenia means split. personality, but it really never did. And it's really a split between your perceptions of reality and

of what's happening inside you. And so, Frida Fromm Reikman was doing this at a time where lots of psycho analysts were blaming mom and dad for lots of things. And of course, by 1960, you have the movie Psycho, you know, the greatest homicidal maniac in all of cinema. His problem is his mother. And everybody says, oh, yes, that must be what happened. And it seems strange now. But when you think about it back then people like Frida Fromm Reikman and Gregory Bateson, they were doing battle against eugenics, at the time a modern feeling that you could breed out schizophrenia and that you should sterilize or even euthanize mentally ill people. And they were also doing battle with people who were committing lobotomies and insulin shock therapy and electroshock therapy. They were doing

battle with a medical field that was treating schizophrenic people as subhuman. And so they felt like they were on the side of the angels. It was really interesting to me that the kind of duality from Reikman, her position, you know, on the one hand, having more compassion than anyone had ever really had before for the people suffering from this disease, but on the other hand, having so little compassion, you know, for the mothers, it was just a very interesting split there. Yes, indeed. And I think she and a lot of other therapists of her generation were threatened by changes in society. Women are working after the war, the family unity. is being threatened in some way. The sexual revolution is about to happen. Any major changes in

society then began to be attached to the idea of mental illness until the researchers who went after the Galvin family, who came up in the late 60s and early 70s at a time when a lot of established psychiatry was telling them still that parents were the problem and that working mothers in particular were the problem. One of the things that really struck me, Bob, was you start in a really interesting place. You begin with a story of training a falcon. And Mimi, you call her a refined daughter of Texas aristocracy by way of New York, clutching a live bird in one hand and a needle and thread in the other, preparing to sew the bird's eyelids shut. Can you tell me, why did you start this huge story about mental illness with this one incredibly vivid and surprising moment? This took place

maybe a week or two after Mimi and her children moved to Colorado Springs in the early 50s to join their husband who had just moved there for the Air Force. The whole thing was unfamiliar to her. It was out of her comfort zone. And then to be thrust into this situation where she was suddenly getting into falconry and having to sew eyelids shut, this was as foreign as it came to her. And the point of the story really is that she accomplishes it. She winds up training and disciplining the falcon, and it winds up becoming almost an allegory for how she approaches the rest of her life, including the raising of children. She thinks if she tries hard enough, does all the right things and does them all in the right way with discipline and pressure, she will get the result she desires.

And we all know that with children, that isn't exactly true, but in the Galvin family's case, it's tragically true, 12 children, six of whom had acute mental illness. And before we get into this particular family and how they dealt with us, I just want to talk also a little bit about up until that moment, the different treatments that had matched up to our understanding of the disease that we had tried. You mentioned insulin shock in the 1930s, lobotomizing attempts and things like that. Can you kind of map out those early therapeutic attempts? Well, lobotomy is about severing nerves in your frontal lobes. It's an extreme measure. And I think most people would consider it barbaric now. but it was intended to impair you just enough so that you would stop hurting yourself mentally. That seemed to be the justification for it at the time. But the other procedures that you mentioned, things like electroshock therapy and insulin shock therapy, all sort of operate on the same principle, which is to somehow induce enough stimulation,

enough of a seizure, even almost a medical coma, so that you shock the patient into focusing and not being so distracted or drawn away by whatever is going on with their brain chemistry. And sometimes it would seem to work, at least temporarily. And other times they would decide that the person needed to be shocked every day. So then in the 1950s, a major development on the drug side, you talk about the entrance of Thorazine onto the scene, which dominates the next second half of the century and still has a huge legacy in how we handle this mental illness.

