001[Music] pointer. We go What's that color? [Music] Are you serious? [Music] She said, Well, the secret It doesn't look good. Oh, dad. James I didn't Okay, welcome. Um, I'm Eric Barerico. I'm uh Anel's dad, but also um um I'm a scientist. So, in the day, I get paid money to interact with really smart people and just talk about science and ideas, which is super cool. So for those of you that are young and still exploring your lives, um we have a real treat because that's how I got into science by having people who were inspirational to me and taught me that just asking questions is really really cool. Um, so on behalf of Principal Aqua, uh, Sally Stalks and the Steam Board, this is our first in a hopefully series of Eureka presentations. And we're
002really lucky that we have uh, Candy Lee and Victor Ambrose here with us. So, just a couple of words um, about how this came to be. Um, I've been active on the steamboard back when Lisa was on the steamboard, I guess, for over a decade. And um, we're always thinking about ideas about how to um, inspire people, get people to think about ideas in the steam fields. And uh this idea really came through me having conversations with Victor on a regular basis about how do we get our society interested in in the value of science and and uh I got a lot of good ideas from him. So when I came up with this thought to have this first person I naturally thought of was uh Victor and Candy are the first people. So, just
003to put this in perspective, I met Victor and Candy in their kitchen. I think um a friend of mine, one of Victor's graduate students, uh Zamchi Louu was going to a scientific conference and I was going to our family retreat New Hampshire and she said to me, we're both assistant professors. She said, "Oh, you know, just we're talking today." and she said, "I'm going to a conference up in New Hampshire." I said, "I'm going to be going up the same week." And I ended up driving her. And it got late because, of course, we were doing experiments in the morning in our respective laboratories. And um half the drive she talked about you two. And um I I got to tell you, this was really a little bit intimidating for me because I worked in
004the same field uh as Victor Candy as a graduate student. And um I don't want to you know lie. I really really looked up to them. And I'll tell you if there was a word cloud about these people. I think one of the biggest words would be kind. Another one would be humble. Embarrassed. um but also inquisitive, incredibly inquisitive um and uh thoughtprovoking and I'll tell you I felt they made me feel right at home and uh insisted to give me some candy was like you got to eat, you gota you know she it was just like you don't remember this, do you? Yeah. Yeah. Well, you see it was very influential on me. Um and um and so Zongi brought me I she was staying with you and I dropped I dropped her off
005basically and you insisted I come in and then you started asking me questions. So anyway, that's how I got to know them. Another my last shorter than I was drinking, you know. Um uh so I just want to put everything in perspective. So the students know central dogma is that the way that our genetic code the DNA gets turned into proteins. Okay. key Nobel Prize for central dogma was awarded in 1965 for the discovery of uh messenger RNA basically and that had not changed since and through a series of very insightful experiments about how organisms time their development. These two discovered microarnas with uh their longtime collaborator and friend Gary Ruffton in his laboratory at Mass General Hospital. So I think there's a big lesson there. First of all, they weren't trying to discover micronese.
006They're trying to figure out developmental timing. So you just never know. You got to ask the right questions and keep your eyes open. So, um, I'll stop talking and let Victor do his thing, but I want to thank Candy and Victor. Oh, hold it, hold it. I do have one more thing. I've got two students that want to give uh Candy and Victor a gift. And I think you have to open it up. You should wait until after that. I told them to do it before. I told them to do it before. It's my fault. I'll take I'll tell you to bull it up. So, you're now you are now part of the Tanto Stag family. All right. Now, you're right. All right. So, the the first thing I have to do is disabuse you
007of all that those superlatives Eric just gave you. Um, yes, but he's right. The main message that I want to uh sort of convey today is that science is done by everyday people. Um, and it's done by uh teams and uh right here the team we're talking about is me and Candy. Uh, we were married in 1976 and then we've been working together since n to the 80s since the 80s. And so Cand's been the um lab manager and collaborator um with me ever since. And the the uh discovery that got the Nobel Prize for me and Gary Ruffkin uh was from work that was actually done by by Candi um and uh her her collaborator a posttock in the lab Ronda Finebound and then in Gary's lab the work was done by um some
008people there. So these this Nobel Prize business is a celebration of science. is not necessarily a celebration of people because I'm here to tell you that uh we're you know that science gets done by people doing it because they're passionate about it because they really you know are curious and the science in this country is supported by public and the all the accomplishments of all the scientists um are are can be something that the public can be proud of. So, it's uh it begins with, you know, I'm going to talk about myself, even though we're talking here about me and Candy. I mean, I just to introduce you, I I grew up in Vermont on a farm. Um that's me. It's a picture. I show this picture because I think I'm cute. Uh this is
