 To us, our neuroscientists, we want to know during different functions, which neurotransmitter in chemical perspective view, what type of neurotransmitter was released and in which brain area and the release for how long or how fast we call it dynamics of the neurotransmitters, everything is unknown so far. I picked up the DNA sequence of our dopamine sensors and inserted it into the embryos of the fruit fly and I raised up the embryo and got the transgenic animal, the fruit fly, with our sensor in its brain. I come up with an idea that the fruit fly loves fruit, so firstly I just give the smell of the fruit as you mentioned, banana. So when the fly smells the banana, there is a flash in my screen. I can look at those fluorescent signals with my naked eyes without any imaging process. The fluorescent signal is relatively big and that's cool. That must have been a big aha moment for a scientist. That is the first aha moment in my graduate career. That's beautiful. Interesting. Identify the whole connectome, record the whole connectome and then manipulate the whole connectome. Yeah, okay, cool. You guys heard it here, get building on that. I love it. You can work on that in the future. Yeah, please, yeah, yeah. I know someone's opinion may contradict yours. Where's my friend Alan? It's all about your perspective. Who are we and what is the nature of this reality? Ni Hao, everyone. Welcome to Simulation. I'm your host, Alan Sakyan. We are on site in the beautiful Beijing, China at Pecking University School of Life Sciences. We are now going to be talking to Big Tree. Hi, Alan. Hello, everyone. I'm Big Tree. Thanks so much for coming on our show. Big Tree really appreciate it. Thank you for inviting me here. So excited for our conversation. For those that don't know Big Tree's bio, he's a graduate researcher at the Lee Lab at Beijing University School of Life Sciences using cutting edge neurobiology to study memory and you can find the links in the bio below. Okay, Big Tree, let's start things off by asking one of our favorite questions. What are your thoughts on the direction of our world? Our direction of our world. If you mean that the whole human community, I think our direction is down on the Mars. The next continent's place for us, because recently I'm writing the biography of Elon Musk. So he pointed out that our next direction is the Mars. Yeah, yeah. Is it Ashley Vance's? His writing? Yes. Yeah, yeah. Okay. That book. Yes. Did you read that? It's such a good book. It's a really good book. It's a very inspirational book. Yes. Yeah. Okay. Why? Yeah, go ahead. I was gonna ask. Go ahead. Go ahead. So why is our direction till the time since we are still on the earth? Personally, I think we need to enjoy our life and taking our responsibility, support myself, support my family. And if I got bigger power, I can support my friend like you and for our whole society or for our whole community making it a better world to live in. Yeah. That is our goal. Yeah, yeah. I love the mentality of of being pure and being love and achieving some sort of our own maximal potential that earns us some power that we can wield in a healthy way and also in a way that enables us to earn and then fulfill ourselves, our families, our communities, our country and the world at large. Like I love that mentality. And it's also interesting that you pick Mars because you pick that answer because we have so many grand challenges to figure out on earth. And we have to also be careful to not just export the same problems to Mars. Yes. And that requires a lot of human evolution and consciousness ascension before we can really in a healthy way be able to colonize another celestial body. Although it is a great idea to continue the process of doing so as we scale civilization and hopefully have billions of more people that are able to enjoy consciousness, creativity, meaning all these types of things. What about your journey? You know my personal journey, personal journey? Where were you born? How did you pick up your interest in science? So I was born in Chongqing, southwestern part of China. And I'm very proud to be a Chongqinger because that is such a beautiful city. And we are famous for hot pot and we are famous for our spicy food. And I love them. I cannot live my life without chili actually. I eat spicy food every day. So even when I live in Beijing. So I was born there and I my first 80 years, I just go to the kindergarten, primary school, middle school and high school. And after the college entrance exam, I pick up my next station in Hunan University. How did you get your interest in science though when you were younger? Because yeah because you ended up studying science in college. But how did you know that? So I do not know. I picked biology as my major in my university because at that time I actually I don't have too much understanding of what ethos are. But I don't know what I don't want. I do not want to study for my career or in my future because it's very interesting. My family work in like my grandpa works as a journalist like you to interview a lot of persons and my mother is an editor for a newspaper. So I know of the work, what they do and but actually I don't know too much about the science and the engineering. I just want to open my heart at that stage. I want to look at how the world works in the scientific way or in the engineering way. So I pick up the biology as my major. There are other majors like the math, like the physics, chemistry and also our engineering field. And why I do not pick those fields as my major because firstly math and physics is very difficult. I must admit that they are difficult and when I was in middle school or in high school I'm good at biology and I still think it is complicated. The most complicated things in the whole universe how they're so far people only find life on our earth instead of other planet. So life is complicated and there is a lot of things to be answered and so it moved to my so I select all just my major and what is even complicated in our life that is our brain. How the how a lot of neurons talking together to each other and the full field our emotion our logic and our soul and I mean our spirit okay so so so my after got the bachelor degree in biology in my university I won't I so in my graduate school I selected the neuroscience as my as my interest to do further studies so it's very interesting that I attend a summer school in peak university when I was a sophomore year graduate student and at that time I needed to pick which field you are interested in firstly I did not pick the neuroscience field a lot of selections like the structural biologists which are neighbor Qinghua University is very good at and the second the second direction is the stem cell the the at that time the IPS just got the Nobel Prize so the stem cell is very it's very hot at that time and the third