Can you talk about what brought Thorisine? Zorazine in and what that moment was like? Like a lot of pharmaceutical advances, it happened sort of sideways or by accident. There was a French surgeon who was trying to come up with a battlefield anesthetic. And he did some combining of traditional anesthetic and narcotics and found that the people he was testing it on, it almost induced a happy coma on them, the way that he described it. this drug eventually was thorazine and even now. Really, thorazine is the great advancement pharmacologically for schizophrenia and still is. And then there's an atypical version or a variety

of a psychotropic drug called chlozapine. And my understanding is that those two drugs really are the Coke and Pepsi of this field and that any drug out there is sort of a derivation of one or the two. There are people who were in such extreme condition and harming themselves, so much that certainly drugs like this could be helpful to them to keep them alive. But I think the other sad fact is that they aren't cures and that it's been decades now and there really has been no revolutionary drug for schizophrenia since the 1950s and 60s. The best clue to actually understanding how to attack a disease is have something that cures the disease, especially something like schizophrenia where the ideology we may be starting to understand some of the underpinnings

with it, but people don't come to us at birth and say, I'm going to have schizophrenia. schizophrenia, please modify me in some way. We wait until the symptoms develop. And so exactly as Bob said, it was the cornerstone advance in the field to find a therapy that you can take as a pill that did in some ways make some patients better. Then you can just simply reverse engineer that therapy and try to find out on a molecular level, what is it doing? And then that leads to understanding of disease, to dopamine receptors, serotonin receptors, and so on. So let's go back now to that moment in the 1950s, which is basically where the Galvin story starts as well. By the 1960s, the oldest of the 12 Calvin children were starting to go off to college. And as we know, schizophrenia's onset is quite often

in late adolescence. And so the oldest son, Donald, the star of the family, the football star, the guy who dated the general's daughter and who was a master falconer and repeller on the cliffs of central Colorado, he had really had secretly felt quite alienated from mainstream, like, and really was struggling in many ways privately, and that struggle went public by the middle of college. He ran into a bonfire and didn't know why. He tortured a cat and killed it and didn't know why. He ended up in student health services for many different reasons

until finally psychiatrists got involved. And this was a panic moment for Don and Mimi Galvin, the parents, because they knew that, first of all, they would be judged because at the time, if your child had a psychiatric, problem, it obviously must have been the parents' fault. And so they went shopping for a good opinion because back then, really, what illness you had psychologically really depended on what doctor you visited. Some would say give him thorazine. Others would say give him a lobotomy. So they went and they found a doctor who recommended he could go back to college and that he would just grow out of it. And then

he got worse and worse. And until finally he had a moment of violence with his young wife. That was it for him. He went off to the state mental institution for a few weeks and then spent the rest of his life really at home with Don and Mimi, with his parents, almost as a revolving door between the state institutions and home. It struck me that every story kind of showed the different lenses that we've used to try and understand this disease. Each had some of these common traits and some wild discrepancies and differences. A lot of the stories began with, we started. We started. We sort of always knew. But some of them, it came completely out of left field. And then some of them even seem like they come from a cultural moment, like Michael, who goes to live on the farm in the

1960s. That's right. Michael's sort of a hippie, and he is rebelling. And then that gets confused with mental illness for a time. He insists that he is not mentally ill. You know, Peter was very, very oppositional as a kid said no all the time. And then he had psychotic breaks. So you could say they saw that coming. Joseph had a detachment from reality. It seemed now and then, and so everybody was sort of waiting for him to finally have his psychotic break, and he did in the early 80s. But then there were surprises. Matt, who was a talented ceramic artist, suddenly one day out of nowhere, you know, smashes something that he made and strips naked in a friend's house, and suddenly, you know, he becomes medicalized as well. So it's interesting how some seem

explainable and others do not. At the same time as we're hearing this story of how our understanding of the disease changed and how this one family that manifested so many of those efforts to understand and manage it, it's also a story of technology, right? The developing technology that we have to understand biology and to understand our brain. Another key moment was when suddenly we start being able to see the brain through scans in the 70s. Can we go to, to how this story evolved when that kind of technology came on the scene? Yes, by the 70s researchers were able to have some glimpses into the brain thanks to technology, thanks to MRIs and PET scans and CT scans and the like.

And with the sequencing of DNA, it became possible to think about being able to actually study the genetics of any sort of population of people with any sort of illness or disease. Technology drives biology across multiple areas. I see that story again and again in whatever field I'm in. If you look at the beginning, the first MRIs, those could only be structure. This might tell you is the structure of the brain different, but it doesn't tell you how it functions. It feels like it's a story about a family, but it's also really a story about kind of modern genomics and going from understanding something as an inherited disease in some way to dialing into a way different level of understanding about genetic information.

