 Well, good evening. My name is Eric Barker. I'm Dean of the Purdue College of Pharmacy, and it's a pleasure to welcome you this evening to yet what is now becoming sort of a tradition around here, but we're beginning to wrap up. This is one of the final ideas festival events as we are wrapping up the 150 years of giant leap celebration here at Purdue University. Tonight, we have the pleasure of welcoming Dr. Gopin Fang to campus. Dr. Fang is the Poitras Professor of Neuroscience and the McGovern Institute for Brain Research at the Department of Brain and Cognitive Sciences at the Massachusetts Institute of Technology. He is also an Institute member of the Broad Institute at MIT and Harvard, and the Director of Model Systems and Neurobiology at the Stanley Center for Psychiatric Research at the Broad Institute. Dr. Fang studied medicine in Hangzhou, China, and then completed his PhD training at the State University of New York at Buffalo and postdoctoral training at Washington University in St. Louis. Prior to joining the faculty at MIT, he was a faculty member in the Department of Neurobiology at the Duke University School of Medicine. Dr. Fang's research is devoted to understanding the mechanisms regulating the development and function of synapses in the brain and how synaptic dysfunction may contribute to psychiatric disorders. Using genetically engineered animal models, Dr. Fang's laboratory combines cutting edge technologies and multidisciplinary approaches to unravel the neurobiological mechanisms of neurodevelopmental and psychiatric disorders. Dr. Fang will be making a brief presentation, and then I will join him on stage for a brief conversation and dialogue, and then we will wrap up the hour by inviting you, our audience, to provide some questions. His ideas, festival question, and theme of his presentation is, what if breakthrough technologies could make us smarter? Please join me in welcoming Dr. Goping Fang to Purdue. Thank you, Dr. Park, for the wonderful introduction. And it's a great honor to be part of the 150 celebration for the wonderful history of Purdue University, and I'm very glad to be here. I toured the campus and had a wonderful time meeting with many extremely talented students and faculty members, so the day so far is great. As long as I don't screw up this last part, it will be a wonderful visit, so I'm trying to do my best. So today I want to, instead of presenting my own work, I want to discuss with you some of the new technology that has been developed and how these new technology may affect our daily life, and for both us and maybe for benefiting of a lot of patients. So you probably know, just I'm focusing on how can we change our cognitive ability, which is our intelligence, and you probably know intelligence just like every other human trait, whether it's behavior or actions, it's a bell curve, right? So most of us in the middle, but there are a few of extremely talented ones like you and on the one side, and then many of us always wish one as smart as Einstein, right? But they are also on the other side of the curve, which some of them just have normal function, but other than extremely other side of the curve, maybe need help that they can have a normal life just like we have. So how do we potentially can move this bell curve all squeeze to this side, right? That's, if they say, if there's a way can improve yourself or your kids they are in intelligence where you do it. Now there's a possibility we can do that. So, and then the question is who should do it, who should decide, and who should pay for it. All these are questions I wanna discuss with you briefly and tell you the technology why we think we can do this now. So what the term in, so IQ actually is very closely linked to success, right? This has, there are a lot of studies. This is just a table I borrowed from Kaufman and show that what kind of professional you do is highly linked to what is child, linked to not only your child, your adult IQ, but also linked to the IQ when you were a child. So this is depend on what kind of IQ almost determine what kind of successful career you can do. So the question is what determine IQ? What determine our intelligence? So how do you decide that? So probably the best evidence is come from study twins, right? You have twins and identical twins which you have almost identical genetic material. Identical genetic, not even almost, identical genetic DNA material. Then you can be raised in the same family or can be adopted into different family or even different continent. So then you can study does their IQ same or different. So this can determine, is the IQ determined by genetic material more or environmental factors more. So this is the kind of one of the generalized results. So this on the left side, why access you can see similarity of our intelligence scores, IQ, their correlations, and these are the raising conditions. All of them are from identical twins. What you can see is that if identical twins are reared together in the same family, you see they are very, very similar IQ. It's almost 90% identical, right? So correlation. But if they are separated into different families or different continent or different countries, you can see that they are actually also very close but not as close as the identical twins. But it's still around about 70%. That means the majority of the intelligence are determined actually by genetic material. And environment do play some role but much smaller than the genetic material. So you can see whether they are identical twins or non-identical twins and siblings and unrelated. So you can see that there's a direct correlation between the genetic factors and IQ, the intelligence. So then comes, so how do genetics determine the intelligence? So based on twin studies, so heritability is around 60 to 80%. That means genetic player significant role but it's not all of them. Because they play a significant role then there's a chance that if you change the genetic material you can improve or impaired intelligence, right? So in disease conditions, such as the neuro-environment disorder I'm gonna talk about a little bit is that you have genetic mutations now lead to intellectual disability. But there's also a chance that you could change the genetic material and make human much more intelligent. And but how genetic is determining the intelligence? So luckily or unluckily, in general it's not determined by one gene. So how do you study that? You basically, we call it GWAS, genome-wide association studies. You can study hundreds of thousands of people with high IQ compare with hundreds of thousands of people with lower IQ to see what are the differences come out. So this is called GWAS studies. What it shows is almost like many other common traits, right? Like