topic is the neuroscience so firstly I pick up the stem cell as my first choice but but it but at that time I at that summer I got an internship study in the I need to do white field study in the in another area of China I cannot go to Beijing at that time so I talked to the I talked to the TA whether I can change another direction so there is only a sloth left in the neuroscience field so I pick up the neuroscience that that that is how it works goes for me and so I pick up the neuroscience as my direction at that summer school and I need to select a PI to read his papers and come and have dinners with the PI and even visit the lab and I got internship experience in the lab so at that time there you know there is a huge there is a lot of PI's in the neuroscience field in Beijing University and a lot of them are very firmers and successful like Irel, like Zhuanzhou, like Chen Jianli and a lot of PI's and Yulong just start that is in 2013 Yulong just start his lab at 2012 so he's very young PI so people people just people just because I am the person who switched to this direction so a lot of the very famous and successful PI's has been selected as by other students so I have no choice so Yulong is the only one who got so I got the only slot from the neuroscience direction and I got the only slot from Yulong's lab so I come to know with Yulong and know his study and in my graduate school he becomes my PhD advisor so I already worked with him for more than five years so that is my way that is how I go to the lab and go to the graduate school and start my study and yes and why I am interested in piloting neuroscience yeah and on a trajectory to tackle the potentially the most complex thing that we know of in the universe what's happening in the human brain and maybe maybe on the process of going through building tools which we're going to talk about on tackling this big challenge we can do massive things like augment our health extend our longevity make ourselves smarter make ourselves more knowledgeable less ignorant all this type of stuff okay it's funny the last slot the last slot yeah yeah yeah and it's good that you know PKU is just this has like you were describing there's just so many really great PIs here and you have a really good opportunity to be doing what could be worldwide world-class research that worldwide makes a big influence on other people picking up and using the tools which is huge let's talk about the the first part of your work when was the work your work with GPCR the G protein coupled receptors when was the first one the dopamine that so my first one I joined the lab or let's just start the new project developing GPCR based near transmitter sensors so shall I talk about something about why we need that exactly let's actually even let's take let's baby step our way through this so first is G protein coupled receptors GPCR a large protein family of receptors that detect molecules outside the cell yes and activate internal signal transduction pathways the cellular response so outside of the cell our GPCR receptors yes that then take information from outside the cell to trigger the cells response gene expression these types of things okay and apparently Yulong was teaching us on the show 40 to 50 percent of all FDA approved drugs are targeting the GPCR receptors okay so this is a very important I mean triggering cellular responses crucial in biology and neuroscience so yeah walk us through some of the yeah the GPCR stuff to start and then yeah why let's talk about why that's important first so our brain is not like it's complicated it's not like other tissues some see happens in the cells that can explain how we how everything goes like in the stem cells or in the or in our like other system circular systems or some other things what make our brain magic in that the brain consists of a lot of neurons and they know neurons working alone but they work together so communication is the most critical function of our nervous system of our neurons and the neurons need to communicate so the major media is the as neural transmitters which released from the upstream we call it pre-synaptic neuron released the neurotransmitters to the post-synaptic neurons and the post-synaptic neuron receives a signal and knows what's going on what's the what's the order and what I need to do in the next step so this is we call it synaptic transmission and the receptors for all of the neurotransmitters we got in our body we have a specific receptor that is the gpcr receptors so basically gpcr defines the major communication function of our brain so study gpcr is quite important but and now people have no idea in the living animals when and where and actually there are more than 100 types of neurotransmitters has been identified and that there are even larger group family of the crespondent gpcr receptors and so more than 100 neurotransmitters neurotransmitters have been identified yes oh my gosh yeah but you can apply like the Pareto distribution like a power law distribution you can say that 20 percent of the of the neurotransmitters account for 80 percent of all neurotransmission like a majority of serotonin dopamine norepinephrine etc yes yeah okay and like the there's like the long tail which is very small occasional uses of the other 80 percent they are rarely yeah that's the truth okay okay so uh there are some major transmitters and as you said something uh less used in our brain but often so so in the chemical aspect of view our brain is so complicated even the communication is so complicated so so we want to so a lot different neurotransmitters get involved in different brain functions like when you are thinking you are looking at me and you are you are nodding everything that is is controlled by your nervous system so different neurotransmitters get involved in different functions and and so to us our neural scientists we want to know during different functions which neurotransmitter chemical in chemical perspective view what type of neurotransmitter was released and in which brain area and for and the release for how long or how fast we call it dynamics of the neurotransmitters everything is unknown so far so so so we want to know how can we detect those neurotransmitters uh actually some uh the the electrophysiologist or the chemist chemist already developed some technologies to detect the neurotransmitters in in in human brain or in the brain of motor organisms and but unfortunately they are they lack some sort of temporal resolution because they collect the sample like in every five minutes or 10 minutes that is much more slower than your thinking than your logic and and so so some of them lack the temporal resolution some of them lacks them a spatial resolution cuts they need to insert a relative big electrode into the brain to detect those signals so the brain and so those electrodes are much bigger