 in a brain is the most complex organ and there are connections that also the most complicated ones, right? so and my long term interest was always trying to understand neuronal communications and and therefore this complexity risk challenges for us to understand and one of the ways I think and this is what we are doing right now to was to developing tools trying to help ourselves and also can help the community other scientists other neuroscientists to Understand the neuronal communication because these communications are really rapid, right? So the cells have this sort of unique connection and many different types So the challenges I think is just to develop in better tools to help us and therefore we are focusing and and very big important aspect of our research was trying to Not just doing research itself, but rather than developing tool as a part of the research Trying to figure out how neurons communicate with each other What's up everyone? Welcome to simulation. I'm your host Alan Sakyam We are in the beautiful Beijing China at Beijing University We are now going to be talking about neurobiology. We have Dr. Yulong Lee joining us on the show. How you like? Hi, thank you so much for coming on the show. I really appreciate it I'm also very grateful to Kirill Piat-Kevich for introducing us and making this happen and for you and your lab in the life Sciences Department here for helping partner with simulation for these great content that we're gonna have together while we're in Well, it's unique opportunity for us to thank you. Thank you And hopefully we can help be a catalyst for greater collaboration amongst us China Hopefully what we hope to yes For those that don't know Yulong's background He is the principal investigator at the school of life sciences at Beijing University Affiliated with the PKU McGovern Brain Research Institute He's founder of the Lee research lab, which has about 30 undergraduate and PhD students studying cutting-edge Neurobiology and you could find the links in the bio below Yulong Lee lab.org as well as the Twitter and LinkedIn profiles Okay Yulong, let's start things off with one of our favorite questions. We love asking our guests What are your thoughts on the direction of our world? well Interesting you ask is You know if you ask me two years ago as other world will be you know better and better in terms of collaboration You know helping each other, but right now. It's an interesting time But in the long run, I think the work will still you know will be better in a way that you know People's life quality will improve throughout the world We've been on that upward trajectory of life quality around the world improving which has been great Similarly, we've also now have the democratization of all of the exponential technologies What would you say is some key? principle to embody as we move into the exponential technology age Well, I think Fundamental research certainly will help so for example, you know the deep learning the AI that has been popular But they are I think they are rooted from the fundamental research in the breakthroughs and likewise For human health the medicine that we have been developing they are also rooted from the generations or years years of fundamental research like that so strong first principle on Fundamental research for health and for deep learning for pursuing the upgrades in our world. I like that a lot. How about Your journey who were you growing up? Where were you born? I? I was born in in Fujian province China in the south part of mainland China and then I Spent my elementary school Junior high school and senior high school there until I In my college year, I went to Beijing and studied if I hear for my bachelor degree How did you figure out when you were young that you wanted to pursue science technology? How did you know? Well, I like technology I remember when I was young in for example in Elementary school in my fourth year our school actually have the first computer that for me to play and I made some programs in files very interesting in programming and And in high schools, I was also interested about chemistry and when I at the time of Trying to get to college in fact my first choice was trying to study computer science in 1996, but I failed to you know Get into the class just because my score is just not good enough for my province and I accidentally Got into the life sciences Interesting so yeah, even the funny moment of pursuing computer science and not getting in for that I've got you into life sciences, which you are now principal investigator Yeah, I'm enjoying doing that. I think my brain is plastic enough Okay, so then So then how did you pick up what you wanted to do here at at picking University? And then how did you make this move to pursue the PhD at Duke University in the United States? Tell us about those years. So again, I You know, even though I was not in a computer science Department, I was in you know life sciences and at that time my major was Biophysics and physiology, so I like science in general Then after the bachelor's school training I have the choices of Further of my education or you know find jobs I Was you know before I graduated I was looking around just to see if I'm sort of securing a job with my bachelor degree Why is that gonna be and I found that most of the jobs are like salesmen Which is for you know retrospective might not be bad but at that time I thought mmm that might not fit with my interest and I was also thinking about going to grad school in Beijing University PKU at that time but mainly the Beijing University At least in the past was more focusing on teaching. So it's a teaching university unlike right now We are trying to build a work card what class research universities So for a person who is interested about science and research at that time I feel you know probably I could have better training opportunities abroad and that's how I applying Grad schools in the States and I was interested about physiology Neuro physiology, you know how the neurons talk to each other and in fact when I was applying for grad school in my Undergraduate years. I was just only focusing on neurobiology because I thought that's so cool the brain is the most complex organ in the world and still now and Understand how you work. It's just really interesting and also Understand the brain is sort of a journey to understand ourselves because we use our brain to you know to talk to communicate and you know This is the the most important organ probably in in our body Maybe even most important discovery for us in the universe one of them. Yeah, yeah, my body will agree with you Yeah, but you I tend to be More politically correct, I don't say anything Yes and on the Shirley Quantum mechanics will have a very big Role this theory of everything with general relativity figuring that out figuring out the brain these things have Big roles in understanding ourselves and sustainable building of a future for us How about where did where did it come up for you that you wanted to do neurophysiology? Like how did that end up being something that you were like hmm? I want to know about that Well, I went to grad school at Duke University very good university and good program. Okay, I Have the opportunity to do rotations and You know including in the labs of neuro genetics Cellular neuroscience and the the sort of experiments I do there I it's just not as exciting at that time for me to feel I Have just few neurophysiologists most exciting because at