height. Height is not determined. Height is very heritable, right? If your parents are tall, the chances you are tall is very, very high. But they are not determined by one gene. It's determined by multiple genes. We call it polygenic. So the GWAS studies for IQs, at least one of the studies show there are over 500 genes actually involved are related or correlated with your IQ. So that means that your intelligence is mostly genetically determined but not determined by single gene, which is probably a good thing, right? So then each gene only play a very small role. So that make a challenge for how do we change the genetic material, make humans smarter, right? So however, on the other hand, single gene mutations can cause very severe intellectual disability, right? We have saw many, many of them, neurodevelopmental disorders with very low IQ. Today, one of them, I use the example, average IQ is only 40. So they can never live independently. So we need to find a way to correct this problem so these people can live independently and have a normal life. So because of the new technology, now we could potentially develop because it's single gene, right? We can correct this gene mutation and actually dramatically improve or even cure this intellectual disability and really change people's life. So because of this genetic engineering, it could be basically part of daily life now if whether it's treated patient or improved intelligence. So what is the new technology? So the new technology you probably heard or at least some of you already heard is called CRISPR technology because basically it's the new type of genome editing technology. The idea is that this is basically a system used by bacteria to destroy viral DNA, right? Bacteria, you know, bacteria phage which is a virus to kill the bacteria and whenever they inject the DNA into the bacteria, bacteria will take some of the DNA integrated into their chromosome. So next time, if it survives, next time you come, I know, I'm going to destroy you. So these are the systems that we can now have been developed to use to manipulate the mammalian genes. So the idea is that you have this... So this is called CRISPR Cas9. The Cas9 is a nucleus. It can cut the DNA. So because the virus DNA coming and incorporated into the bacteria DNA, bacteria will actually remember it. So next time, if the virus comes again, the virus or the bacteria will release a piece of DNA, the RNA used as a guide RNA, guided basically the Cas9, the nucleus to the viral DNA and cut it. So that will destroy the virus, right? So now scientists, many of them, I listed here, you know, Champagnier lab, Feinzans lab at MIT and the Donner's lab at Berkeley, Georgia lab at Harvard, they actually changed the system. Now we can use it to manipulate almost any cell type, in any species almost. So the idea is that you use the system, you design whatever you want. It's a guide RNA, right? As long as it matches the gene, you will bind it to the DNA and you can cut the DNA. So now we have all the genome sequences. So we can specifically design a guide RNA and bind to whatever gene you want to cut. You want it to manipulate, it will cut the DNA. Now that gene is cut, your cell will try to fix it, right? So that's how we get UV irradiated, we go to beach, your DNA is probably damaged in some cells, but you don't get cancer because your cell is always trying to repair it and most of the time repair perfectly. So however, occasionally they make mistakes. Once they make mistakes, you will have cancer or you will have other problems or cell may die. So in this case, basically it will have a mutation. That's how you can generate genealogy mutation not in any species. On the other hand, if you say, okay, I want to change this gene because I know if I put this, change this amino acid, we'll make the, we'll collect the mutation for humans. And then you can put a template, we call it precise integration. You can replace the piece of DNA with whatever you provide. So this made it possible to do anything, right? You can generate mutation, you can repair mutation. So if you, we know there's a patient have a single gene mutation, let's say reticentrum, reticentrum affecting many, many of the girls and they were born to normal. Then after two years later, they started deteriorating, right? Many of them will die at a very young age. So we know these are single gene mutation called MECP2. We now can potentially go in, correct the mutation, they will be probably live normal life. So this you can do both make genetic models or you can repair human mutations. So this technology is unbelievably powerful and efficient. So it can be basically, it can do multipurpose now. I'm not going to go a lot of details, but you can, I mentioned you can do make mutations or you can repair mutations, we call the knockings. But the most important thing is it's highly efficient. It can use almost any species. You can use animals, plants, even humans, right? So many of them may have multiple, let's say intelligence determined by 500 genes, but maybe they are five genes very important. And if you change it, you can slightly move the bell curve. So this system can multiplex. You can do five genes at the same time. So now it's possible. So these have been now in the, it's only less than six years old actually, but it has been widely used. So some of the clinical trial are being started to try to correct some of mutations. And so give you a couple of example. One example is we can now genetic engineering pick as organ donors. So there are a lot of patients waiting for a long time for kidney transplant. So now the idea is that you can actually modify the DNA in the pig that will have a match and it will get rid of all the viral, retro-viral fragment in the pig DNA, which is detrimental to humans. And you correct it, then you basically can, every time you need it, you can harvest the kidney from pig and transplant to the patient, right? So my joke is we can do any of these things. So in the future, when you're getting old, your organ can be replaced one by one by pig. You walk like everything in your body is a pig, except your head is still human, right? So, but they are functional, right? No one can tell. And so the other really important implication, which is even more direct and more impactful is for gene therapy, right? So there are many, many severe neurodevelopment disorders. Many of them you probably know and you probably encountered or you have relatively related, these are patients have very severe neurodevelopment disorder. They are very low IQ, right? So they cannot live independently. And these are very big problem for, not only for the patient, but also for the family. So one of my main research goal is try to find a ways to help this patient because they are