009me in the sixth grade. Um and I have here I didn't really get super good grades, you know, in math and that so forth. Um, but I also like to show this because this was my dad's signature. You sign I don't know if you guys get report cards now. They still do. The parents have to sign it. Yeah. Oh. Oh, I see. Yeah. Okay. This is the day you had to sign it. That's my dad's signature. He he he wrote everything like that. Everything. So, letters, sign checks. This is me. I I gave a talk at my old high school last month and they they dredged up this picture and allowed me to and and I'm showing it. Um okay, so I started out as a scientist. In other words, I can't really recall when
010I didn't want to be a scientist. So um but my first point I want to give you make is of course all kids are scientists, right? If you guys have a younger brother or sister, especially a little one, a baby, a toddler, and so forth, you see them exploring the world, right? And how do they figure out how the world works? By doing experiments, right? Does this thing what happens when I pull on this thing? What happens when I throw this thing down? What happens when I smear this on my face? You know, so they're doing experiments all the time. And so that's how we learn about the world, right? So curiosity. So everybody is curious, right? That's a an innate characteristic of a of people. Um, what what happens next? And whoops. So, doing
011science is a natural instinct. So, you might not think of it this way, but let's think about it, right? Cur exercising curiosity. You can't resist being curios curious about stuff. Kids experiment. This is how we learn about the world, you know? So doing this is something that we have evolved to do but what is curiosity right and basically it's like you know you know I wonder what's going on here right you know um what is it with that you know what what's going on you know that kind of thing right it's a very innate sort of impulse right so I want to say a little bit about you know um what I wondered about right so when I was a kid I mean one of the earliest things that I wondered about I remember wondering
012about was like uh you know why are all the leaves on a maple tree shaped like a maple leaf right like where's where's the instructions for that how come every leaf looks like a maple leaf right and then moreover how come whatever this is a birch or something um why do they look different in all the leaves on the birch tree so you know so this one of the earliest things I remember wondering about and I think well there must be some sort of information in there you know and so if you reflect on it you realize it's a pretty amazing thing isn't it right that all these trees have their leaves are of certain shape there must be something about the information in the seed of that plant in the seed of that plant
013is the information for that tree to make all the leaves shape go a certain way and all of the leaves a light right so that's fundamentally kind of the sorts of things that we we wonder about I you also wondered about where comets came from I was a amateur astronomer uh I wondered about what our shadow bands now I'm going to tell you a story of my first published scientific result right this is 1970 we went down to Virginia to observe a total solar eclipse and this magazine sky and telescope ahead of time had said hey people You go down there, you can watch for these shadow bands that they're only visible at a total solar eclipse, you know, in the line of totality. And they they shoot along the ground. If you're not looking
014for them, you don't see them. If you're looking up, they wanted people kind of like observe them and describe them and like measure make measurements about it and stuff like that. So, I thought that's fantastic. So, that's my first published result. This is an actual magazine and it says here, Victor Ambrose. Let me see where is it. Right. Victor Ambrose and his station was in Chadik, Virginia. And I just loved that term station because when I read that I said, man, I'm a scientist because scientists have stations and this magazine said I had a station, you know? So, I mean, honest to God, that was like my I felt affirmed as a scientist, right? This is my dad who was the sponsor. And this is just a you you all may have seen this just
015last year. So my pathway to becoming a professional scientist you know obviously as a I was an amateur and then you know I went to MIT went to a college and the important thing in college is those of you who might be thinking about college what's one of the cool things about college is everything you experience there is almost basically unexpected right and one of the things I didn't expect is that other students would influence me so I went there wanting to be an astronomer but these other students were just like really excited about biology and this is back in the 1970s So this was like ancient times but it was a time when molecular biology and genetics was really emerging and I got really excited by what these other students are telling me about
016and I I did research in a lab and this is the gentleman who really uh taught me a lot about how how to do science. Then I did a PhD with uh this guy David Baltimore studied a virus and then I went to Bob Corman's lab to do post-docctoral research which is where you're trying to put together your own kind of direction that you want to take your lab you know so Eric did this went to post you did your posttock and he he figured out questions that he's really passionate about and so when I'm in Bob's lab I'm trying to figure out what are the questions that I'm really passionate about what can I learn from Bob and the other people in the lab that's really gonna put me on on some direction. Um,