that time we can poke it actual to the Neuronal cells and when this neuron gets you know activated They will generate action potentials and then you can really in real time Seen the waveform of action potential generation in the offsets go on your computer screens as if you are just really talking to those neurons and We are to the neuro genetics lab that which is really good lab But you know we at that time we use a neuro genetic techniques will generally Special genetic modify mice no cows, but it will just take her like two years for you to really Know the phenotype and knowing what happened if you eliminate this is very important gene for their mice and probably I'm just not patient enough to wait for this Period time. This is a longitudinal study. You're trying to see if you eliminate a gene What happens over years to this because of the way to remove this gene knocking out this gene takes time and You know to generate this genetic modify mice takes time and mice, you know if you want to start You know they are in their adult who takes time to grow Right, so so it takes time and for the cell biology at that time, you know, I just feel Again using the technique of immuno staining knowing, you know in the fixed cell what happened But I was just more excited about in real time how neurons talk to each other And in fact, that's also related to my current work and if my PA my post out to work and my current lab's work We want to study the real time, you know, and how neurons talk to each other and I think this is a you know Very challenging, but very interesting and important. Yeah, we'll get into a neurotransmission We'll get into all of that neuromodulation So then what was the the PhD on and then what was the postdoc work at Stanford on? So my PhD I work with a Dr. George Ox team and I was using maybe using a unique animal organism Cascade and in fact, I spend quite some time in the marine biology like in Wuzhou Well, we use the fresh screen and screen is a really unique creature. Well, he has this giant Neurons Well, in a very famous Nobel laureate hot-gain Huxley using screen to really understand the Molecular the mechanism of so-called action potentials, but this giant screen neurons also has a giant Synapse where it's big. Are we talking this neuron compared to like a human? Probably a thousand times bigger or even bigger because the diameter of the neuron is the axons is Let's see Well, it's been some time, but it's that can be five hundred micron Wow, but the the let's just the diameter right and in our brain our Neuron in the brain excite to neurons that axon usually is a one micron So we are talking about using this giant neuron and giant synapse They have this so-called special structural synapse the whether the transmitter been released and because this neuron is big Historically clever Scientists figure out the ways that you can poke the electrode into this big neurons and Trying to understand how they react how they talk to each other and my PhD thesis was using this Nature's gift to study the neural communication with this giant No fibers where we can poke four electrodes to in a prisoner neuron the neural net sending the information to the downstream Post-nap neuron, which also has two electrodes and because this is electrodes can amplify the teeny tiny current that generate from those neurons and Then you can really read out what happened, you know doing when those neurons are talking to each other Yeah, so so that was a really unique Experiences and also because of this is marine biology lab where we use the Screte we also have a quite a number of neighboring labs Using the gifts of nature different gifts of nature. I like the way you put that there There are ways that nature has made it easier for us to study Biology and neuroscience that if we can find those places and study it there It can give us better insights into how to study it in our own bodies, right? So so the gifts of nature so that was judicity truth truth and by scientists, you know different animal motor system including not just in the Neurosystem but also during development for example, you can use a sea urchins there to study the Development and you can start you can use the goldfish to study the how the auditory pathway integration because it turns out the goldfish has this giant Also neurons that integrate this auditory Impulse to it is based on its gay behaviors And so that was a sort of interesting in a way just seeing how people were really using different sort of motor systems to study their favorite questions and also Frequently the Fundamental understanding that you obtain using screen using goldfish sea urchin that Turns out to be conserved Throughout the species including in human cells and but because of nature's gift They are unique structure unique size or their simplicity of anatomy Really allow us much easier to probe their secrets Then one can use those known Principles derived from those simple elegant systems trying to understand in a more complex Organisms like in including human in human diseases And I will also say just to elaborate a little bit more even if sometimes you found the principles derived from screen from sea urchin as I mentioned are not conserved to mammals to humans, but you can still provide interesting Diversity for example how really nature solve the problem you know to enable vision right even if the maybe the squeeze eyes are different than humans, but The the principle after you really understood understanding that Then can help you to appreciate how nature use diversified Magnets and to solve the same problem for example to detecting light and And sometimes you can also find out that the same principle maybe was not using in the visual system But it might use other sensory system. So the the molecular aspect sometimes are Still conserved even though the the system is different. Okay When you're giving the example of these natures gifts and how they Can you can find potentially neurons a thousand times the size of a human neurons for me? It was kind of funny beginning to yeah start thinking about where all are all these nature gifts And how do we start understanding them better and scientifically researching them? but also it came up this idea that You're a neuron and I'm a neuron and our words are the neurotransmission What probably it's probably more complicated than that It's just it was an interesting analogy that that came to mind How about what was going on then for the cutting-edge tools for understanding Mapping that neural modulation that neural activity, but also you said, you know, I'm trying to envision here You know, you guys having these two electrodes for on two on each neuron there and also Trying to see what's happening in the synapse trying to see what is actually going on with the neurotransmission How are you? How are you visualizing that? How are you actually being able to record it and learn from it? Well, the most classical Approaches people develop that promise more than 50 years. Oh is using the glass Electro as I mentioned why you can poke those electrodes then it actually has these teeny tiny tips So when you are poking the electrode into the neuronal cells hoping that the cells are still healthy and has teeny tiny hope but no damage and That you are connecting the the cells and with the glass Electro and where you also have a glass electrode that that you insert Amplifier that can amplify to the current that the leaking out through the cell. Okay, and Then then the