really need help to be living independently. Now, these many, many of examples, including Rachsinger might mention fragile mental retardation, feeling McDermal syndrome, which is also very severe. Their average IQ is only 40. So I'm gonna use feeling McDermal syndrome tonight to show what can we do to potentially in the future help with this patient. And so the general features, all these have very severe intellectual disability. Then they have many other problems, including autism spectrum disorders, seizure, sleep problems. And for these severe ones, actually genetic mutation play a key role. Actually, now we already know, so at least 25% of them are caused by mutation in a single gene. And for single gene, we now can model them and we now can potentially go correct them, right? With this new technology or with similar technologies. So, and so because of single gene, we call them monogenic mutation. These are ideal for gene therapy. So in the next five, 10 years, you will see a lot of new gene therapy approaches try to really cure this disease. I wanna mention that although these are monogenic, which means single gene mutation, their pathology is yet generally not a single gene because each gene can affect many other genes. So it's almost impossible to find a drug that can correct all different pathways, all different processes that it disrupt. So gene therapy probably is the only way to really cure them. The other approaches, such as the manipulations or pathway interference, these probably can correct part of the pathology, but not all of them. So I wanna use Phelan magnum syndrome as an example. This is a mutation in a gene called Shank-3. Shank-3 is critical for build neuron-neuron interactions. We call synapse, right? Neuron is very different, brain is very different from the rest of bodies. We have 80 billion neurons in the brain. We have trillion of synapses as they connect each other. Neurons do not function autonomously. They have to interact with other neurons to make circuits. Everything you do, every thought you have, these are millions and millions of neurons involved to form a computational process, then end up having results and have output. So even lift my hand is a very complex neural circuits problem. And so these have very low IQ and they're really very intellectually disabled, so you need a lot of help. And so we want to see how can we study them? How can we help them in the long run? So these patients have repetitive behaviors because they are auto-inspectrum disorder. They have social interacting problem. They have sensory problems. Like sensory overload is one of the major issues of auto-inspectrum disorder. So we made a mouse model to start with and you can see the repetitive grooming themselves, right? And they also have social interaction problems. So if I can have this video played, so you can see these are on the left side is two y-type mice and the right side two mutant mice. For y-type mice, their social is whenever two mice together, they basically sniff other mouse's behind. That's their social interaction. It's very different from humans, but it's a social behavior. For mutant you will see, they even bump into each other. They were completely ignored, right? So now they stay very far away. You see y-type, they are, you know, social with each other, they're coloring together, right? So I'm not sure this is related to human, but at least it's a very interesting biological phenomena. What causes, why a single gene mutation can cause mice behavior so differently, right? So then there's another phenomena we think is also very interesting. So these are two, not the y-type is on the right and the mutants are on the left. We just, in their home cage, we put a plastic ball in the middle, right? See what happens. This is a new thing they never saw it before. And so you can see y-type is very interesting. We explore pretty soon, they will go on top of it. And mutants, you can see, when their head is getting closed, they startle back. So that means their whisk touch it. They're very sensitive. They're afraid of this thing. They never will play with it, right? So this reminds us that this is called sensory overload. It's over sensitivity, right? A lot of neurodevelopmental disorder patients, including autism spectrum patients, they are very sensitive to light, noise, all these things that, so that's why they like, one of them they like stay on the side and alone, right? So this is a good model probably to study. Why, what is, now our study show, they actually have a hyperactivity in their sensory cortex, actually. Whenever they receive information, they are neuronally hyperactive. So now we can find a way to try to, you see the y-type is on top of it, they are never getting even close to them. So these models help us to understand how these genetic mutations generally is that kind of behavior. So then the question is, although this behavior you can see in adults, these are all neurodevelopmental disorders. If we develop gene therapy or treatment, can we actually reverse it later on, right? There's a reason we call the neurodevelopmental disorder because the development defect. So a lot of things when you develop, afterwards you cannot reverse, right? We call it critical window, right? So I have an accent because I didn't grow up here. I came 29 years old, so I already way past my critical period. So my English is not as good as anyone or my son who you cannot tell if you don't see him the year he was my son, right? So this is, so the question is, how do you tell? Can you, how can we test what age we can treat a patient in the future still effective? So we designed genetic ways to test in mice first. So basically, we let the mouse grow like mutant. Then in any age, we can give a drug to restore the gene function, right? Just like gene therapy, similarly. And see, what can you reverse what you cannot reverse? So we did that, what we found is in adults, when these mice are four months old, which is a complete adult, and then you re-express the gene, can you reverse anything? Surprisingly, in some of the brain regions, you can. So the top figure is the electrophysiology, look at a synaptic function, they are restored. The bottom is the structural function. Not only functionally, you can restore, but structurally, you can make new connections. That is very exciting, right? So you can make new connections. That means if whatever defect you have in this brain area, this is stritum, which is very important for motor and repetitive behavior, all these things, and you can restore them. Now, do they restore the behavior? Yes, so you can see this is like, so they are repetitive, compulsive, grooming their skin off, but after you turn it on, the hair grow back. The only difference is the hair grow back