So what was the genomic story of what we understood of schizophrenia, pre-galvins, why was the family such a turning point in the context of the human genome project? And then what did we learn from them? I write about Robert Friedman, who's at the University of Colorado Hospital, and Lynn DeLisi, who is at the National Institute of Mental Health. Lynn's story really intersects with Stefan's, my fellow guest on this show. And before she met Stefan, she was a pioneer in studying families like the Galvins. and the Galvins were the biggest family she ever found in those early years. And she was convinced that families were the best way to take a look at this illness

because you weren't searching for a needle in a haystack. You had a much smaller haystack to look through. There were a closed petri dish of shared genetic data with a lot of incidents of schizophrenia. Multiplex families like the Galvins with lots of schizophrenia in them have something to teach us. And she amassed the largest collection of family DNA for this purpose. But there came a time in the 90s when the... human genome project was underway, when everyone thought that once the genome was sequenced, they'd be able to do entire population-wide studies. And that anyone with schizophrenia or with any

other complex genetic disorder would sort of stick out like a sore thumb, you would find the smoking gun gene or genes, and then you'd have a target to medicate with a drug. And bingo, we'd all be cured by the time, you know, dinner came. But the problem is that with complex conditions like schizophrenia, it only complicated things so much more. They found one genetic irregularity for schizophrenia and then another and then another and then another until now there are far over 100 genetic issues. Unfortunately, each one of these irregularities contributes just a fraction of a percentage of the probability that you might get the illness. And so it winds up being meaningless. It strikes me as just as fluid and complicated and long a list

as the list of symptoms that over the last century have been associated with the disease, the manifestations of it. Exactly. And it's not helpful clinically. It might be helpful for future research, but at the moment, it just makes the mystery more mysterious, which is what makes it so interesting that when Stefan recognized that families might have something to offer and wondered, hmm, who out there has been studying families? And lo and behold, there was a woman who had been doing it all this time.

and the two of them teamed up. Stefan, can you talk about what it was like to enter on the scene in that moment and what the genomic aha was for you there? Yeah, the technology had not been there to really analyze the families that Lynn collected. She collected them so much before the technology was available to really look in fine depth at the genome and find, is there something different? Back when I was in grad school studying genetics, it was mustard weed and fruit flies and sort of model organisms.

When the genomic revolution came along, so much computational power came to be developed. The technology just kept developing to be able to sequence entire genomes rapidly and inexpensively, comparatively and expensively. People sort of thought, with a disorder that is so strongly heritable as schizophrenia, there must be something there. And again, what was turned up in surveys of tens of thousands of schizophrenia, looking at all the genetic variants they carried, versus tens of thousands of people matched controls as best they could, say for ethnicity and other

factors. No question there are differences. Those have led to some hypotheses like sort of a general overall role of the immune system. But in terms of discovering what is the driver for a disease like schizophrenia, it just simply didn't work that way. And we still don't understand why. Where are we starting to make progress there in understanding kind of the biology and the drivers and potentially how to treat them. You talked about looking at when a drug like Thorazine works and trying to work backwards from that to understand more of the biology. Are we still there?

Or does our understanding of the underlying genomics shifted a bit? Shifted a bit. I think we've gone from a picture of, again, as Bob said, evil spirits or dreams or some environmental influence or a mother to sort of a holistic picture of the brain whereby following Thorazine. We would say, okay, well, dopamine is dysregulated or glutamate is dysregulated. And these are chemicals, neurotransmitters, for how nerve cells communicate with one another. Now we're verging towards a sort of cellular synaptic view.

Another of the technology that developed probably in the 80s and especially 1990s was the ability to really look in very, very fine detail in sort of millisecond scale resolution at how nerves communicate with one another. You can stick an electrode on one nerve and stick an electrode on the other and really record how they're communicating. So this is, I think, how our overall picture of biology is evolving into as to what it means, how we cure the disease. Classic analogy, in order to fix a broken TV set, you have to know what makes it work in the first place. And we're still not there, but we're getting closer. What is the technology that's coming onto the scene now that is changing, you know, our potential understanding moving forward?