than the neurons or even comparing the synapses which is much more smaller than the neurons so the electrodes are too big so we don't know exactly where this different neurotransmitter released so uh in the aspect of temporal resolution spatial resolution there is also chemical identities as i mentioned more than 100 neurotransmitters was involved in different functions so people lacks the technology to identify the transmitter type just based on their electro or chemical feature uh electrophysiological feature or electro chemistry features so biology question needed to answer by biology tools biological tools so that is what we think why we start as our biologists what we can do to develop new tools to answer these old questions so um so our nature has evolved for billions of years and we got those neurotransmitters and we also evolved their corresponding receptors that is that is how the in how the nature detects different neurotransmitters that is the gpcrs so we focus on their native receptors to develop our native detectors that is our basic logic and so what uh so the gpcr um from previous studies people already got Nobel prize for solving the structure of gpcr and people found that when specific neurotransmitter bind with the gpcr the gpcr just tweaked a little bit that we call it conformational change yeah and we we expected that if we can if we can attach a just a fluorescent protein into this gpcr and during the the tweeting of the gpcr the fluorescent protein tweet with it and there might be we can there might be some fluorescent change yeah and in this way we transfer a chemical signal into a light signal so we can detect it by the very cutting edge imaging tools yes like the two photon confocal or a lot of new image cutting light shade along with imaging tools yes oh okay so let's do that talk too much so good such a good breakdown for us a very good breakdown okay so let's start with this point so we were talking about how we have gpcr receptors on the outside of cells and on the outside of the neuron especially on the uh the postsynaptic side uh on so on the receiving end of the neurotransmission there has to be gpcr receptors because they detect the neurochemical yes okay and then you guys figure out how to add fluorescence to the gpcr receptor yes okay through what through what engineer through what engineering enables stuff yeah oh that um so that is what we call protein engineering work that is the multiple most critical process during a sensor development we pick up we pick up those we amplify those genes which encode the gpcrs from our human genome from our human DNAs we clone those stuff use a technological PCR polymerase chain reaction we got the DNA encoding those gpcr and then we can use some enzymes to split it into like two or three different segments and then you got some slot to do and and you got you like you got like one slot if you cut it uh you cut it this way you got one slot and then I clone we clone the fluorescent protein from jellyfish yes from jellyfish the green fluorescent proteins from the jellyfish the red fluorescent proteins from the coral so we clone the fluorescent protein from the coral or from the jellyfish and we got the DNA fragment and we insert the DNA fragment into the gpcr slot and these three part comes together was sealed by some enzymes and we in this way we got the whole DNA sequence for neural transmitter sensors actually um you can not just do it that way and we got a very perfect sensor with good expression level with good fluorescence even with good signal to noise ratio you need to you need to engineer very carefully where to insert the fluorescent protein into the gpcr backbone and you need to also engineer the linkers the linker protein or DNA sequence between them that will defines how efficient how how the efficient of the so-called conformational change transfer from gpcr to the fluorescent protein there might be some linkers so you need to tweet uh you need to do we call it random mutation to those linker sequence to see which amino acid is the perfect and after that we also engineer some uh do some mutations within the gpcr we call the the uh neural transmitter is very small that will bind with some specific place within the gpcr we call it binding pocket and within the binding pocket um DNA sequence or amino acid sequence will defines the affinity between sensor or between gpcr with the neural transmitter so we also engineer some sort of specific site within the binding pocket you got the perfect sensor with with good spatial temporal uh not not with fast kinetics with good signal to noise ratio to transfer the chemical signal into fluorescent signal and uh yes that is a lot of work if you are a first year graduate student just start to do such kind of we call it protein engineering you take like three days or two days like three days to get such a construct and test it whether it works or not and uh to get a perfect sensor probably you need to try more than one thousand alternatives to get a perfect construct and you need to that that is a lot of work but but we we figure out some way to do it parallel so that can save some time but it's still a lot of work for a graduate student to get such a perfect sensor and actually i'm very lucky when i joined the lab we already got those sensors some are prior students in our lab already built those sensors and tested those sensors um the most simple uh model culture sales artificial culture sales in the medium sales in the medium we tested those sensors and we already know that it works and what so so it turns to me i i take the job to create transgenic animals to test whether they're the sensors can whether there's this sensor it can be used for in vivo studies in intact animals in the living brain there being specific behavior so i took the fruit fly for science we call it jasophila monogaster to as an animal model fruit fly has been used at the model organism for more than at least 100 years from morgan and who got after genetic screen after metagenesis he got the white eye white white eye fly that i think that is a star of the fly genetics so people use fly to study the to study the biology for a lot of years why people use fly that is because fly is very easy firstly fly is very easy to do genetic manipulations if you you cannot clone you cannot do gene manipulation on humans but if you want to create a transgenic mouse or rat it takes half a year to get such a transgenic animal if you want to do transgenic manipulation on higher model organisms like monkeys it takes several years like one or several just several years to get a transgenic animal but if you want to test the fly within one month you can get thousands of different mutants that is very fast to study the biology from with genetic tools so we start from and that is the first thing for the benefit to use fly as an animal model the