is the white. This has something to do with the drug we induce for the gene expression. But they also restore the social behavior. So in the middle is the knockout, this is the white type, you put the mice, let them choose whether they want to interact with the mice or interact with the object. You can see white type like interact with mice is the heat map and mutant like the object, but once you restore gene expression adult, they're not go back to like interact with the mice. So that means that some aspect can be restored even in adult. They give us a hope. However, that's not the whole story. There are actually things you cannot reverse. So a lot of things you cannot reverse. For example, there are motor defects. This is what we call the open field. You just let the mouse running around to measure their activity. You can see that the white type on the top line, muting and restored, no difference. So there are things you cannot, what you cannot, anxiety you cannot, motor defect you cannot, also this sensory defect we call novel object phobia you cannot restore. So there are many things you cannot restore them in adult. So now, what if I return the gene earlier, right? Before they become adult. This is turned on after three weeks of birth and you can see many things that we cannot restore before. Now you can restore them. So this tells us that if the mice are humans, which they are not, we can conclude right now that at least in mice, neuronal connection function in the adult brain have certain plasticity. In certain part of brain, they are plastic. Even you have developmental defect, we can still restore them in mice, right? But there are also critical developer windows that we people have studied for decades that we know they are language, they are many visual, you know, critical window. These are critical development windows are key. That many of them, once you pass the critical window, we cannot restore anymore. That means we really have to treat as early as possible if we want a full restoration of function in neural development. It's the same thing. If we want to improve intelligence, we may also want to deal with much earlier, right? Because what is the intelligence, what is the cognition? Cognition basically is your computation power in your brain. So they depend on the connections. So if you wire something wrong, unless you correct that wiring in your computer, your computer is not gonna work very well. So it's the same kind of thing. But your connection made during development, refined after birth usually. So that's critical period. You still has plasticity. After you pass that, you don't have that plasticity. So that's why the only certain part of brain is plastic. The one I showed you plastic is stritum. Stritum is for habit formation, motor activity. Even at my age, I can still pick up a bad habit. That's why it's very plastic. But there are a lot of things people say, oh, old people are very stubborn. Yes, our cortex is fixed. We cannot change our views anymore. Much harder to change our views anymore. So they are different brain regions have different plasticity. So the good news, if mice are humans, there is a post-anatal window. That means we don't have to deal with embryonic. Because we cannot even diagnose them. That means after birth, we still have a window that are called a critical window. We can still diagnose them, figure out a way to treat them, and correct them. So this is the hope that this might be effective. No, this is all our mice. I was specifically written here, if mice are like humans, unfortunately, they are not. So the reason is we have done all these things in mice and worked really well. However, none of them have been translated into humans. There are many clinical trials failed, almost all of them, for CNS disorders. So for example, one of the most famous doing is the Frieda X rental retardation. Three companies all failed a clinical trial. They published wonderful papers in neurons, all different journals. And Pfizer also worked really well in hunting and disease, and also failed a clinical trial. The most recently, just next to our building in Cambridge, Biogen. So this worked really well in mice for Alzheimer's disease failed. That failure overnight cost Biden $18 billion. They stopped job, still haven't recovered. So the joke right now in the field is, it's a great time to be a mouse because we can cure anything you have. It's almost everything. But our goal is not to understand a mouse. Actually, we use a mouse as a model, try to help human. So what do we do? So that lead us to think we need additional models. Mice is always going to be a wonderful model. It's genetic manipulation. There are mammals, so a lot of things are conserved. But we now realize there are a lot of things that are not conserved either. So one of the biggest problem, probably, by the way, it's not a mouse's fault. So it's always scientists how we use the model properly. Every model is useful. Whether it's a C. elegans, Drosophila, they're all useful to help us understanding the human biology. Celdas was discovering C. elegans. It's all conserved in humans. So every model, but for understanding cognitive function, hybrid function, maybe we need additional models, not to replace other models, but further to understand them. So one of the biggest problem actually is the prefront cortex. During evolution, the most expanded area of the brain is the prefront cortex. The prefront cortex is the main reason we make decisions. We make cognitive calculations, right? So if you look at this, these humans, macaque monkeys, the marmoset monkeys, you can see their prefront cortex is much, much bigger than the rodents. This is the rat, actually. Many of the gray areas, these are critical areas, evolved in the monkeys and humans, but they barely exist in rodents. So that probably make a very big difference because it's not only affect this brain region, but since they're all circuits, cortical, subcortical circuits, so it affects the whole brain function. So this is probably one of the reasons why so many things work so well in mice actually do not work in humans. So the idea is, then can we use better models? Or models, we should not say better because we don't have a proof they are better. But can we use a model which more close evolution to humans? So the CRISPR technology now allows us to do this. So we now can put human mutations into monkeys to see whether the model better of some of the higher function defect in humans. So right now in the world, all over the country, world including in Japan, China and in the US, two major monkey models have been used. One is the mamaset. Mamaset is very small. It's about 350 grams with almost like a rat and they are very fluffy, so they look bigger. And the other is a macaque