I think one of the areas that's exciting now is you can actually take a skin cell from somebody and treat it with appropriate biological factors, and it will differentiate into something that to first approximation might be a human neuron. I haven't seen therapies come out of it yet. In fact, it may be another blind alley, as with all areas of research. But there is the hope that if you take a skin cell or a group of skin cells from somebody with schizophrenia, perhaps that mutation is genetic. Perhaps that mutation then is still carried in the skin cells and their nerves might look different. So this is a possible angle. It's a bit of a risky one for many reasons. You never know if you're actually dealing with a neuron. What do you mean by it's hard to even know if you

have a neuron? Well, you've taken a fibroblast, a skin cell. You've treated it with appropriate factors. And certainly it elongates. It starts sending out processes. And if you can stick an electrode in it, you can see that it's electrically active. Does that mean that it really is close enough to a human neuron in a human brain that has developed through its entire life, through the entire life of the individual, and has been exposed to all the different environmental influences? Right. The question isn't, is one thing like the other? They are like on some level, unlike on others. Is it enough alike that you could actually try to turn a therapeutic on it and try to do your modification now you've got sort of a disease in a dish?

And that's an open question. Bob, where would you see the Galvin's their story if it was unfolding today? Can you talk a little bit about how it kind of mapped to where the understanding is, where their story ended? Well, the two separate teams who studied the Galvin's each have come forward with some really interesting advances, both of which offer a lot of hope. Lynn, Delisi, and Stefan sequenced the genome of the Galvin family and found one irregularity in a gene called Shank 2. this is not a silver bullet or a smoking gun. It's not like the shanktou gene is the key to schizophrenia. However, assuming that it is the player that really did its trick on the Galvin family,

it is a gene that's highly related to brain function and could, with further study, point the way to understanding how schizophrenia works, how that TV set works, as Stefan had said before. And so that's exciting. And more broadly, in terms of drug discovery, families like the Galvins can be almost sort of test kitchens, you can look at how their genetic code might interact with certain potential therapies and see perhaps how it might go with the broader population. Then with that second set of researchers led by Robert Friedman over in the University of Colorado, he, with help from the Galvins and other families, identified another genetic area called Churna 7. And Churna 7 is related to the vulnerability theory of schizophrenia, which is that perhaps

one is oversensitive or has a sensitivity issue to stimuli. It looks at schizophrenia as a developmental disease, one that really begins in utero, even though it manifests itself much later. And over the years, he struggled to find a way to perhaps make the churn a seven area more healthy or more resilient and less vulnerable. And he has a hypothesis that there actually is a safe nutritional supplement, Colleen, can strengthen brain health generally of the unborn child, but also perhaps cross your finger 16 times, perhaps many years from now prove to make the children more resilient, less vulnerable to psychosis. And they're doing longitudinal studies right now using Colleen. And if it shows any promise at all, he has the Galvins and other families like them to thank.

Stephanie, it would be very interesting to hear from your side of the kind of story of the pharma industry attempt to manage this as well. Where would you see those attempts after Thorzine? Then where did we go next? And what was the sort of industry response? Where are we today in the possibilities? Yeah, there was a quite productive age where drugs like Cyprexo were developed, where we were looking for simply animal behaviors that were related to schizophrenia. And here is where having sort of a toolkit is quite valuable in a sense. Because if you know, for example, if there's some odd behavior that an animal is showing, that thorazine mitigates, then without even knowing the receptors involved, perhaps you can test drugs and

animals for other drugs that mitigate those behaviors and perhaps don't have side effects. So the problem, of course, is that rats don't get schizophrenia. They don't even have sort of the massive cortical structures and the folding that we think is where the higher processes that are affected in schizophrenia reside. So to your point about cells in a dish, I mean, it's really a problem of models. it's a problem of models how do you before doing a clinical trial in humans how do you get confidence that your drug is going to work and i think in the 1990s there were a number of very good efforts based on sort of synaptic studies people have known again going back to some of the early

pharmacology that dopamine was involved that glutamate was involved now we started to identify with the human genome project and just molecular cloning in general we started to uncover what the molecules are that regulate glutamate and regulate dopamine. And a number of clinical trials were done on these as well. What still does stymie the field today is if you take the overall disease, what is your model? What do you test it on that gives you confidence that you can test this safely in humans and that it will have some effect? How do people even do that? I mean, are there any other tools before you begin clinical trials in humans when there's a disease that really doesn't present to anywhere else outside of humans?