017and from that you get a, you know, professor position where you're teaching and doing research. And so I run a laboratory that studies biological questions that interest me. And so I've moved around and finally I'm at UMass. So during this whole time by the way with the green arrow uh Candi is there uh helping running the lab and uh sort of providing absolutely incredible uh scientific support as well as um support in running the lab as a personal you know personnel management u issue. So, so what do we wonder about in the lab is like how do animals get their shapes, right? And when you think about this, it's pretty amazing, right? I mean, there's incredible diversity of animals live today and there's a whole incredible diversity of animals that have gone extinct. Um, and
018they all what's in common amongst all of them is their DNA contains instructions for a developmental program so that it the animal develops into what it finally looks like. This can be very complicated, you know, like in insects um and so forth and butterflies even with these larve and pupy and stuff and metamorphosis. It's like incredibly intricate and amazing process animal development. Now we focus on this animal here in our lab which is scenario elegance. is a very very simple animal compared to all these other ones. But it represents the fundamental problem which is how do animals develop? Now all the animals that you can imagine that are like us. Let's say bilaterally symmetric you know are called the bilaterians and they all originated 500 600 million years ago. There was a common ancestor that
019gave a rise to all these animals. So what we do today is we try to compare and contrast how these things develop by choosing animals that are easy to do experiments with and they they're called the model organisms. So sea elegance is one. Drosophila malicaster is an insect that we use. And the idea is that it's a fish flower an ail. And so these model organisms are used to do experiments that couldn't be done for example on people but it enables us to learn fundamentals of how animals develop and that those fundamentals can be applied uh to humans. So the idea is that by studying the genes of the neatode segance and how those genes contain information such that the sea elegance develops properly we will learn about how animals general in general develop and
020learn about fundamentals important for human biology. So this is the animal that we we uh study. Whoops. Yay. It works. So you see this is this is an adult sea elegance and there's another one crawling away. I don't know if you can see you see like a little oval things. Those are eggs like here's a couple of them here. Then there's some larve crawling around. So the animals develop in the egg and then crawl out. Then there are larve. Then they go crawl around and eat this bacteria. That's their food. And this is an adult. And the animal develops from something about this size to this size in about two days. So, it's a very rapid life cycle. This animal here is, this is a microscope. Taking this video, that's about a millimeter long. So,
021the worm is tiny. Ordinarily, these animals live in the dirt. So, you can actually get them out of the dirt if you want to. You just get some dirt, some rotting organic material in it and put it on a petri dish and worms will crawl out. You may not get this particular worm sea elegance, but you get there's thousands and thousands of species of these nematodeses living, you know, in the dirt. So, all right, get ready. This is an amazing video. Okay, first time I saw this video, it just blew my mind. Okay, and so what we're going to do is sort of think about it. How does it work? Oh, yeah. Let's watch. This is a This is a fertilized egg of sea elegance. So you can see the eggshell. It's after the sperm
022and the oite got together. They make this single cell egg. It looks like two, but it's actually a little bit uh you know it's actually just before nuclear fusion. And when what happens now is once it goes there's two cells, four cells, eight cells, 16 cells. See those two cells go in the middle? That's the intestine precursors. See how all the cells are getting smaller? because each one is dividing, right? It started out with one cell with the DNA of this animal. Each cell has the same DNA as the original cell, but look what they're doing. It's now it has about 550 cells and those cells are turning themselves into a worm, right? Okay, think about that. All the information for that thing, that process happening was contained in that eggshell in the DNA of
023that first single cell, right? And I'm here to tell you that today we still can't tell you how that works. We can give you some of the rudiments of it. I can tell you a little bit about differential gene expression and so forth, but I we can't say, "Oh, yeah, it's obvious how that happens. Let me tell you how it happens, right? I mean, it's mostly we can just describe this amazing process, right? and tell you little bits about it, fascinating, amazing things about it that have been figured out using genetics and molecular biology, but still the the mystery remains. So what's the deal? Single cell egg goes to 550 cells. That's the larve, right? And so they all have the same DNA to begin with. So you know what happens is different genes are