monkey. So mamaset is a new water monkey, so it's a little further than humans. A macaque is an old water monkey, so it's closer to humans, their brain structure is much closer to humans. But each has an advantage or disadvantage, right? So macaque monkeys live for 30 to 35 years. If you wanna study late onset disease like hunting disease, Parkinson's disease, Alzheimer's disease, you don't wanna be a graduate since you work on them. You'll be a long, long time before you, so you probably will quit. So mamaset is much shorter, so it's a good chance that some will make a model you can probably study them. So we, with many others, we try to understand whether this model can help us to understand autism spectrum disorder, like social cognition, social behavior. And so we actually work with a large group of scientists in China. They have so far all the macaque monkey knock out genetic mutation papers are published from China and the mamaset are from Japan. These are two leading countries in this. So we work with them together to generate the shanks remutation. I told you, shanks lead to a severe intellectual disability. And so we were lucky we had homozygous monkeys and helozygous monkeys. In humans, they are all helozygous. So, and we found that in these monkeys, you can give them active to watch, right? Just like we carry, we say, oh, how many hours did I sleep last night? So you can do the same thing. You give them two weeks, then taking them off to see, retrieving the data to see. You can see why type of the blue, they have day and night activity are very obvious, right? They, they have very active night, they have very little activity. So they sleep really well. But in the mutant that you see helozygous in the middle, is a day activity reduced because patients also have reduced the motor activity. They have motor problems. But night activity is a dramatic increase, right? So this is a very mimic human condition. If we have tested drug, so now we are testing, we identify target, we test the drug. If we can improve the sleeping problem, right? It may have better chance to translate into humans. So that's kind of a use we think we can, it can help us to understand and develop drugs. Then the most interesting is cognitive activity, right? Social, I showed you mice social is sniffed at the mouse behind. That's not a normal social, human social, right? So, but if you see this monkey, so this is a two monkeys, for each monkey we have a Y type called probe monkey. They never saw each other before. Then for the test monkey, either it's a Y type or mutant. The probe monkey has a green collar on it, so you can tell which. We use the same monkey to probe every mutant dog, control monkey, right? So you put them together, they divide in the middle. They cannot see each other. For five minutes they get used to the smell and everything. Then a scientist will come, you know, take the divide off, then the monkey can see each other. You will see how they interact. Could I have the video play please? So you can see this is a Y type with Y type, right? So you can see this person coming, you know, take the divide off, now suddenly the monkey can see each other, right? So what you will see is they immediately get engaged, but they never saw each other before, so they are cautious. So they see the green collar, that's the probe monkey. The other is our control monkey for testing. You can see they are engaged, they follow each other, they are very engaged, and they're back and forth, right? So they will look at each other, and so if one goes the other side it will go and when it will back off. So they are very engaged, they look at each other. That's a normal social behavior for monkey, right? Almost like, you know, if you're not gonna hug someone you never see, never met them one before, you usually shake hands, you talk, and then you become friends. So that's what they're doing. So next video is identical. Same green monkey, right? The collar monkey. But the other monkey is the mutant with a hydrozygous mutation of Shank Sri which you found in human patient. What you will find is, could I have the video please? So see repetitive behavior, repetitive flipping. That's a very common repetitive behavior in monkeys, but human is different repetitive behavior. You can see repetitive behavior. Then you will see, you know, this person will release the barrier, then they can see each other, right? So you can see this is the problem monkey come, this monkey goes the other side, this is the mutant monkey. The monkey is interesting something, but it never looked at the other monkey. It's just a look at the outside, look at something, right? Even getting very close to each other, it doesn't look. It just goes somewhere else. So actually after a while, this is a wild type problem monkey get frustrated, actually completely ignore, because it seems this monkey, see this monkey is always interesting something, but never really interesting as a monkey. We think this kind of social behavior, we can understand what is the brain circuits defects, when come, when go. So they never engage each other, right? This monkey is not interested. This monkey we know engage, we test with 10 different monkeys. So you can tell that there's a very significant difference between the social behavior. And this social behavior is much closer to what we think is the human social behavior compared to the mouse if other mouse behind. So if we can correct this problem, maybe there is a better chance that this can be translated into humans. So we can, this can really help us. So, and then because their structure is so similar to humans, so we can actually do functional MRI to see are there biomarkers, they are activity changing in the brain. We actually found a very significant difference between wild type and mutant monkeys. So this could potentially, these are non-invasive life form humans, we do the same thing. So this can be translated into humans to see whether human patient also have this kind of defect in their neural circuits, in different brain reading, in chrythalamus, striatum, sensory cortex, the video cortex. If they do, then this can use a biomarker. Did our treatment improve this basic function of the brain? So that now, these are monkey monkeys. Now with the help, we now have a large colony at a broad and MIT. So the mama said we do all at MIT. Now we have Shank Sri mama said now, we just generally mimic a human mutation. We only have one monkey so we have to wait for the second generation before we can study it. And these could be help us doing genes, test the gene therapy, test drug treatment. And like you are very close to Eli Lilly, they, you know, I heard they are gonna shut down the neuroscience research program, actually I just heard of today. And the