Schizophrenia is a tough one. It's very tough. Now, nothing is easy, but, for example, tumors do grow in animals, and you can implant a patient-derived explant, a patient-derived tumor into an animal, and perhaps test therapies there. Or you do have cancer cell lines.

Tumors will actually, cell lines will actually grow in a dish. And so something that kills those could reasonably be called to be acting on the tumor. And we simply don't have that equivalent for schizophrenia. So what was the next moment where there was sort of something that seemed on the pharmacology side, like a real viable treatment that we were, you know, that people were getting excited about and where are we now? People were excited about metapotropic glutamate receptors. That's a particular type, a subtype of glutamate, which is the main excitatory neurotransmitter in the

nervous system in humans. People were excited about sort of finer manipulations of dopamine receptors. And again, by reverse engineering some of the atypical antipsychotics, you could find out that serotonin receptors also had involvement. Now, each of these is going to be a broad family of many, many genes. So can you do more finer manipulations of these? Not every advance in drug therapy has to be a totally new mechanism. Schizophrenics and other CNS disorders are famous for going off their medications. So if you can perhaps make a medication that just simply lasts longer and can be given maybe every month or even at less duration under doctor's supervision, that's a significant medical advance. And this is an engineering challenge.

I started life as an engineer, and drug discovery is really biological engineering. I'm not saying it's easy, but we do know how to make drugs last longer in the body. There's a very interesting story in there with nicotine. The receptor that Robert Friedman in Colorado had identified with help from the Galvin family and other families like them was a nicotinic receptor. And strictly speaking, that's a receptor that when medicated might actually help with focus in concentration. I mean, there's a stereotype of schizophrenic patients actually getting some relief from chain smoking because it focuses their mind. And there's a hypothesis related to nicotine. There was for a time that if you could somehow drug this receptor a little bit to help it along, that perhaps this would prevent delusions

or even prevent psychotic breaks. And Robert Friedman did try for a while to work on a drug for that and he reports anecdotal excellent results from many patients, but it was a drug that you had to take several times a day, and that was something that the pharmaceutical companies couldn't bring through trials to make into a once-a-day drug. So it went away. So he decided to go after the nicotinic receptor in utero, through coline. Especially in the 1990s, there was a lot of companies

and a lot of academic researchers investigating nicotine and nicotinic receptors, and again, there did seem to be a clear link to schizophrenia. Perhaps schizophrenics are self-medicating by smoking. If so, perhaps you can make sort of a subtype of nicotine that gives you some benefit or perhaps even some more benefit. And again, as Bob said, that perhaps lasts long enough in the body to be practical to be taken as a drug. So in this case, there was a biological challenge there, no question,

but it became also an engineering challenge, as all drug discovery does. Nicotine is quite a non-selective molecule. Well, everything it hits is called a nicotinic receptor, but your body has something like 14, 15 genes for individual subunits that together come together to form a receptor for nicotine. And they all mix and match in very unpredictable ways and ways that still are not well known. So the challenge was quite formidable.

People did go ahead for technical reasons. It turned out to be easy to make sort of a subform of nicotine that would only hit alpha-7 receptors. Not easy, but not impossible either. People had good reason to think that this might work. No question, it was a huge downer for patients for the field for everybody when this entire class of drugs just sort of didn't seem to come to nothing. But we learned.

And the negative result often is just as informative as the positive result. We do learn. Can I ask how incentivized is the sort of pharmaceutical index? right now to find other alternatives to things like the class of drugs that, you know, Thorazine and some others that you've mentioned. I mean, because those do work to some extent, yes? To some extent. So I'm not a clinician. About 50% of the patients respond well to atypical antipsychotics. But this doesn't touch sort of the cognitive and the emotional problems. And one of the things, one of the many things I'm grateful to Lynn for was really taking me to

visit her patients so that I could really see there's no question something is wrong just sort of a very emotionless flat affect the cognition is fine clearly these people are very articulate they're very bright in many cases but something's badly wrong so to your question what is the incentive for pharmaceutical companies it's a huge incentive I think lots of people would love to do it because schizophrenia is 1% of the population this is across populations across cultures. So it's a huge opportunity to make therapies that help patients. For what is not a rare disease? For what is not a rare disease. And if you go beyond that, again, as Bob's book so amply demonstrates to the toll on people's lives, it's far beyond