way to understand your own communication is then you can record those teeny tiny currents that was generated when this neuron receiving the The Pre-synaptic input receiving the input from the sender cells. That's the most classical Approach which is still being used one of the challenging part is You need to be really skillful and Also, you better to have that Animal or that neuron to be sitting still right because this glass Electro are so dedicated Dedicated, you know, just since I'm moving I just scratching the Cells membrane the cell will just die. Yeah, and also the soup who of their approaches, you know Only can recall most likely one cell at a time. So it's a lower through pool Yeah, which is now in the hundreds of neurons at a time hope as well so so imaging in that regard that will be useful because If you have a spatial resolution, you can imperial just like this video You can just take an image of what happened. You can see in the scenes and in fact around that time people have already generated Dyes to try to look at your own communication There's a special die called fn die that is being used in the field and this fn die has this unique property that Once you get incorporated into the membrane You will be become frozen So some clever scientists then they just pull those die out of the cell and then Stimulate those neuron and neuron use those vesicles to release transmitter, but once the vesicle been released you will merge with the surface membrane and Therefore the diet we just sort of attached to it and after the transmitter been released neuron also use this so-called Indocytosis or internalization process will take on the diet and therefore this diet will just be This artificial diet that it will just be taking out into the vesicle and what you do is you just wash it out The rest of the plasma membrane die. You only retain the dye in those vesicles that contain Transmitters and then you can just use the camera to look at how those dyes that is being released the florescing the Flossens Generally from those dyes in different colors Could be in different colors and that's been you know a powerful way to again using image methods to look at How the transmitter been released, but you are actually not exactly looking at transmitters, but looking at The dye as a pseudo transmitter. Yeah, and similar principle has also be extended to Using a Green-flossened protein the so-called GIP and you can take advantage of some GIP has a unique pH sensitivity and therefore you can engineer in this genetic encoded protein to Target to those teeny tiny vesicle contain transmitters and this vesicle it is actually known to be very Acidic because they contain the protons that those those energy currency to generate the to load those transmitters and therefore this GIP if they are not been released or Gain touch with external world they will be dim because they are Quenched by this acidic environment But once you really fuse with the plasma membrane the outside world is pH neutral and then the GIP will just be bright and you can just see the signal Flossens signal increase so that's also been used and those are all efforts people are trying to you know Compliment the glass Electro or the electrical physiology mess is trying to understand how you don't talk to each other Yeah, an expansion microscopy is also a big one Expansion microscopy Pioneer by my friend at Boyden in MIT. That's us. There's a different ways not just to look at neural Communication in real time, but instead I think mainly but also powerful in a way to look at how Neuron connect with each other in structure because of the as I mentioned the neural connections are through this unique structural synapse and Neurons are teeny tiny in our brain so the expansion microscopy when at Boyden was developing was really you know in large the size of those Neurons clear cells well Maintain maintaining their morphology and their geometry and therefore you will allow one to visualize which neuron connects to which neuron and helping us to build a blueprint of understanding the neuronal Kinetomics and you can also be combined with some special molecular markers So we normally know the neuronal morphology, but we also know which type of neuron there. They might be that they sort of a secret group to me secret Gabba or secret dopamine Yeah and then how about the Trend how about the transition for the postdoc work at Stanford, you know, how did you went to the other coast? You were able to explore California you're able to see that and what were you doing there? So interesting, huh? So I Went to Stanford for postdoc was also a little bit by Aston so I was attending a Society of Neuroscience meeting when I was a grad student and I was presently a poster if a poster if I remember correctly and my postdoc advisor Dick Chen or Richard Chen He was a professor at Stanford at that time He was just passing by my poster and because I being a grad student I know his work and and I like his work and so he was just passing by my poster so I Actually, I think he just like stare at my poster for like 10 seconds or 15 seconds about to leave And I was jumping out of the crowd to grab him and just having some thoughts about you know trying to talk to him and maybe impressing and seeking some Post-op position opportunities and and dick was kind enough and so he He was not offended by my rudeness and so actually I got to talk to him Visioning you jumping out of the crowd. Hey, are you grabbing? Yeah? Yeah, I could be more violent. All right So so again dick was very generous and nice and in a way We talked and then he Invited me to interview at Stanford and then After interview he actually gave me the offer and in fact Dicks that is the only that I interviewed and and and I decided to I like the lab I decided to go and so I went to Stanford and work with him and Also actually trying to understand more how neuronal communication occurs was the molecular mechanism and How to visualize? Just following why I said before this communication Yeah, and then how about then the transition back to picking University to be the principal investigator here in the life sciences How did that happen? We are being a poster for quite some time, you know poster is a temporary job, right? So I Think both My wife and I we are both in a sign scientist. We will both poster at Stanford at that time. So we were thinking about You know after post art training and What would be the next move, right? We are both are still very into research into trying to understand how things work and I Was also thinking about jobs in the States, which I happen to have some faculty job offers and Also at that time also by as then or coincidence that my PhD advisor was hosting one of the symposium in a International biophysics meeting in China in Beijing So he wrote to me, you know, knowing that I was working on some aspect of research in neuronal communication and Inquiring me whether I was interested into attending the symposium. He's organizing in Beijing and Of course not carrying my flight flight fares, okay, but but could sort of cover my Longing and you know with with the The the the conference Registration fee and just you know because I was in Beijing starting for quite some time and haven't been back for some time so I was I Was thinking oh, that's a you know good opportunity just to you know visiting Beijing and you know just check things out. Yeah, and Since I was an undergraduate student in Beijing and big University PING University