reason is not, there's no market, they are not interested. The reason is they did so many years and worked so well in mice, none of them were working in clinic. So they cannot afford to keep doing these failed things. So we're hoping these kinds of things maybe will generate a new interest investment into because we have a lot of, a lot of neurodevelopmental patients, Alzheimer's patients, Parkinson's patients. We need help. So we hope this kind of study will help us to improve the development of the treatment. So, and these monkeys we have automated behavior tracking and these are much faster than, so computerized machine learning program. So we work with a lot of AI people at MIT to develop this system to automatic tracking. So we don't have to ask MIT undergraduates to watch hours and hundreds of hours of videos to scope for us. So computer can do this kind of work now. So now we're mostly testing their gene therapy approaches and drug development for these models. And so now the question is, if we can use in monkeys, can we use in humans? Yes, people already showed that the CRISPR technology, not only can you make a mutation, correct mutation in monkeys, you can actually correct mutations in humans. This was done by Oregon Primary Center. They actually have science university and primary center. They actually use human embryos. You can correct human mutations. So if you can correct human mutations, then we can also change the human genes. In normal people, make it better, right? So the question is, what can you change? We actually know if someone wanna ask this, you want a bigger muscle, they are genes to do that. Should we do that? So all these are become society questions and ethical questions. So I want everyone to think about this. It's not science fiction. It's real. Actually, we need everyone to evolve to think about it. What should be done? What should not be done, right? And there are many questions involved. There were several meetings discuss this. The technology, we still have problems because they have off-target effect. But this could be fixed in the next few years. What if we fix everything? It's perfect technology. Now what are we gonna do, right? So they are targeted, then who needs it? For genetic disease, actually there are very, very, very rare cases you need it. Why? Because we have perfect IVF technology now. You can always test the embryo and before implantation, select the right one, implant. There are tens of thousands of babies born normal. Why do we need to modify the gene? They are only very, very rare conditions. If both parents are dominant, homozygous, dominant or recessive, then it's become a problem, right? But these are really, really, really rare. In that case, you need to correct them. All other cases, you can always use the IVF to select. The right embryo and implant, there's no problem at all. So then the question is, can we use it to enhance human traits? There are many, many traits we want to enhance, right? So you want your kids to play football. You want to be more athletic. You want to be kids go to Harvard. You want to be more high IQ, have a little bit of competitive edge. You actually don't have to change a lot, a lot of significant magnitude of IQ. Small change can give you a competitive edge, right? But the question is, who has the right to determine? Because once you change the genomic DNA, it will pass along to the next generation forever, right? And the major problem is, we actually don't know if you change the gene, what else will change, right? It could be a lot of things become worse, once they become better. So how will we determine this? Without testing in human, you may never know. So, but if let's say everything's perfect, we can increase the intelligence, who should decide? Who can afford it? If it's really expensive, who can afford it? Then you have these equality problems, right? The rich is getting better, then what are you gonna do? You cannot compete with them anymore. So all these are society questions we should start to think about now, right? So these are not science fiction. These are totally possible to do. And it's actually not going to be in the far future. It will be in the near future. At least for gene therapy to help patient, to help intellectual disability patient, I see it within 10 years. And maybe five years will be in clinical trial. In 10 years, maybe a few of them will be developed in clinical use. So, one of the best example is Alzheimer's disease. Now we know there are many, many factors can contribute to Alzheimer's disease. But one of the biggest risk factor is apple E. If you're apple E4, you actually, sorry, I'll just do my, so I may stop in a minute. So apple E4, if you're homozygous, you have very high risk of developing Alzheimer's disease. If you have apple E2, you have very low risk. It's protective. Should we all go change the human race into apple E2, homozygous? We can do that, right? Then we come very, very much delayed happening of Alzheimer's disease. There's a large study in the Netherlands show 1,700 people, over 100 years old, very clear mind, can do anything. And only one of them has apple E4. All of them, all the rest, doesn't have it. That tells you how strong this effect. Now we can change them. There are people actually doing that in the lab to test, because it's not a gene. It's actually a small fragment change between apple E2 and apple E4. So these are real questions we will encounter very soon in the society, determine what should not be done. And I want everyone think about this, and you should really get involved in the future. And MIT did a survey. MIT Technology Review did a survey. A few years ago, majority of us in the US think that if you want to change the baby just for enhanced intelligence, it's probably going too far. But a slightly majority think that reduce the risk of serious disease is OK. And you can have your own opinions. I think society debate should be starting right now, and it should not be determined by a few people or even a few scientists. So I'm going to start here at technology. All many, many people involved in the lab. The monkey worker actually is a large collaboration. And I'm particularly grateful to all the people, especially our donors, to support our research. Thank you. Oh, hi. Well, lots to talk about. I suspect for many of the folks in the audience, the opportunity to see for the first time genetically modified monkeys was new. For some, it's a bit scary. And so to your point, when science fiction talks about genetically engineering the super human race, what we're talking about is within a short period of time we'll be able to do these things. And so from your perspective, what are some of the first things that we as a culture, as a society, really as a world society