024turned on and off. So that's what we've been studying now for decades in this field of molecular biology and genetics is how are genes regulating each other so that that information is elaborated so beautifully to make the worm. So in a nerve cell that happens to be a nerve cell right there nerve genes are on muscle cell muscle genes are on intestinal cell for example intestine genes are on but muscle genes are off nerve genes are off. So you see genes are turned off and turned on in some in an organized fashion and that's basically how you get this complex larvae. So let's think about so the experimental approach we use is we study mutants and the idea is that there if there are genes that are controlling the information that's making the egg the
025the worm those genes if we mutate that gene it should alter the development of the worm. So that's the idea. So we look for mutants that alter development and then we try to identify what those mutants can tell us because a mutation tells us there's a gene and that gene is controlling developmental process. So we'd like to take the mutation and find the DNA and then find the product of the gene. This is RNA protein and we know that those molecules made by that gene are going to be somehow regulating development. So that's the path we take. And the the the part that uh that Roslin did was start with a mutation and find the gene product. And as Eric alluded, it was an RNA product, but not the usual protein product. So that was
026what was novel about what we came up with. So we're actually starting with these mutants, amazing mutants. This is a lin mutant and it is uh essentially a persistent juvenile. So because unlike the wild type or the normal adult which has all kinds of adult features to it, this one is missing all sorts of adult features and it has extra larvae features. So it actually duplicates laral structures over and over and never advances to making adult structures. So we call it a like a persistent big juvenile. And the opposite uh result comes from mutating this gene called lin 14. And so this animal is a precocious adult. So it actually skips over laral stages, goes right to the adult. So I think you're hearing, you're saying, "Oh, wow. You're telling me that one mutant goes
027over and over and over repeating laral, you know, programs and the other one skips laral programs and goes right to the adult." Feels like these genes might be parts of a clock of some kind, right? you know that is telling the animal what time in development to make different parts of itself. So that's the basic idea. So we we came up with you know the mutations tell us that maybe LIN 4 and LIN 14 are like parts of some kind of clock that's the output of the clock is juvenile and then adult and we progress from juvenile to adult by turning off LIN1 14 who would turn it off Lin 4. So that's where we started and now these there were these two labs that Eric told you about my lab with Ros Candy and
028Rhonda working on Lin 4 and in RVin's lab a bunch of people working on Lin 14 and so in parallel we figured this out. I mean Gary's lab found that lin 14 makes an RNA which is translated into a protein but found that the lin 4 is makes a unusual kind of RNA that has an unusual structure and it turns out that it makes a little piece of RNA that's unusually short compared to all other RNAs and it's complimementaryary those of you who've had AP biology or whatever you know about about um base pairing right So the lin 4 RNA recognizes lin14 by base pairing and then shuts off production protein from that lin 14. So that was the novel discovery. And it turns out Gary show that lin 14 itself is a regulatory protein.
029It regulates the production of of RNA from many other genes. So that's how it controls this juvenile versus adult transition by regulating other genes. So what's the message here? We were just, as G said, we're just curious about these mutants. That's all it was. We were just curious about the mutants. And we figured if we could figure out maybe what these mutants are telling us about developmental timing, sort of clocks that may be happening in during development, we should probably learn something new about biology. But there was no expectation that we would be identifying some completely unexpected kind of genetic regulate. So that's the you know the very important point here is that the curiosity is what motivates the research and that and the results come from the research we and and in this case
030what the new insights that came you know was pretty interesting that you have this new kind of RNA and it turns out that there's um many micronas not just in worms but in humans as well and in fact the lin 4 microna that we discovered is in our genomes as well. So that common ancestor that I showed you of all of animals had lin and we've all had one ever since. So I want to just close with things we wonder about um that we're starting to work on in the lab today. And this is a a hostenia which is a little worm called the banded panther worm. Um and our collaborator Monty Servosta has developed this as an experimental model organism for studying regeneration. Okay. So now if you cut this worm in half you
031get these two halves and about a day later you see that the the wound heals over at both sides. Now this is a tail and this is a head and the head has a brain and everything right? This one doesn't ever break. But evolution has provided mechanisms for these animals to do what's called whole body regeneration. So the back end regenerates a head, right? And the front end regenerates a tail. And notice what you have at the end. You have two worms that are about by mass about half the size of the original worm, but they're shaped perfectly like the original worm. Right? And so this is a kind of like you know I wonder how this works right and so Moni Svastapa and the people in her lab and then the the co-work the