so I was inquiry some of the faculties here and just thinking about you know, how is the The University doing and how is the life sciences research and in fact, I also got good encouragement from my I would say mentor Li Qinluo Stanford faculty that I collaborate with and so It turns out that my trip to Beijing then become both attending for the Conference and that I was giving talk but also I arranged in a way that I visiting back picking University and Giving a job talk and I guess that job talk went well so I got a job offer from picking University and and and I think We we were debating because we were being in the states for like close to 11 years and And also that's good science there We are we are we were familiar with the funding system You know how to setting our labs how to you know teach in English but I on the other hand I was thinking about the The opportunities here. I feel that this is also a unique opportunity where you can get into Society and into University where to that's this rapid sort of a Change or rise in terms of the academic research Accompany the economical booming and Comparing with the states Even though the I will say the derivative the increase race higher than the states but the total Mass of the good scientists or the other preparation for the good research are still Tiny by comparison with the states and therefore being a society here if you could make positive progress that you potentially could have I think larger impact and And that is one of the incentives and the other incentive was I think that we have quite good students Because I was a student here and we also have good Grand support Because you know in globally around around our time because of the financial downturn starting from 2008 That actually was causing quite some troubles For scientists as well and I feel that a lot of scientists including ones in the states and some other places Just because of the economic downturn. They are just more spending time trying to Really secure funding to keep their lab alive Instead of focusing on Trying to put thoughts and efforts into research and into making research progress and and in Beijing potentially It could provide this unique opportunity So that was my thought and also I would say part of it just being naive. Okay, and I Because you know in fact I have no I you know, I have not been bad for you know more than 10 years. I actually I Don't know exactly how this funding system works out to write grants in Chinese and But I was I'm just naive enough and then taking a risk and I thought maybe since we'll just work out, okay And and my students they don't know that right so they just you're naively you know work with me and then Maybe thinking I'm just really figure all the things out, but I was still sort of trying to saw things out as well yeah, so the The factors of the The big university growths plus the big economic growth plus You being just naive enough to be like I'll figure out how to write grants and Chinese out and back in Beijing and figure that out So so you take this role and then you started introducing us to this And I really like how you put it because it's important to get behind the eyes of These principal investigators or these lab directors because in many ways The the students that are coming in to work in the lab are a look Equipment a look we can conduct our science no problem, but Get behind the eyes of you who had to put together all of the grant applications all of the funding to be able to buy the equipment to Make conducting the science easy So there's a lot of nuance in this operational process will you teach us about what that's been like for you? Interesting so in fact that when I was in grad school and as opposed to I was both I was in both relative Sort of established faculties lab So I myself Did not witness how a lab Star from scratch so So that's actually in fact a lot of learning course for me just and also in a Environment in Beijing which I I did not get my PhD training and my post-doc training So that that quite a lot of Scenes that especially at the beginning didn't go well I remember like like in the first two years that once you know yet, you know Some of our sales get contaminated, you know, and I was talking to myself Again, the students are all good, but they are lacking experience And then there's just there's a lot of nitty-gritty details both of in terms of equipment lab skills, you know Be careful and just a lot of things to work on and I was talking to myself I was like, oh my goodness. I cannot make it here because you know, there's just nothing works, right? so so But I guess, you know Since eventually work out and I I think I have good students and I really think that they are fearless or Naive, okay, so they are fearless. They they work with me They you know So, you know, even though we met a lot of Troubles in because we are doing research, you know, if you think about research research, right? This is the common scene. That's just a lot of Fidious, but I think they are and my students. They are energetic and and in a way we also have a good University support we already have a Good critical mass of good scientists and who Some of them are more senior than me, but a lot of a lot of them they have the similar There they are similar age and then we shared our experience and then we help each others And so we got no support and in fact at least initially I did not put a lot of efforts into writing crimes but trying to source things out just to you know, eliminate a Contamination problem for the cell and the medical biology doesn't work problem and that the camera just broken problem So I was more focusing on that And then how did you end up figuring out the? Vision of being this principal investigator in life sciences, what do you like? You know biology being the code of life and there's so much complexity across all of it Neuroscience we're talking about the complexity of the brain and has such an incredible organ for us to understand How do you figure out the vision? How do you figure out where to allocate resources? How do you figure all this out? so indeed In a brain is the most complex organ and there are connections that also the most complicated ones, right? so and my long-term interest was always trying to understand neuronal communications and and therefore this complexity risk challenges for us to understand and one of the ways I think and this is what we are doing right now to was to developing tools trying to help ourselves and also help the community other scientists other neuroscientists to Understand the neuronal communication because these communications are really rapid right so The cells have this sort of unique connection and many different types So the challenges I think is just to develop in better tools to help us and therefore we are focusing and and very big important aspect of our research was trying to Not just doing research itself, but rather than Developing to as a part of the research trying to figure out how neurons communicate with each other and one of the ways Just a photo our previous conversation was trying to develop in tools that can enable parallel Detection or enable detection with a spatial resolution And that realize, you know as most of you all are aware of imaging right the videos that has this sort of spatial resolution and also if one work the since From from a different angle because the neurons are in the brain are so complex There are so many different types if we can figure out