need to think about it in terms of putting guardrails around the uses of these technologies? So that's a really good question. It's a tough question. Probably everyone has a different opinion. My own opinion is I think that it's really important to develop this technology for treating severe disorders. And I meet a lot of parents. They sometimes bring their baby two years old, three years old to my office. Just try to say, OK, whatever you do, please help my baby. My baby has red syndrome. It's deteriorating. They have seizures all the day. And they cry all the time. I think these are the patients we really can do. But there's also dangers to modify our genetic material. You are not talking about the drugs. You are talking about forever changing the human DNA. And in one hand, it's kind of directed evolution. You make the mutation. You make it better. But better is we think it's better. We actually don't know it will be better. Because every gene has multiple functions. None of the genes so far, we completely understand it's a function. So it's very dangerous to go on to say, oh, changing the gene will enhance the ability. Yeah, we'll enhance the ability we know. But it will probably cause a lot of other problems we don't know. So in my view, many of us think it should be at least temporarily banned on any human embryo manipulation until we really have a society debate. Because it should not be determined by a few people. It should have the right to decide what is the best way to move forward. Technology still can be developed, but not applying to humans. That's my view. And many of these scientists already voiced similar views. And I totally agree with them. So one of the things that you point out in the survey in the MIT article was, while making babies smarter, was certainly controversial. The use of technology for therapeutic treatment, though, on the other hand, was a little more accepted. And so as we think about neurodevelopmental or neuropsychiatric disorders, many of them are the result of a small battery of changes in a battery of genes. And it's difficult to study those disorders and understand the complicated genetic changes that occur in those disorders. How do you think CRISPR and maybe some of the other emerging technologies can help us tackle those very challenging. Yeah, so this is a very, very good question. So as I mentioned, even in the neurodevelopmental disorders, only 25% are identifiable genetic mutations. Many of them, majority of them so far, is considered polygenic. That each variant, actually not a mutation, they're considered mutated. Each variant only contributes very little. Maybe 100 of them together. So that's why the parents are generally normal, but for bad luck, all their mutations, we all have mutations, right? So passed on to the single kids, then that kid is in bad luck to disrupt, to a certain degree, that you have a neurodevelopmental disorder. So there are multiple ways right now to study them. Actually, what people have done is using IPSL technology, because you take the skin cell from patients. They have the perfect combination for the disease. You culture them, then you can use CRISPR technology to repair or mimic some of the conditions to see which one they play a key role. So I don't believe, even there are hundreds of mutations, I don't believe each one contributed similarly. So they are probably major contributed and minor contributed, but you just need them all together to make a very severe case. So there are now technologies that can do multiplexing. So let's say with this IPSL cell-deriving neuron, we found 50 genes are changed, expression changed. Can we just regulate 10 of them? And will that improve? The answer is probably yes, because the whole concept of the polygenic is you need everything together. If you take 10% away, maybe they are just much improved because they don't have everything to make the patient clinically significant. So it is possible you don't have to collect everything, but you have to collect a whole bunch of them. And CRISPR technology is completely capable doing multiplex even for 100. People have done hundreds of them at the same time to regulate gene expression or correct the mutation. So that is a feasibility in the future. Of course, the more you put to change, the more off-target you will have. So that problem we have not solved. So I'm not recommending using humans at all at the moment. I'm going to ask one more question, and then we'll open it up to questions from the audience. So if you have a question out there, we do have microphones on the sides of the stage, and I'll invite you up in just a moment. I'm going to ask, how much more potential do you think the human brain has left to be explored? There is probably an urban myth out there that we use just 10% of our brains. But do you think that we are indeed underutilizing our brains? And if so, do you envision any technology to help us unleash our brain power? OK, that's a really tough question. So my view is for most of us, we are not using old brain power. What I think is, if you think about the difference between our capability, whether it's athletics or brains, so if you ask me, play football, I can be crushed by anybody. So I'm, what are you, 1,000 times worse than the athletes? It's the same thing for brain power. So I think the best comparison is whatever on the planet we have found that incredible capability. But it's more on individual tasks, actually, not on the whole brain. So whole brain power, maybe because of the combination, maybe we are, I don't know, I'm not saying we only use 10%. Maybe we use more than 10%. But for individual tasks, they are very, very smart people. They are very, very capable. Extreme people have extreme memories. So these individual tasks, I think we can explore many, many, many faults. Because these people exist on the planet. So I think it's the best comparison. Compared to regular people like, my memory is maybe a little average. But with the extreme memory, and you can tell the difference. I think the difference is huge. So we do have a lot of power to explore. How do we explore these kind of ability, use them? And I don't think neuroscientists know yet. So there are many, many myths out there. But I really don't think I can provide any advice. I don't want to screw up your exam next. Well, I do want to open up the floor for questions from our audience. And so if you would, please make your way to one of the microphones to ask Dr. Fang a question or two. So I do mouse behavior. I'm a grad student in my third year. And I'm just wondering, with all the translation crisis going on with Big Pharma, how is that going to change the landscape of academic research institutions? Are we going to start ditching the mouse model and moving to