second thing that even for especially for our neuroscience field the fly brain is quite small and there is a less neuron in the brain and its brain is less complicated comparing with mammals so it is a simpler model to study very conserved functions of the nervous system which the things we shared between our humans with other animals even as more of the fruit flies like people already done a very beautiful a lot of beautiful work use fly in the nervous system to study like the circadian clock the daily life which shares between humans and flies and the first mutant of the circadian is identified by sumo benzer at keltec in the 1970s in the fruit fly instead of human or rat or mouse so fly is a very just perfect model organism to study the nervous system to study conserved biological functions in the nervous system so and again for in the perspective of neural thrusting in the perspective of neural transmitters we share most of the major neurotransmitters our human has acetylcholine glutamate GABA dopamine nipinephrine adrenaline and of those neurotransmitters exist in the fly brain and it controls major functions so so you have to then figure out how to engineer the the gpcr sensor to create up the fly brain for even a specific neurotransmitter so so you want to know when it's when you're received when the nerve when the neurotransmitter that you're receiving um when you're sent when you're sensing dopamine versus serotonin versus nipinephrine sedrate you need to know which one you the fly what's flowing yeah yeah yeah yeah sure so so you have to engineer the sensor to let you know which one so that way when you're so bringing the banana peel to the fruit fly and the fruit fly smells the banana peel because it's like yeah because that's you know just like with us too we're very similar when we smell some food it's big yeah neural activity happening because that's that's our that's our that's our sustenance that's how we live that's how our genes can live on when we eat so same thing in the fruit fly brain you have to know we have to you have to know what neurotransmitters is is being secreted being in flow in the in the brain this activity yeah yeah that's what I do so when I get into the lab we already got the first dopamine sensors probably the first one in the world so I pick up the DNA sequence of our dopamine sensors inserted it into the embryos of the fruit fly and the and I reach up the embryo and we got the transgenic animal the fruit fly with our sensor in its brain so so so I mean the whole no not in the hell how many neurons how many has the sensor expressed that that that defines the firstly I just test our sensors because it's a dopamine sensor so I expressed our dopamine sensor in all of the dopaminergic neurons in the fly brain and how many how many let me see probably several hundred several hundred neurons in the fly brain and you were all imaging several hundred neurons over time and spatially yes either two photon microscopy or con confocal confocal microscopy okay yes either one of those are one of those work better for it um for in vivo imaging in in animal brain people usually use uh two photon microscopy compare two photon can see much deeper in the brain comparing ways they can focus so uh because the animal brain is relatively deep so people use two photon so it's very interesting I got those transgenic animals expressing dopamine sensor in like several hundred dopamine neurons in the fly brain and at firstly at first I have no idea where should I look at where whether there is really dopamine release in the fly brain and the weather our sensor is capable to give us the fluorescent signal so I have no idea the enough I just look at the screen of our microscope and cannot figure out what to do next I can see some fluorescent signals but there is no dopamine release no fluorescent change and so I I just I I come out with an idea that the fruit fly loves fruit so firstly I just give the flight of smell of the fruit as you mentioned banana so I when I when the fly smell the smell the banana I I find those there is a flash in my screen I can I can look at those fluorescent signals with my naked eyes without any imaging process the fluorescent signal is relatively big and that's cool and that must have been a big aha moment for a scientist of yeah that's it wow that is the first aha moment in my graduate career that's beautiful so and actually it is not all of the dopamine neurons all of the sensors in the fly brain it's just like subset like several like less than 100 less than 100 neurons in the fly brain get activated and I just look at those signals with my naked eyes and when I come back to my computer to analyze those signals and I found oh those sensor really works it's the first time we gotta know that our sensor cannot only be used for cultural sales but also to study the real biology how animal smell things yes and it's as it's complicated but it's also as simple as taking the genetically encoded sensor and embedding it in the embryo of the fruit fly aha and then having that embryo divide and divide and divide and divide and make the fruit fly thousands of the fruit fly aha because they multiply really fast after you have one yeah that breeds because the fruit fly will make new babies and often new babies carry our new sensors they carry the sensors yes wow and so then after just a couple months you have thousands of flies with your sensors okay and then the fly has to you know be that that safe glue has to be used to keep it on the on the foil or the paper so that you can I think you must talk with some fly person previously do you you long mentioned it on the show oh you have to have a safe non-harmful glue yes to keep the fruit fly on the we call it chamber the imaging chamber the imaging chamber yeah to mount the flies mount the flies and we use we choose twitters to open a very small window on the fly's head and expose the brain but do not touch and do not hurt the brain keep the brain intact and let the fly think everything it wants you to think yes really so you can use very small tweezers to open the fruit flies brain just a little bit and not not just a little bit quite a bit but not I do not touch I do not touch the brain I I hope I cut up the cuticle or the skin of the head of the head and the expose the brain so that the two-fold tom microscopy can go past the skin yes more easily to the brain yeah and then the the banana is brought up yes and then you are looking at the two-fold tom microscopy and then you see the as the fruit fly smells the tiny little piece of the banana you see the fluorescence of about a hundred or so of your yeah lights up light lights up of the neurons yes that have the dopamine sensors yes attached to them yeah yeah genetically encoded these sensors from the embryo until that's how this is this is an excellent scientific advancement that has