a way to label those neurons with specificity In meeting light Then in the dark we can just see those lights and that can help us and one of the best way to label those cells with specificity is to Again rely on Nature's principle nature's gift that's using the DNA using those sort of DNA inside a cell to encode those labels and Using the genetic program Inside of cells to turn on those light turn on those label in a specific cell type Okay, in fact this principle has already been used Quite some time by different scientists in the field not just for neuroscience, but also for development Right, so then the the the challenger will be if you want to develop this sort of so-called genetic encoded ones that they can put those label in the DNA and You also want to develop something that will emit light right Then how do you make those things? Sensitive to the secret language neuron communicate with each other right neuron Release different chemicals To activate their downstream targets, so then the question becomes how do you design a way to Pull those special protein which are genetic encoded encoded by DNA Which so the immediate so you can borrow from for example Jellyfish has this green for supporting or borrow from fireflies, which they have this luciferous Which will emit light and but you want to make them also not only just it may lie But also it may lie only in the presence of this secret Neurochemicals those individual cells are secret right and so that's why we were working on when I was sitting on my lap and so one more time to see if we get this straight so then it's the engineering of the protein which then goes into the neuron which then is able to enable the neuron to for if to be able to showcase what which Neurochemicals are coming and then it's you can detect. Yeah And and it's through a Fluorescence process and it can be a specific color fluorescence for a specific neuro right different colors of different light intensity right in different For instance is the one way the other one luciferous is not for sense But it's a sort of bio illuminance is using this chemical energy to generalize the difference between fluorescence and bio illuminance are the fluorescence required Excitation line and then they usually will emit a longer wavelength of light That's for sense the bio illuminance sense From fireflies right we don't use in light to illuminate those fireflies But the fireflies in the dark they will just emit light because they use those Chemical energies that they will just so chemical reaction catalyzed by this luciferous this enzyme That which is in me four times. How do you get the neuron to not reject the genetically engineered protein? So that has already been worked out by many others in the past always works now the neuron never rejects now They have that different ways. We are using this Model organisms that this genetic techniques has already been worked out by many scientists So so you can you can specifically? designed genetic tools to allow fireflies full flies or zebrafish or mice to express this piece of DNA Non-tastic DNA. Yeah. Yeah getting past the immune responses critical and okay, and now it's About being able to map neural communication using these techniques So what so then at the lab then? Well, how how are you working by? With the different undergraduate and PhD students, how is there some sort of a lab Communication that you do for figuring out where to understand neural communication What resources are going into which of the buckets? Well, it depends on at which stage so for the initial stage, for example We are just scratching our heads are just trying to see for example The principal I mentioned that we are trying to develop developing this genetic encoding sensors that can express in the cells we We don't have anything working yet. So so we have a group of students that really focus in just trying to Test, you know again, we also Take advantage of nature's gift harness How nature detect those neurochemicals? Okay, and for example we hijacking or tap into Nature's so-called receptors it turns out nature have a different receptors Sensing those neurochemicals like dopamine or acetylcholine or glutamate and then we Really relying on nature's designs this molecule once they interact with or receiving the Messages these chemicals they will undergo some conformational change that our structure will be changed and we were painstakingly testing if we put a Light emitting green frozen protein There maybe this structure changes Can lead to the Ability to emit light change So at the beginning it was just you know sort of slow tedious and and we were really focusing on that After Five or six years after we actually are pretty good at this We figure out some generic ways that we can make this to work and we actually figure out the ways that can make He emit not just green light, but you know red line Other lines, okay, and we also figure out through our optimization that we can Let them immobilize bright lights rather than right team lights and Therefore That the lab now is different than at the beginning because once we have in the pseudo experiments We figure those things out the lab now we are sort of dividing in a Set of different questions that we ask using different sensors when that we design and development will Not only have those tools that we distribute to some other federal scientists But we also use this first available tools and pull them in the brain for them in full flies brain and Just trying to decode how the through fly when they sense flower banana what happened to that brain and They are neurochemical important neurochemical and interesting enough through fly share a lot of common important neurochemicals just like humans like Serotonin in a way. It's similar to when we see a banana. We get some sort of excitement Excitement happens as well. They you are they have different neural anatomy, but you know soon for jumping natural seduction They are also very sensitive to their banana order, right? Because there's a there's a source of food, right? So they so they evolve to detect it with sensitivity, right? So then we can look at for example, what happened with their fruit flies serotonin level and Because we have the two years that we can really look at where it will be released and how is the Related to their sort of a physiology function. In fact before us, you know people already know that the serotonin is a very important neurochemical and in human brain is actually related to Depression, right? So they are FDA approved drugs that target serotonin systems for therapeutic effects and Now we have those two as we we can look at full flies mice and we Just for curiosity, we look at since it's simple, right? And for example, it's known that full flies also they learn they remember they can associate with sound in a full food order with sound in a good approaching behaviors and serotonin is in full flies is also very important if you somehow eliminate serotonin Do not allow you to seek with security. They don't remember full flight. Don't remember and Now we have this unique tool then we can just look at full flies brain try to understand this teeny tiny creature Why serotonin is important? Where do they secrete and how fast they secrete secret at which cells and how does it relate to the learning ability? this teeny tiny creature might have and in hoping that our understanding my share Lies of human physiology or disease in the future. We don't know yet, but At least it