non-human primates? Is that the only way to be competitive nowadays? That's a really good question. I don't think that's the only way to be competitive. I think we should never focus on one model. I have said, and I always say, we actually have no proof. We have no success yet in monkey model. So it's still very explorative. It's only because evolutionally they are closer to humans. So we have a better hope. So I would say we have failed many times in mice. We have not failed yet in monkeys. So maybe it's also failure. Maybe the human is the only model we have. Then it will be a problem. So there are people. There are many different ways. IPCSL is the one way, but they don't have perfect circuits. And transplanted human cells into mouse brain, monkey brain is another way. Then people really start to think, how do we develop drugs without animal model? If animal model 99% fail, why do I test them? So before you test the animal model, you want to ask if this mouse model fails, do I stop this project or do I move on? If you still move on, why do you want to test them? So there are a lot of debates. So I think all needed to be used. And I don't think monkey is the only way. And I'm not even sure monkey is the best way. Human is probably the only perfect model. Even humans are not perfect. One human is not perfect model for another human. So we have a lot of problems in this. But don't be discouraged by Bigger Farmer's decision. Bigger Farmer has moved out, has continued to move out, Eli did announce today, they are cutting their neuroscience research in England. That's the only major research they have now in neuroscience. But a lot of venture in the last few years, ventures and biotech start. So the Bigger Farmer's decided, I'm going to put a cash in my bank account. Whenever you figure out something, I'm buying you. You said you're not going to sell? Not true, it's just I didn't have not offered you enough money. If I offered you enough, you will sell yours into me. So that's the mentality. Actually, there are many, many venture starting companies. If you are around MIT, there are many, many ventures looking for opportunity to invest in neuroscience. So it's not that bad, actually. It's actually getting really good. So I encourage all of you, actually, if you have a good idea, start something. Talk to the venture. Actually, one of the impressions today I got is, people are very, very active in actually translational research here. So it's really fun to see, actually. Very much like MIT culture. Another question? Hello, I'm Marshall. I'm a second year pharmacy student. I work with Dr. Yang. And my question is if we alter genes which would alter, say, the structure of transmembrane proteins or cell surface proteins, could that lead to a potentially serious autoimmune response? Since we are born with self-identifying antibodies, could changing those surface proteins could that cause like an autoimmune response similar to like an organ transplant? And if so, how frequently, how serious do you think that that might be? Yeah, so that's also a really good question. So the two parts of them, if we change them during embryos, germline in humans, it's probably not a problem. Immune tolerance, you can tolerate its own protein. However, if we change it later on, and it could be a problem, postnatally, if the patient never sees this protein, then it will become a problem. You could intrude, although it's a human gene, you intrude this new gene to this person. Luckily, most of them are heterozygous. They already have the protein. You just increase them. So in most cases, okay. The major problem is CRISPR is a bacterial protein. You introduce your world-generally immune reaction. How do you deal with that? That's a problem we have not solved. So it is possible that if you long-term, so people have tried to use short-term delivery protein, once you fix the gene, protein will be degraded, you're totally fine. But these have not been really successful in the brain yet, but people are working on delivery systems. I think we have another question over here. Hello, thank you for your talk. So in your talk, you mentioned that there are certain areas that can be fixed. So the critical thinking and executive thinking, can, is it the part that can be fixed, or is it the part that cannot be fixed? So right now, in mice, that's the part that we cannot fix in adult. But you probably can fix if you put the gene back much earlier, postnatally, but before they are mature. So in prefront cortex circuits, we believe in adult it's quite fixed and it doesn't have the plasticity we want to, and we couldn't fix it in adult mice. But if you give them earlier, the restored gene function earlier, like three weeks old or two weeks old, you can actually fix them. Okay, thank you. But I was reading somewhere that adults, even older people are fully capable of learning a new language. If so, then how come they are able to learn in old age? So yeah, so really good question. So that's what I'm saying in some part of brain, right? So learning language and, but they are never gonna learn as good as the young people. So for a lot of circuits involved learning skills, strident, they are very plastic. Actually in mice and in humans, that's why if older people can pick up bad habits or get addicted, these are all involved cortical strident circuits. So they have certain very significant amount of plasticity in adult. That has been done in mice and has been probably shown in humans. For example, visual system, binocular vision, right? Binocular vision in people in poor country, they have cataracts. If you remove them before 10 years old, they perfectly have binocular vision because you all know if you study vision, the axon has to cross, they have to segregate, right? So, but that's the critical period. But if you adult, you take out the cataracts, they can see perfectly, but they will never have binocular vision. So the plasticity is gone. So in cortex, the plasticity really are limited. But in the subcortical area, they are very much active, so. So you're saying if somebody is like a, what is considered an adult brain? Is 18, 19, an adult brain? In humans, the reason to study such as that, maybe after 25, you are much less plastic. So we have a long time too. So you're all plastic. Thank you. Well, one of the goals of our Ideas Festival here at Purdue for the past year has really been to provide our campus community the opportunity to go deep into some areas around science and technology, how it interfaces with society and culture. And I think you have certainly done that this evening with your presentation, Dr. Fang. Thank you for coming to Purdue. Let's join me in thanking Dr. Fang one more time. Thank you. Thank you. Have a great night. Thank you. Thank you. Be happy.