032collaborator I mean the the postoc in my lab who's working um on this system here in collaboration with them are trying to understand how this works and this interesting fact is that this whole body regeneration is not a peculiarity of these A seals. Now on this phoggenetic tree, the ail is a very very distantly related animal compared to us and insects and nematodeses and plenarians. Some of you may know about plenarians also. You they can do whole body regeneration. Cut it in half, you get two plenarians. Perfectly, right? So we figure that if we can study this whole body regeneration, we must be studying something that this animal could do, right? And that all these animals have inherited this ability to carry out this kind of regeneration. Um, for example, you know, you may know
033the starfish can regenerate quite a bit of its body and there's others animals that can do that. Now sometimes humans are criticized for not being able to do whole body regeneration right you say like a seals can do it can do it but humans can't do it so if why you know why study this process of these animals here and I'm here to say no no no that's exactly why we study this is because we all can do it right and so it's just that let's let's think about this here's my thing, right? And so this uh this was a this was an experiment that was act it was an unintended experiment, right? So a router that I was doing woodworking took a chunk out of my finger, right? And so I took a picture
034and then I did a time course, you know, whatever this is a little later. little later. Now we're getting into September, October. By the end of the year, actually you can't quite see see it here, but you know the the fingerprints are totally restored, right? So now this I like to show as an example of everyday things that we take for granted, right? Which are actually wondrous and mysterious, right? You know, scientists cannot tell you how that works. We can tell you a little bit. We know something about some of the molecules that are important for it. We can talk about recruitment of different kinds of cells happening in there. We know there's gene expression changes going on. But we can't tell you how that skin is replaced perfectly, right? Because notice what happens. Like
035my thumb, it didn't make too much thumb skin. It didn't make too little thumb skin. It didn't make like shoulder skin or ear skin, right? Or big toe skin, right? So, this process was an incredible process where the tissue this this stuff that was remaining somehow knew, damn, there's stuff missing and and here's exactly what we have to do to replace it, you know, and and that's happening automatically, right? And it happens every day in our in our bodies, right? We get wounds that heal. You know, your your intestine gets replaced all the time. You know, your skin is replaced what five, six, 10 times if you live long enough during your life. And liver can regenerate, you know. So this ability to regenerate tissues in this amazing amazing amazing fashion that's actually mostly error
036error-free right is um I think a part of everyday life and and it's a it's a phenomenon that um we still wonder about and we figure um we feel tremendous compunction to try to figure out everything you can about it because we know it's going to be first of all we'll learn about the evolution of that amazing biotarian ancestor. We all should think about our biotarian ancestor and say thank you bioteterian ancestor right that was one heck of an animal you know and uh so so my final comments are um maybe you won't maybe you won't be a scientist or maybe you're not a scientist maybe you won't be a scientist who knows we want to inspire all the young people in the room to be scientists because we're here to tell you that anybody
037can do it um because it's done by it's done by teams done by communities, you're not alone. Um, so and it's a kind of enterprise where all sorts of people are are u are actually required to make it work. But what if we're not a scientist? So here we're just now I'm just proitizing about a scientific way of living, right? So um knowing how to find things out, right? What are reliable sources of information? critically evaluating evidence. You know, I think of an example where I experienced um being on a on a jury jury duty and it was an actual crime and I had to sit there and evaluate evidence. It was such an interesting experience because you were you were told by the judge, don't pay any attention to your biases or your preconceived
038notions. Put those aside. Look at the evidence. Think about the evidence. Right? And I thought that's a pretty amazing thing that uh first of all he's trusting us to do that, right? Um and it's you don't have to be a scientist to do that, right? But it's it's it takes attention to do it. The healthy thinking habits questioning our own assumptions and those those you know this is something that um we learn as as we go along. Hopefully we learned it earlier. What are our own cognitive biases? re recognize uncertainty and the limits of knowledge. This is as you know Eric and the other scientists in the in the room know that this is that's what it's all about is we're always trying to figure out okay what do we know and what we don't