that 1%. We just don't know how to do it. Not for the broad schizophrenia there. And this is where I came from my angle to sort of look at perhaps there might be subtypes of schizophrenia defined by genetics, where you really would have one particular form of schizophrenia. So Stefan, if you, as a researcher, if you could wave a magic wand right now, you know, you mentioned better models. What are the things that if you could wish something here tomorrow in the form of a new technology or a new capability, what would that be that would really push us forward into a new chapter. I'll go way afield, but if we could monitor the brains of a schizophrenic with sufficient resolution, with high resolution, right now we get

about a millimeter voxel with the best bold fMRI experiments while they're actually having a psychotic break. The resolution is still, of course, could be made finer and finer. We still can't get down to the level of a single cell. But now with the blood oxygen level dependent, magnetic resonance imaging, we can get a measure of function in somebody's brain in real time. Difficult to do, takes a lot of equipment, takes a particular stimulus, but one could perhaps hope that this will lead to more insights. Oh my gosh, how fascinating that we've never seen. We actually have no idea what's really happening. I mean, consider the logistics. You can't consent somebody and get them to

sit in a machine and then wait for them to have a psychotic break. Yeah. What would you be looking for? We need mechanism. If the field as a whole could say, here is a particular area where the excitability is abnormal, an area of brain tissue that is abnormally excitable, or a particular receptor that is abnormally excitable. That gives us a good place to start. That gives us mechanism. And then perhaps we could study what do existing drugs do to that,

what is missing with existing drugs. That's fascinating. It almost sounds like you need like a wearable MRI of a very high resolution, like some sort of. Silicon Valley, go to it. What about things like CRISPR? If you do start defining some very specific, narrow, very, entirely genetic cause, is that a possibility as well? So we'll give a possibility.

Say if we knew that a baby galvan or their modern-day counterpart babies had a variant in a gene that we thought, because of families like the galvins, that we had good reason to believe would make them develop schizophrenia. Can we get in there and change that one nucleotide to the wild type? It's conceivable, but again, the challenge here is the engineering challenge. We can do it in a dish, but trying to get just that one gene edited, trying to get it in just that one nucleotide changed, in every cell in the brain, and no changes in any other nucleotides in the brain, and delivering something that will actually cross the blood brain barrier, and then doing it on an infant.

How would you even test this? Very, very difficult. Bob, you describe when Lynn Delisi first met the Galvin family, and you write this incredibly profound line that really stuck out for me. As she walked through the door of the house at Hidden Valley Road, she couldn't help but recognize a perfect sample. This could be the most mentally ill family in America. And you really dove into every element of what that meant for them

into this family's innermost suffering and struggles. It was just so intimate on some level and also such a big story on another level of not just schizophrenia, but the way we struggle with all mental illness, including trauma and depression. What was the kind of big takeaway for you for having lived inside this family's mental illness for several generations, really? Well, I really think the day, I mean, hopefully, not too long from now that all this research yields real rewards will be the day that this family's sacrifice will finally find its true meaning. But also, this is a story about experiencing

unbelievable and mysterious tragedies one after the other and coming out the other side. There are members of this family who have found a way through this and found meaning in life when everything seemed to be going against them. It's really about the value of family, in my opinion, this story and the hope for the future. the research side, what's coming that we should be aware of, that might be bringing hope to the next generation of galvins? It's tough. I could answer this for Parkinson's.

I could answer for Alzheimer's. I could answer for any number of diseases. Schizophrenia is really, really tough. We need some help. We need something to break in the academic world, and that break will come from studying people. There are ever better ways of studying what is really going on with human biology in people who are kind enough and selfless enough to volunteer themselves and their families for research. Not just their genome, we can measure the proteins circulating in their blood.

There are ways to do this massively in parallel. Stem cells, organoids, I think it's too early to see if these are going to be helpful, but no question, these are a way to explore. People can do longitudinal studies for how people are changing over time. Imaging lets us look into the brain better than ever before, and these technologies just keep accelerating and improving. We need somebody to set the goalposts. there's a lot of advanced technology. Technology will drive biology. We are focused on human subjects. Something's got a break. That's amazing. Thank you so much for both of you joining us on the A16Z podcast, and here's hoping we get to that break soon.