so much potential thank you yeah because yes because one big problem in previously that when people also want to detect the different like even dopamine signals in the fly brain people can use electrophysiology method to record the electrical signals from single neuron but as I mentioned there are a lot of neurons in the fly brain and people cannot record it one by one because it takes a lot of time to do even one recording and if you want to go through off the neurons it's almost impossible but for image method we can just open the window and look at all of the neurons at the same time and within several seconds we can know which one is working which one is not is silent and we can do it all we can record off different neurons parallely that is the benefit of the imaging comparing with previous electro chemical method and the imaging has so you can put say the image method has high throughput and in the yeah that's it yeah yeah wow now no no you want to create sensors for all of the other important especially neurotransmitters yes okay yes that's what I'm doing and I already I think our sensors already cover major neurotransmitters and exist in the fly brain including dopamine, serotonin, acetylcholine and the adrenaline of the free flight called dopamine and now we even switch to we already started to develop other non-major neurotransmitters we call it neuropeptide but they are very important and the neuropeptide contribute to like 80 percent of the neurotransmitters identified in the brain but previous people just got no way to observe those momentary cells and it we are very lucky because our method can be can be also adopted to develop sensors not only for the major neurotransmitters small we call it small monocone neurotransmitters but also for other types of neurotransmitters and this method is universal so we are lucky now we are working on that to explain the sensor palette and we want to cover as small as major neurotransmitters where else can the genetically encoded sensors for gpcr sites be useful because the brain is very useful place for this can other cells on our body also use the similar techniques for especially pharmacology if so many of the fda approved drugs are for targeting gpcr receptors then shouldn't we also have sensors on those gpcr receptor sites so that we know if the pharmacology is actually connecting with the targeted cells that is what we are that is one potential application for our sensors to screen for new drugs because during pharmacology in i know in the pharmacologic field or in the companies people want to screen for different drugs that can target gpcr as you mentioned but what people are recording is actually the downstream signal lanes of native gpcr because downstream of the downstream signal lanes of different gpcrs and then that takes time and after and then that takes time that is one disadvantage and the second disadvantage is that people don't know there is an amplification effect of the downstream signal ends so people don't know to what extent the gpcr is real activated or inhibited so with our sensors we attached a fluorescent protein onto different gpcrs and we got a sensor and this fluorescent protein just those fluorescent signal just comes from the gpcr itself so we can quantitatively and to screen for the chemicals and the potential drugs which can activate or activate different gpcrs and in a very fast in a very high throughput that is our benefit and the potential application of our sensor and actually we are we are we already started to try on that project excellent excellent seems like especially with the vast amount of money that the pharmaceutical industry spends on drug design and development that it would be really helpful to increase efficacy of knowing if they hit the targeted cells with your sensors yes yeah using your sensors for that process now let's talk about the work with memory sure because when the fruit fly smells the banana and we see the neural activity and we map it spatially temporally then that that becomes a memory that the fly holds no it doesn't interesting okay that is not the memory I mentioned I think you mean what is what do you mean is more like familiarity or familiarity yes okay you you smell something and then you smell it all the time and you just get desensitized with that smell and you no longer pay attention to that smell that we call a familiarity well maybe more so that my all of our collective human ancestry has for the last millions of years been smelling food and when we smell food from a million years ago we figured out okay I smelled this food it tastes good oh then several hundred thousand years ago I smell it tastes good ten thousand years ago I smell it tastes good you know even up until now oh you we still smell it it tastes good so it's like literally encoded in millions of years of memory you mean the you mean the native preference to a smell which is evolved during the history during human evolution and that is one kind of memory encoded we can call it a native memory encoded in your gene and in this case it would also be a native memory encoded in the fruit fly right yes this native memory will also encode in the fruit fly that is why a fruit fly called fruit fly because they like fruit so what I call is we I'm studying the associative memory that's a lot more complicated yes yeah our brain works so much differently than a computer does in the sense of associative memory versus storing a file in a very specific place that can only be accessed by going to that specific place in the computer memory whereas with us it's so associative if I start talking about my visit to Peking University I'll start thinking about all of the science you were teaching all of the people that I was meeting all of the culture experience yes so associative yeah that that is the associative memory so the fruit fly is not as dumb as you think the fruit fly is relatively smart and the fruit fly can link a smell with with a previous experience and if the experience is harmful or it's a punishment the next time after the after bridging the connection the next time when the fly smell the same odor it knows to get a void from that and if the experience is something good like the food the fly learned to get approached to that odor this phenomenon has been identified for like more than 50 years half half century by Seymour Bender a professor in Caltech in 1970s and the people studied this field for half after half century study people already know that a lot of neurotransmitters take part in this critical function include among them including dopamine, serotonin, acetylcholine, octopamine all of the neurotransmitters we already got sensors yeah and we do not intentionally create our sensor to fit this specific neural circuitry but now we previous people know that flies with with abnormal neurotransmitters like dopamine serotonin