039yet know what you know what do we really know and what's the evidence for that okay how well do we know that then given what the evidence is right but this is a way we can all approach our our everyday living right so then finally curiosity I mentioned that curiosity is a I think you know a natural human instinct but it has to be nurtured and it can be inhibited by circumstances, right? So, it's something that we need to nurture in each other and ourselves um and um be careful not to inhibit it in others. Curious about our world, ourselves and others. And so that curiosity, as I said, that's really the fuel for discovery and and so in science and everyday life. The other thing is maintain a sense of wonder. You know, when
040I told you an example of this healing of my thumb, you know, as an everyday thing um that you think about it, wow, that's pretty amazing. You know, you can take it for granted or you can sort of look at these everyday phenomenon around us and say, wow, you know, this is really amazing. You know, so the mysteries all around us and most of what there is to know is still unknown. And that's something that I think um maybe we don't always think about, right? in when we're doing science, we always are trying to answer the next question and then people sometimes ask, well, um, you know, have you figured out everything? So, now we can just put it to work, right? And the fact and the fact is, yeah, we figured out a lot,
041but there's there's just so much more to know. Um, I I think there's more to know than we can possibly imagine, right? So that's why those of you who are thinking about going into science, I'm telling you, it's not that. Everything's been figured out. And once you get there, be like, uh, what do I do? Everything's been figured out. No way, man. Everything that we ever I mean, so much about the world, the universe is yet to be discovered, and it's almost certainly surprising and entertaining once to know. So, thank you very much. Um, I hope that was good. And I think we're going to What's next? Are we going to go to another room or we do questions in here? And and Candi's here. So if you have any questions for Candy, she can
042ask she can answer almost anything about about my Yeah. Yeah. about me. Do you want her to tell the truth? Yeah. Frankly, truthful. So, thank you. Thank you, Victor. That was really fantastic, I gotta say. Questions? All right, we have a curious young man over here. Do you want to scream or do you want the microphone? I'll scream. I've seen him run. He's really fast. The biotitarian ancestor, do we know like which traits it had or and which ones that we evolved to have? That's a really good question. Yeah. So I mean you notice I was claiming that maybe whole body regeneration was a characteristic of the original biotherine ancestor pointing out these very diverse animals can do it but what I didn't tell you is that we know something about the molecular mechanisms the
043fundamental molecular mechanisms in the flatworm and in the ail and it's the same fundamental molecules you know wind signaling and a certain kind of transcription factor So you can see that the the parts the gene parts of the genome that are guiding this process in this animal and that animal are the same. So it probably was back there. So that's the kind of uh arguments that you can bring to bear but basically comparing genomes. So there's for example we all can do um inflammation you know innate immune responses and so forth. And so if we look at the genans required for immune responses, innate immune responses, they'll be conserved across all these organisms. So it suggests that our our our you know ancestors have already evolved those things. Adaptive immunity is a different thing that's
044evolved later. Something we can do that most other many other animals can't do. Yeah. I have a question for ah that's for hi how was your process in the lab? Were there any like really bigots you came across? Oh. Um, well, you know, the clinical info for was not straightforward at all. And we didn't have technology back then that we have now. And so it it was just coming against a roadblock because we thought we would find a protein and we kept on trying to find a protein and that was what made us realize that it wasn't a protein. So everything we did was to try to prove it was a protein and coming against you know this roadblock. And so you have to have an open mind and say there's something really strange going
045on here. And so that's um you know it was fantastic because it was such a surprise um to find something so novel. Um but you know when you are a scientist you have to um be ready to you know have a lot of failure and have your notions challenged but be open to trying is there some way that this all makes sense and so that's you want What's a Nobel Prize? Um, so Nobel Prize is a a prize that comes out. It's every year the people in Sweden um an organization in my case it's a it's a it's a university the Karolinsky Institute and what happened was I don't know how long ago this guy named Alfred Nobel who was a rich man in Sweden he died and he had written his will and in
046his will he said uh each year uh we want to celebrate scientific discoveries and the people associ associated with those discoveries and there'll be a prize and then they'll and it'll be like in the newspapers and you didn't there was no TV then but then it's going to be on TV now and so it's a way to it's a way that the Swedish country celebrates science right so you may hear about the Nobel Prize in medicine Nobel Prize in chemistry and physics there's a Nobel Peace Prize and the Nobel Prize in economics you see it's all trying to sort of raise the world's attention to the importance of scientific discovery and scientific research. That was the vision of this guy Alfred Nobel who basically he he um invented dynamite. Okay. So he's known for two