is what just be interesting is I hope my student will be curious enough just to understand that Yes And then what how do you how do you do that? The imaging of such faint light? For something like a serotonin secretion in a fruit fly. How are you doing that imaging? For just small creature again Yeah, you should ask my students. They are the one doing the experiments so It's it's kind of challenging because fruit fly are so teeny tiny, right? So my students they figure out the way and in fact there are other scientists also in a work on full flies It's a pretty popular animal model organism especially for genetics For development studies because it grows really fast and has a lot of gene available genetic tools, but for full flies we sort of carefully anaesthetize them and mountain using some non-invasive glue to mountain on certain Paper or in a tin paper or something and then we can pull them under a Very sophisticated Microscope that people have been developing for years and it's microscope that is called two-photo microscope And this microscope has this unique ability that it can sort of using a longer wavelength of light that it can read Relative deeper into the brain just to see things. Okay, and therefore we can just sort of non-invasive Now the fly are still alive and then you can still you know Give them different orders and if you see the their legs, they are still sort of a running using long wave length of The illumination light right more than a thousand nanometer line, right? Our eyes cannot perceive. Yes. Yes, right Okay, and then that can send you the Imaging of what's happening right that you can sort of scan point-by-point and just collapse point-by-point Signal together you have an imaging and then you can also scan over time that will create movies And when you bring the banana you watch the neural activity Yes, yes, okay, and I can see all of the Interesting applicabilities and insights that that actually gives into our own neurophysiology and all the other Creatures with nervous systems. What about your ideal? tool, what would be your ideal neural science tool for? Achieving this desire for understanding neural communication. What would be a tool that you imagine as this Epic pinnacle tool that could be so great for us Well, I think you know if you think about tools in general, right? The tools usually will be the tools that allow us to Manipulate things That will also be tools that allow us to Recall things and I'll be these two generally general categories, right? So the nervous system is so complex and in a way the idea to if I could think about and Again people are trying to do that, but it's still not available yet if you have an idea to for animal studies that you can Simultaneously control You know a hundred different types of neurons activity using orthogonally don't interfere with each other and then you also have the master can simultaneously reading out a hundred different type of neurons Activity and knowing which type is which type orthogonally Then this can really for understand how neuron Compute this can provide a powerful tool because then you can reading out in the native condition What happened with those neuronal activities? You can read Read out in a disease condition in animal models What happened with different type of neurons and then then picking up all is this type that went wrong Not the other one And but I only provides you the correlations right because we are just reading out the during this thing What happened the then the the tools that can allow you Simultaneously commentary No, orthogonally control is a hundred type of neurons activity then you can Really precisely just to perturb those neurons of interest and then just try use that to establish a causality and That will be the you know Perfect to help to understand in the in tech system those neuronal functions and you will have a long I think implications of understanding the disease causes and then provide therapeutic approaches in a long run, okay, so Again, this is gonna be challenging, but this will be very useful and That being said for humans there will be even more challenging right just because of the you know Ethical issues and then the the it's just even more challenging to to do that in humans and Let me just lower the bar just if one can do that with the animal models including human primaries and that will already be very useful for the neural systems I like that tool a lot and how about on a Neural communication level of Disease many people especially cyber neticians talk about how Every disease that we experience is a disease of communication That's happening within the body How do you what do you feel about that statement and then how do you feel about the onset of things like neuro degeneration related to Misfunctional neural communication Well indeed a lot of diseases are sort of due to Cell-cell communication problems. Okay. In fact, if you look at the FDA approved drugs They are about probably 40% to 50% are directly or indirectly targeting to this Sort of protein receptor protein car gPCR G protein couple receptors which are sitting on the cell membrane receiving the input from other cells and then talk to the innest part of the cell as than to do things Okay, and the drugs currently available are targeting those surface receptors 40 to 50 percent of them and and Using them to give them some better instructions Some of them are over-activated. It's just the drugs just keep them quiet Southern are weak activity the drugs just you know activated activated and in a better strength and that provides the the therapeutic Value for a lot of patients. So just by that definition that probably about 50% of those diseases are really related to the cell-cell communication not just neurons you know the Fat cells the heart cells. They are also having those receptors and since in the hormones and and then and then I Think in that regard. There's also other opportunities to further sort of design drugs and Target those protein for therapeutic purpose for example in human genome. They're probably around a hundred of those gPCRs Still often meaning that they we don't know why is there indulgence ligand The physiological relevant ligand to activate them and therefore we have poor understanding of their function even though for every sense of evidence we Could guess they are important, but we don't know what kind of sense they sense. What is their physiological function and therefore you Do not right now offer a really therapeutic target for drug development, but with their fundamental research for example de-organize them identify their physiological ligand and understand their Pathophysiological function they can provide more targets that again aiming at the receiving end Because those they are the receptors receiving the ligand for therapeutic purpose And we can also target at the signal sending in Sending the information right you can prevent The cell to be over activated sending the wrong signal or you can you know sort of a boost sending off the signal right now there are some drugs doing that but still relative feel and I think there are more opportunities in that regard, but Probably it requires especially for the nervous system. It requires our better understanding Which cell is doing what because to really have a therapeutic effects you want to boost the relevant signal communication and Minimize this off-target effect, but right now because the complexity of the nervous system only for The tip of iceberg