it cannot form such type of associative memory or they forget more quicker or they or they when you see it has deficit in long-term memory or they just can only remember the good things but cannot remember the negative things so the fly experience different deficit of associative memory weighs the loss of different neurotransmitters people already know that from behavior studies to test whether the fly go or no go to different smell so but no one has ever know which when and where does different neurotransmitters was released even during the association and during the memory recall and this is really interesting for a lot of our current neurological diseases specifically like depression and anxiety and and ADHD PTSD yes it is what we created is just a PTSD in the fly brain and want to see what happens during the PTSD during the PTSD happening and what happens when the fly just experience it once again how to we try we quite retrieve those memories in their brain yeah in their deeper mind yes wow yeah it seems as though if a if we can approximate that a human to a monkey to a mouse to a fish to a fruit fly is at least somewhat similar there may be a a pretty serious discovery awaiting us that says something along the lines of if there is a lack of neurotransmission occurring where there is supposed to be when it's supposed to happen for especially when you're doing some sort of a task that usually gets you neurotransmission like a reward like a behavior that usually gets you a reward like in the case of people with depression it's like if you get out of the house and go and exercise or go and read a book or go and do something meet with friends do something that is drives you closer to your goals if you're not getting the same neurochemical flows that you should be that's a big problem that's it yeah that's that's why we want to study this phenomenon because the associative memory is just so it's the learning ability is some critical ability should just push our human life or push our history forward so and we and what is very interesting that all of those chemical chemicals used in the fly brain to form the memory or to forget a specific memory is just conserved between humans with the flies and the humans also use things like dopamine serotonin and the citricoline to kill the memory to form the memory and so the study in the free fly will give us a lot of hints of what's going on in our brain and how we can treat ourselves in case of anything bad happens if our memory encoding system is having issues with neurochemical flows then there may be a much better specifically targeted way of doing stimulation to to reintroduce those original neurochemical flows to continue people in the direction of when I do something when I'm supposed to get a neurochemical release then I actually get it and brain stimulation is a very interesting field that has a lot of you know ultrasound electrical stimulation magnetic stimulation a lot of interesting very careful stimulation is very important very precise stimulation is very important but healing people is very important healing people bringing people back to their their their healthiest and most creative flow states of being is very important sure do you do you feel like that's like one of your main reasons why you're studying like what are the main reasons why you are studying the memory like healthy and happy for humans or what my study of memory because it's just curious i drift by curiosity the memory created the person defines our our defines our identity defines who we are people cannot can cannot connect itself with if people cannot connect itself with previous experience they'll just feel lonely and feel abandoned by the world or by the community because like something like you know the people will with health hemorrhage disease people forget everything it just experienced and that's sad and and so for people lost the memory we I don't know what's the feeling of lost the memory but I know what's the feeling when I face a person who lost his memory the and the ad patients and just my grandma and I feel I have no way to help her but that's sad because the current science cannot help people with ad but I want probably there is a way to figure it out by the study of how memory was formed how memory was lost and I do not want to have that experience when I getting out and possibly that is a deep drive of wine pursuing that question and we like to use the analogy of the library you have the big library in your in your brain and that you experience neurodegeneration and the library books are on fire in the library we're losing big volumes of yes of memory and sleep is another really good way to understand memory that everything that we experienced today we sleep so that we can integrate everything today with our last for me 26 years of my life and that when you have issues with sleep or when you have issues with encoding memory you lose it would be so cool for for us to could we could we remember all of the cool things that we experienced today but no we're not we're only going to experience we're only going to remember certain key things yeah from today yeah that we're going to encode with our last 26 years but what if I wanted to come back to the exact part in this interview from you know well we have we have our recording of it which enables us to do exactly that come back to this exact point that's why we do things like record great conversation so we can do exactly that and share it but if we weren't recording it and I really wanted to come back to that sentence or that paragraph that you said that was really inspiring to me to for me to be able to go back for us to be able to have really cool recording of our entire day of our entire life stream of memory and to be able to go back fast forward rewind pause it's very interesting I like that a lot and it can more easily be stored that content then the entire life of victory or the entire life of even your grandmother before the neurodegeneration happens that we could capture her memories and then be able to go back and like see what life was like for her oh you know and you know and that type of it's a pretty interesting field of upcoming study with memory and and the retention of knowledge and the transmission of knowledge over time yes that's very important interesting and I think what we want to keep is what you mean keep the memory or keep the moment is keeping the state of how the neurons are connected now interesting how they're connected and what is transmitting uh how chemicals basically the chemo electro connectome yes okay yes of that exact time period that we were talking about those exact 15 seconds of you reading that paragraph yes I need the chemo electro connectome of that 15 second period yes probably you can click the play button and then oh that's what I felt like probably that's a way how you can go