047things. Number one, inventing dynamite and number two the Nobel Prize which is based on all the money he made making dynamite. You know another one. Let's do this. So, is micro RNA basically just the on and off switch for other genes? Yeah. Oh, cool. Yeah, exactly. Right. So, and what's cool there? So, microns are on and off switch for other genes. And what's cool about them is that um the microna doesn't have to match the gene very much, just a few of these nucleotides, right? And so evolution can contrive to make a gene become a migron target or to now lose its migron target. So lots of the variation amongst animals and speciation stuff can be attributed to microRNAs uh you know rewiring themselves basically. So it's a regulator of other genes and regulate lots
048of genes and it's also easily rew rewirable by evolution. Save me. Take a break. I was just curious if you think it's possible that an error with micro RNA could be involved with that rapid aging disease. It involves the timing. Yes. The question is about proeria, right? Uh rapid aging. Yeah. um uh your instincts are good that you could have a regulatory change right that could have such an effect but in fact I think are mutations in nuclear laminate right after that I don't know the mechanism though there's not there's not a lot known yeah it's a mutation in a in the gene that encodes a protein that that it makes up a part of the nucleus of our cells DNA is yeah where the DNA is in there. So it's thought probably to perturb
049how DNA is organized in the nucleus. Yeah. Do you want to show you again? save your voice for. So, when you're looking at the baby worm over there, while it's still in the egg, how do you know which um you saw like there was a nerve and a muscle and an intestine. How do you know which ones are which? Yeah, that's that's I'll bring it back. That's a super question, right? So the the [Music] um no I don't but the um yeah so basically the using light microscopy and there's a way there's a kind of light microscopy that allows you to visualize really in stark relief the nucleus of a cell right and different cell types have different nuclear morphologies that can be recognized. It's like a face, you know. So neurons are small and
050kind of pink, you know, punct ponte big and so that's helpful. But moreover, when that animal develops is in that movie from one to two to four to eight, 32 32, you you can actually watch that happening and it produces a chart you can draw out called the lineage cell lineage from 1 to 550 cells. That was first figured out by a guy named John Solston in England who sat in a room for two years looking through a microscope watching embryos develop and taking notes and drawing. Right? So, and then he and he worked it out and then he determined that if I watch this again, it'll do it exactly the same way. If I watch it again, it'll do exactly the same way. So he actually established that the development of sea elegance is
051invariant in terms of who which cells divide when and what they become when they divide all the way through. To do that yeah he got paid he got a he got a Nobel Prize for doing that actually. So um yeah so that it's worth noting that that Nobel Prize also was the Victor's post. Yeah. Postto advisor Bob Horvitz. Yeah. Discovered the genes that regulate how cells die. Yeah. Program cell death which we all do, right? Every minute. Every minute of every day. Yeah. Put a plug in for study. Really? Yeah. So you wonder what a Nobel Prize is. Maybe you can take this out there. Nobel Prize. There were four Nobel prizes so far for studies of this this animal, right? and at least two for Drosophila, I think. Yeah. Yeah. So, these model organisms.
052Yeah, it could be. Let's give it to them. Yeah. There's a warm fly competition. Yeah. But the key thing is Yeah. Yeah. So, you can tell what they are because we actually have a chart, right? Nowadays you can do things like you can take you can actually engineer the genome of the worm to produce for example fluorescent proteins from a particular gene that allows you to say oh this is when that gene comes on this when it comes off you know and things like that. So we can trace these cells characteristics of these cells in terms of single gene activity. I mean one thing that we've recently started working on is that the the proteins that help accompany the micronas you know to the mRNAs and and make them function um have you know uh
053I mean the they have develop well um neurological diseases. Yes, the mutants. And so we've really uh recently um connected with families of kids who have mutants in their proteins that work with the microase. And we've been able to make those same mutants in our worms. to see how that changes how the micronas interact. So they're not, you know, working, you know, in a neurological, you know, system, but we can see how things change. And what we see is that, um, by mutating those, they're called argonauts, we find that the argonauts can't release the micronese. And so that's a a way that they are just preventing them from working. So you know people um from just one one mutation um can have a whole uh spectrum of symptoms. And so you know you see how
054easy it is for us to just you know do stuff with nematodes that has effect on human health. So we're very hopeful you know that we can try and solve this kind of problem and then you know then it's up to the people you know also at UMass who are doing RNA therapeutics to develop drugs to you know change that. So this, you know, it's a very exciting time to be a scientist. There's so much um that we don't know and still needs to be done and lots and lots of questions. Yeah, that's a really good point. The sea elegance is a a model model organisms can be studied, right, to sort of learn stuff and then sort of make inferences about human biology. In this case, the human families can patients contain a mutation