subset of cells or brain regions. We have some understanding of their physiology and pathophysiological roles And for the majority I would say more than 90% or 95% of the brain region and with specific cells We actually have no idea of their function. We don't even know You know the blueprint the kinetomics of the human neurons yet because it's just so complex and so so they're still I Requirements and incentives for For scientists and for the society with the governmental support private foundation support trying to sort of help us to Understand the fundamentals the basic research in hoping to provide therapeutic more therapeutic Interventions I love that that also ties us to that first thing that you said about the fundamental Scientific research being done and it can help enable so much of the therapeutic effects that we soon want and need What about neural Prosthetics, I'm curious about what your thoughts are about that field and about jamming Chips into our brains. What do you think about that? Well, I think it's a very Unique and promising area, right? That's already FDA approved Therapeutic approaches through deep brain stimulation for certain diseases and and neuro prosthetics will be a better way To help to buy integrate sensory information and to feedback to the The the the neuron or specific type neurons that for example can cool in principle enable at least to start with those disabled persons to have a better control of their lives and Also has implications of you know Enhance the human Ability sports ability Compact Ability which might not be the direction we want to go creative ability possibly I Think right now. I think it's promising, but there are Still quite Bissful on why I know Knowledge gaps in a way how to really implement those things with Rationary design so we don't make them predict if you're doing this That it will have this Beneficial value, and I think this Is still a walking progress Yes, does it ever feel like We have a little way to figure out some of our Ethical or moral challenges first before jamming the chips into our brains Of course, we need to consider for human studies. That's this is the ethical concern the ethical issues need to be well thought out and discuss and In fact, you know since go through waves, for example, you know, just As done for many years ago when Scientists first in one way is to generate recombinant DNA That's already serious discussion about the implication of this technique and now is this genome editing CRISPR-Cas system that can have a higher efficiency to edit Genes with will this edge create is another wave but it's actually since that of Sort of ethical concern and rigor need to need to be exercised and then need to be discussed and and also is a Is a I think it's not just for one country and it's also Global international efforts and it's challenging in a way that he also Integrates with different cultural differences Okay, so Well, I'm not Clinical scientist working on human subject per se, but At least right now for us working on animal models that we have less Sort of Concerns right now, but for the therapeutic purpose one of course need to think in advance Yeah, like how you put it that this is Important on a whole geopolitical on a global level and there are cultural differences that need to be accounted for all of this type of stuff the current state of our world as you mentioned at the beginning is going in the direction of Prosperity maximizing flourishing meeting the basic needs of people all this type of stuff Yet we have the most Massive gap in wealth inequality ever What do you think about that Well, it's a big question Let's see well, I think some fundamental sort of rights for example rights to have a good education that My help in a way so to sort of reduce this imbalance, okay, and you know China for example, you know just Like many country including in the states. There's also huge regional differences, right? So For example in China, that's usually along the coast are more economic development and therefore are having good or relatively good resources for education and healthcare etc and in the in the West Countryside and that that will be just that's but in terms of the Education or as a fundamental right just to to make it happen to everyone and with With a guarantee support, I think that can help helped to reduce the the imbalance and also Modern technique wise right so for example the the the cell phone Cell phones are being very popular in a way that has the internet connection has a network and In China it's been popular that can be used for almost every single thing, you know, are they pay, you know We chat in Implement the infrastructure Sort of a Relative for equally meaning that allowed the access of cell phone signal in Every single corner of the country Will be useful for those less developed countries because then they have access to the connected world to for information for education for, you know Convenience services and the capital or Sort of Sort of the economic value itself might not do it because of you know, economic wise for the cell phone company probably will be more beneficial to install the cell phone towers in the dense population dense regions where the well economically it makes sense and therefore I think mental or Charity private sectors in a way trying to counter the pure economic Drive but sort of an increase the basic infrastructure the education rights To every corner and and I mean to that probably also not in China But in other countries, there's always this economic drive led to make profits that based on you know develop country develop cities or certain generations certain Edi groups, but how to really implement the infrastructure that counter this profit-driven market force, I think it will be Important in to ensure to the sort of the balance and the reduce of this huge gap For the different classes. Yeah, I like that answer a lot figuring out how to democratize education around the world and how to create incentives for that democratization. I like that a lot and And With the explosion of exponential technologies that are happening right now Especially at your lab. This is really interesting. How do you and your students in the lab? keep up with Neurobiological research that's happening in China in the United States around the world How do you keep up with all of the advances that are happening? Well, we use both I would say all fashion ways and also use New technology ways right so all fashion ways well with repapers so the the scientific publication are still the probably one of the oldest way but still Very valuable way to communicate your So ideas and your sort of inventions. So we have our regular general clubs that we read sort of research articles Relevant to our interests. We also attended Good research conferences both in China and abroad including in the states Society of Neuroscience meetings probably the largest meeting for the neuroscientists and We almost every year we've been there and more than three students that from my lab They go there. We also use the social media right the for example V chair has been popular in China and there are some special in Chinese Gong Zhong Hao and There's a sort of a certain sort of a special group that will collect some of those latest development They sort of broadcasts through we chat and then we can subscribe and also there is There's private sectors. There's some individual research groups For example, if they are in our own field They also