back and just feel exactly the same way and see the things here the things filled with the wind the air the smell yeah that's a way interesting how neuron communicates and yeah how you feel yeah okay what about your ideal neuroscience tool oh my ideal neuroscience too we were just talking about like this you know chemo electro connectome right or what would be your ideal neuroscience tool that would help you do exactly what we are striving to achieve in the field of neuroscience maybe 50 or 100 years down the line what will that tool look like that will enable us to do everything that we want today with neuroscience that must be there must be one only one tool for as the best tool to study the neuroscience questions for such kind of tool firstly you keep the whole brain intact but you can get the whole information of the activities of different neurons with without any perturbation you don't need to open the brain you don't need to you don't need to cut a window and you just got all of the neuron activated all the chemical flows in the brain simultaneously from every neuron and in on the top of that you got the identity of which neuron you are looking at the identity what i mean the identity is the genetic background of the neuron which gene it expressed and which RNA is transcribed and with that you already know you can do all of the recording things and then plus another thing you need to you can get access to manipulate every activity you can either turn on the neuron turn off the neuron and or turn thousands or billions neuron simultaneously to see whether you can you can drive a real function with the activity of a combination of the matrix of the neurons so that is that so for such kind of tool so let me summarize it you need to know the identity of the cell where it is and which gene which RNA is transcribed and expressed and then you can record every neural activity and then you can manipulate every neuron activity yes yes but there is no such a tool yeah i like that ideal tool yes yeah it gives us that big vision actually people push our current human technology from these three aspects orthogonally but there is no such a tool which can give you even two type of functions together no one no such kind of tool now that can even do two of those no i don't think so isn't isn't there something that is doing both readout of electrical activity and stimulation nothing's doing both right now readout and manipulation people can achieve such kind of stuff with two combined technologies but you have to combine two yes but okay interesting but to turn that into even one yeah yeah okay and what was the third one third one cell identity identify record and then record and manipulate yes interesting identify the whole connectome record the whole connectome and then manipulate manipulate the whole connectome yeah okay cool you guys heard it here get building on that i love it you can work on that in the future yeah please yeah yeah and orthogonally i like that at the same time tackling it at the same time how can we inspire more people around the world to work together learn english gosh that is the first step for everyone to communicate and after communication and then you can work together you can disagree you can agree but you know what to do next if you if you don't talk to each other it's nothing happens and just kidding so communication is crucial yes yes yes what will get off the people united to work for one goal and to overcome our current challenge i don't think there is such a there is such a thing which can get everyone united and keep and work on one thing to overcome some problem that is not the way how human or animal was designed to do every life lives for its own benefit that is how gene tell us to do not for the others you know gene selfish yeah so we just we just but the self achievement has different aspect someone achieved in the science someone in business someone in arts so that makes how the how the earth of versatile place or the human community of versatile place and thrilled in different aspect and that is why our earth are beautiful we are not stands where we got every colorful we got colorful view we got colorful life yeah yeah what do you think is the overall meaning or purpose of life what what do you think may ask your answer can you give me some inspirations ones that i've really enjoyed are to understand the source code source code of our reality okay and then to maximize flourishing maximize creativity meaning consciousness and then to take that source code that we understand and create more life from that initial source code and let it evolve again to complexity so complete the circle wow yeah that's too complicated in my mind the purpose of our life from the from the nervous system it tells us the purpose for life is just a seeking for dopamine people want people are trying to get reward from enjoying simple things like enjoying in the food enjoying a love relationship enjoying in enjoying in the very beautiful side view and from a higher level people work people devote itself to the things they love and to fulfill themselves that is that is another addiction every addiction is a pursuit for dopamine when there is no dopamine in in your brain you feel no meaning of your life that's what i think interesting interesting even the most meditative people on the planet do you think they still live for dopamine sure i think because they are pursuing some like philosophy wisdoms and they are searching for something they think the real meaning of the world and everything will make itself or make himself or make herself feel oh i'm the smartest person in the world that we call it self achievement and at that moment that you can if you put a grab sensor in its mind in his or her mind you will see there is a lot of dopamine but the person may be doing it with no agenda they may just be being meditative without the agenda to be the most enlightened person you you mean must be very silent and did i probably did i get to ask you uh maybe i did why do you why do you call it the grab sensor the grab sensor it's because you can think we catch up the dynamics of the different neurotransmitters in the brain so grab is is mimicking the the behavior of catching all the so okay so you guys call your your your genetically encoded sensor that goes on the where the gpcr took fluoresce you guys call that grabbing because it's grabbing the neurotransmitter that's coming yes you guys call it grab sensors okay good to know good to okay and then what's one skill that every child should know going into the exponential technology age for the 21st century skill well it's good to learn some coding it's learn some coding to to to solve the problems which can not be solved with single hand you need to think things synchronously and work things synchronously with a huge amount of data because we already got a huge