Schizophrenia, Nicotine, BOB discussed on a16z

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With help from the Galvin's and other families identified another genetic area called. Churn seven and turn a seven is related to the vulnerability theory of schizophrenia. Which is that. Perhaps one is over sensitive or has a sensitivity issue to stimuli. That looks schizophrenia. As a developmental disease one that really begins in utero. Even though it manifest itself much later and over the years he struggled to find a way to perhaps make the area more healthier more resilient and less vulnerable and he has a hypothesis that there actually is a safe. Nutritional Supplement Choline can strengthen brain health generally of the unborn child but also perhaps cross your fingers sixteen times perhaps many years from now prove to make the children more resilient less vulnerable to psychosis and they're doing on all studies right now using choline and if it shows any promise at all he has the Galvin's and other families like them to thank Stephan. It'd 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 sourcing? Then where did we go next? And what was the sort of industry response? Where are we today? In the past. There was a quite productive age. Where drugs like Zyprexa were developed. Where we're looking for simply animal behaviors. That were related to schizophrenia. And here is where having sort of a tool kit 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 in 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 cortisol structures in the folding. That would be we think is where the higher processes that are affected in schizophrenia reside. So to your point about cells dish. I mean it's really a problem of models right. 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 nineteen nineties? There were a number of very good efforts. Based on sort of synoptic 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 uncover what the molecules are that regulate glutamate and regulate dopamine and a number of clinical trials. Were done on these as well but still does stymie. The field today is if you take the overall disease what is your model. What do you tested on? That gives you confidence that you can test this safely in humans and that 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 anywhere else outside of humans? Schizophrenia tough one. It's very tough now. Nothing is easy. But for example tumors do grow animals. And you can implant. A patient derived x plan. 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 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 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 Matab Petro Glutamate receptors. That's a particular type. A subtype of glutamate. Which is the main excited Tori 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 anti psychotics. 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 famous for going off their medications. So if you can perhaps make a medication that is simply last longer and can be given maybe every month or even less duration under a doctor's supervision that's a significant medical advances 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 Freedman 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 focusing concentration. I mean there's a stereotype of schizophrenic patients. Getting some relief from chain smoking because it focuses their mind and there's a hypothesis related to nicotine. There was for 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 Freedman did try for a while to work on a drug for that and he reports anecdotal excellent results for 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. You know through Coleen especially in the nineteen nineties. There was a lot of companies and a lot of academic researchers investigating nicotine nicotinic receptors. And again there did seem to be a clear linked to schizophrenia. Perhaps schizophrenics are self medicating by smoking. If so perhaps you can make a sort of sub type of nicotine that gives you some benefit or perhaps even some war benefit and again as Bob said that perhaps last 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 nonselective molecule. While everything hits is called a nicotinic receptor but your body has something like fourteen fifteen genes for individual sub units that together come together for a receptor for nicotine and they all mix and match and 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 sub form of nicotine that would only hit seven 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 industry right now to find other alternatives to things like the class of drugs that you know. Sore Zine and some others that you've mentioned I mean those do work to some extent yes to some extent so I'm not a clinician about fifty percent of the patients well to a typical psychotics. But this doesn't touch sort of the cognitive and emotional problems and one of the things one of the many things 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 cognition is fine clearly. These people are very articulate very bright in many cases but some things 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 one percent of the population. This is across populations across cultures. So it's a huge opportunity to make therapies that help patients what is not a rare disease for what is not a rare disease and we go beyond that again as Bob's book so amply demonstrates the toll on people's lives it's far beyond that one percent. 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 sub types of schizophrenia defined genetics where you really would have one particular form of schizophrenia. So Stephan 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 new capability? What would that be? That would really push us forward into a new chapter all go way afield but if we could monitor the brains of a schizophrenic with sufficient resolution with high resolution right now we've got about a millimeter Vauxhall with the best bold FM 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. 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 area of brain tissue that has 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 to existing drugs due to that. What is missing with existing drugs? That's fascinating it almost sounds like you need like a wearable. Mri very high resolution. Silicon Valley go to it. What about things like crisper? If you do start defining some very specific narrow very entire medic causes that the possibility is 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 families like the Galvin's that we had good reason to believe would make them develop schizophrenia. Can we get in there and change that one nuclear tied 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 nucleotides changed in every cell in the brain and no changes in any other nucleotides in the brain and delivering something that will actually crossed 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 I 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..

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