create our own private we chat sort of group that they disseminate They are general club. Okay, there are thoughts about certain paper certain techniques and we also join the discussion and subscribe that and in fact, we also embrace ourselves for example, we use by our archive in a way to sort of review our Preprint researches before its official sort of publication So in a way that the scientists will have a early access to some of our research and our that has a Twitter account and some students are managing mainly for our research and discoveries and and I'm also hoping to have a better investment of sort of our own website and have a better updates and also with our own groups Gong Zhong Hao And some of my students if they listen, please help me to do that I like the variety of Techniques and processes that you described there and I'm happy to hear that there's these groups that are happening within things like we chat where they're Compressing the the scientific discoveries and disseminating them through the platform to other people in getting more people engaged I like that a lot Also in the Sex Penitential Technology Age, what would be something you have a child? Six years old. Yes. Yes, and We have many people that have children What is something that they can learn Going into the Sex Penitential Technology Age that you think is a critical skill to learn I I wish He's not addicted to iPad. Okay, I think it's a little bit too much So while while while we meaning me and my wife while we are trying to do is actually Getting into an old-fashioned way to read books So essentially while we are trying to do is counter this market force or this attractiveness of iPad which is a Colorful app with this sound with this cartoon, but in a way trying to get him to read books Honestly speaking, I don't have a good solution. Okay, so so right now while I'm really forcing a way to Balance like five minutes iPad equals five pages of book Books so so he has to read five pages before he can ask for five minutes of iPad But probably you know, I could get more advice from others and it's been challenging for me. Yeah Yeah, yeah Then there may be some sort of really interesting Aspects to old Principled ways of learning like reading books that are just really critical to knowledge Accumulation that we may not be able to get from iPads But also vice versa certain things that we can get from the newest technological revolutions that we couldn't get from the older technologies does it feel like there's some sort of Meaning to this big human experiment that we're all a part of on this plan It what is the meaning of it? I don't know. I don't think about a lot about that But the phone, you know, there are a lot of sauce right just looking at not just human, right? their sauce that Even as books called a selfish selfish DNA, right? So so one of the meaning if you put it this way as a creature as a biological species Is we just been sedated in a way that we need to pass out pass on our genetic material to our offspring, right and Yeah, I probably should think more about that and you know if I have less grass students to worry about, you know we have a a a amount of of Computational capacity that is now starting to become more and more able to do simulations digital twins All these kinds of things Does it feel like we're in a simulation? Again, I I I don't think about is I I hope not When I was reading or learning some simulation usually The other part of my brain is how can I put this to help my students? like or help our research projects that well we can Using this computation power that has been generated for example, including deep mind or they have this alpha go But also they have this alpha thought which is a a program to help to try to predict protein structures I probably promote source of how to use those simulation instead of worrying about in a doing in an artificial Intelligent to do to do ever since but how to harness like alpha thought or similar programs to provide predicting Assays or predicting structures that can help our research no or help our understanding of the brain That's why I'm probably support source of that. Yes. Yes the creative capacity of super intelligence to run all of the permutations and find the ones that are most Relevant is so so important Well, I wish I could find one and it is to solve our Structure biology problem. Okay. I you know, I'm trying to then a little bit myself, but it's too challenging for me I'm too old Does it feel like consciousness Arises from the biological complexity does it feel like it comes from Somewhere and takes the seat in the body. Yeah. Yeah, I think so You know, just looking at again the neural system from, you know, if we define those different animal species, right? so you can look at the sins from So the simple organisms like a sea elegant sea elegant worms or Jossophila the a lot of Sort of fundamental neural connections at the two cell level might be the same but of course the human beings or primates That really have this expansion of this complexity that that enable a more sophisticated Control and at least correlated with higher cognitive function including, you know depression happiness, you know You know all different emotions Emphasis right, so yeah, I think that this is a good correlation and The causality is always challenging to to prove What is the role of love in life? Well, I think it is to Make people happier You know, we have again we have a 60-year-old son for our family and You know, he's for sure to the source of joy. Just, you know, even though fighting him not to Get addicted to iPad, right? So it's you know, it's just really source of joy just in thinking You know making mistakes in doing City things or you know or really pretend to be an adult to be a loving person and you know giving greetings, you know, it's you know, I think In that regard the love it just makes people happy And what do you think is the most beautiful thing in the world? Well, I just right now The center of gravity for me or my family is our son. Okay, so the with the kids actually you know, I Think this is a special relationship and then just seeing them. I think this is I Think it is irreplaceable the selfish gene procreation But it's also such a central source of love and and light and joy and Beauty, yeah Well, this has been really fun. All right. Well good to talk to you. Yeah. All right. Thank you so much for coming on our show Yeah, sure. Thanks for bringing us out to Beijing University. Okay, I hope I hope Some of my students see or don't see in either way I will be happy if you see the show Please help me do something. Okay. If you don't that's okay. I don't feel the embarrassment I love it. Thank you everyone for tuning in. We greatly appreciate it We'd love to hear thoughts in the comments below on the episode. Let us know what you're thinking Have more conversations with your friends families co-workers people online about neurobiology and about all these tools That we were describing today in the episode Also support the artists the entrepreneurs the leaders around the world. Do you believe in? Support them help them grow support our show simulation. You can find all of our links below for support and also check out the links in the bio to support you along lead lab.org also the Twitter profile for the lab as well as Ulong's LinkedIn profile and Go and build the future everyone manifest your dreams into the world. 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