hundreds of thousands gigabytes of gigabytes of data at the same time with our modern technologies we need to figure out a way to analyze that no matter it's light it's sound it's magnetic or it's anything it's huge the only code can help you to solve that problem and do you think that consciousness evolves from the biological process do you think it comes from somewhere it takes its seat you mean the god versus the nature people you can describe it however you will not want what do you think consciousness is and how do you think it originates i don't think there is real so-called consciousness there is just the connecting network of the nervous system it it process informations it process the common information and give out the output behavior that we call it reflects and every conscious i think it's just can become and explain as a reflect of our nervous system and your how but so the next question is how the connecting network are built for each different individual so that depends on the previous experience the appearance shapes the connection pattern of your nervous system and if there is another one if there is another one who has exactly the same experience like you and it will give every output exactly the same like you i think that is what you call conscious it exists in our humans but it also exists in lower animals like invertebrates if anything exists in the plant it's just a reflect reflect yeah yeah do you think we have free will i used to discuss this question topic with my friend and i still have my point of no i do not think everyone has a free will our will is as i said defined by the connection patterns of the brain and the brain is shaped by the experience and you don't not you do not you do not have an idea or give out a behavior by yourself but defined by your previous experience that is you are doomed to think so or do so have the idea or give a behavior yeah millions of years of behavioral evolution for human and then billions of years for the microbes that live inside of us so yeah a slave to our behavioral patterns of biology over billions of years yes yeah and even our last 26 years of memory and decisions and our parents i still think our everything in life can be explained by chemical reactions by enzymatic activities by basic physics and the the combination of the biology physics and chemistry defines our every behavior in an event thing and the spirit everything can be explained even though we do not know exactly how they work together we'll get to the source code soon and we'll be able to better explain every behavior by the biology the chemistry so that that depends on the development of new tools that does depend on the development of new tools yes so please fund the lab and other labs around the world that are building the tools to do the scientific probing please exactly what do you think is the role of love in life role of love in life you need to firstly people i'm not such a person who just grown up with a very defined direction of what i'm going to do in the future or next or as my career so according to my experience i think the way to find the love is to experience to try to come from with the exactly thing or exactly the person you want to stick on and and and you find get along with the people or get along with the stuff you just feel make you feel better and you so this is the thing you love and people just try try different things last question how about you are you the person who know what are you going to do before even before you're trying that do you believe something like the destiny yeah oh you already know that before you test it no matter how you get disappointed like you want to pursue a girl and but she just don't like you and will you just keep on keep on going and do that i like the word destiny there's a lot of nuance to that word and and some say that you come with a destiny you come with some sort of gift or gem to unleash into the world that you are born into i like that i think there's something very deeply true about that you have every one of us has a unique potential to bring to the world it could be that we have some sort of free will in the sense of how much of that destiny do we actually get to what percentage of it we actually get to and then it could be that maybe whether you got to 90 percent of your destiny or 60 percent of your destiny that maybe that that was already determined from the moment that you're born these are interesting questions and that's why we ask them on the show yeah sure the last question yes what is the most beautiful thing in the world the most beautiful thing in the world is life itself the most complicated chemical and the physical and mathematical things happens is within such a short with such a short temporal resolution and with such a small spatial resolution all those equations come together to build the life life is the most valuable thing everything everybody needs to treasure big tree yes this has been such an enlightening episode thank you thank you thank you so much for coming on the show teaching us thank you asked me so much questions i have never think about that's so hard even harder than the college interest examination oh what a funny quote we'll have to pull that quote that's a good one so many good questions harder than the college entrance examination i love it i love it thanks everyone for tuning in we greatly appreciate it we'd love to hear your thoughts in the comments below on the episode let us know what you're thinking also have more conversations with your friends families co-workers people online about cutting edge neuroscience tools have more conversations around gpcr g protein coupled receptors more conversations around studying memory have more conversations around how to run these experiments and how to best understand that source code and make these scientific fundamental advancements check out the link in the bio below to big tree check out the link to you long lead lab dot org as well and support the artist the entrepreneurs the leaders the organizations around the world that you believe in support simulation our links are below you can find our links to our patreon paypal cryptocurrency you can design cool merch and get paid all those links are below help us continue doing cool things like coming on site to great places like Beijing to conduct these interviews and go and build the future everyone manifest your dreams into the world we love you very much thank you for tuning in and we'll see you soon okay that's great wow thank you that's really good that was really good really yeah yeah that's my first yeah tons of just neuroscience knowledge and then tons of really good back and forth at the end around these complex questions that was really good oh thank you so much good neuroscience explanation you're a really good communicator good job in english too you're doing really well