055but it's in this in a protein that the worm also has and the protein is almost identical and it's the partner of micron. So this is a great opportunity for the model organism now to say we take a model organism and you model that mutation and see what you can learn from it. So are the genes that control your thumb repair. The same that controlled Anel's knee repair. He destroyed his knee a couple work in progress. Are they the same genes? And why aren't they forming eyes on his knees versus the skin? I mean, it's just a rhetorical question. Yeah. We don't we don't know. Yeah. I mean wound healing is but broadly speaking that was I was trying to allude you know and uh so what happened to your knee? But it's better now
056right? I mean imagine what it must take to heal a knee. I mean that's a very complicated thing you know. Um it's it's amazing. So I would say it's probably way more complicated than what happened. Thank you for the talk. Um research is always dependent on technology. So comparing the 70s and now and then the future is research becoming more less or the same dependency on technological advances? Is it getting better? are getting worse. Yeah. Yeah. I mean, when you were doing this project, we were actually technological advances were actually really helpful, right? There was like new stuff that was emerging that you could do. There was um but in the 70s everything was I mean relatively speaking it was much more labor intensive to do almost any of these things. like it took you
057and Rhonda three four years to to do this. Um and you know with the genome sequences which came online you know around 2000 or so um it becomes much more efficient to make inferences for example about about genes and how they're organized and how they're connected to each other and stuff like that. um well, you know, to clone um the first microna, we actually did use evolution to tell us what was the important parts. So, I I cloned this gene from several other species and then compared their DNA. Um but that you had to do that. I had to do that by hand. But now you know we have genomes and we can tell if a gene is conserved all through the whole evolutionary uh families that it's important because otherwise it would just have
058been kicked out or just it's a specific for just that organism. So yeah, those of you who who are like middle schoolers or high schools, you want to do projects that don't involve actual experiments, you can actually do um studies of the data that's in these public databases. Um when you said like you didn't use technology to find us out, like what did you use to like discover it? Yeah. Didn't mean to say we didn't use technology. We used the technology that was there at the time, right? But this was in the 80s and it was much crudder than today, right? Computer programs. Yeah. Right. We did not use computers. So that nowadays there's gene genome editing right which became something that we knew about 2012 or so where um where it was discovered from
059basic science research into the inner workings of yogurt bacteria. right, is that the Danon Yogurt Company started studying issues that they had with their yogurt bacteria and that along with studies that were going on in other labs, they converged on the discovery of crisper which is a adaptive immune system in bacteria was completely unexpected and then it turns out that with further study they realized you could actually turn that bacterial machinery into a tool for editing any genome. So we edit the sea elegance genome routinely the fly genome people you just imagine a mutation you say I wonder what would happen if I mutate it right here this way you actually design it do it it's incredible and so and you may be aware that a lot of crop plants and and domestic animals you
060know are being edited routinely for advantageous traits and so forth. So but for uh as a practical matter that that's really powerful but as a technology that for driving research it's been absolutely accelerator you know I can talk loudly okay so uh I'm a chemist I worked in the pharmaceutical industry for most of the time so I'm assuming I believe this um the microRNA is implicated in some cancer and things like that. Um it seems to have a pretty unique structure. Do do you know if there are drugs that target the structure of the micro RNA? Yeah, that's a good question. I mean the the primary sort of drug that um folks have tried to make is just another nucleic acid that's complimentary to the micron right so yeah and so it would they mimic
061the target and sponge up the micro you know encumber it so u it's called an anti-me all of them do good therapies um yeah that's primarily The approach was I he wants he wanted you to grow. The Lin 4 CL again it said it repeated its adolescent lifespan over and over and over again, right? Could you alter it enough to like expand its make it live longer essentially? To live longer. Yeah. Yeah. I mean, ironically, those mutants live shorter. So, it's like uh counterintuitive, isn't it? And um yeah, they they live shorter. Now, this is going to get gruesome. Okay. reason one of the main reasons they live shorter is because you know they don't have the apparatus for egg laying so they can't lay their eggs but they they are hermaphrodites so they self-fertilize
062internally and that's really convenient for us the experimenters because we can grow this mutant and it propagates and it's very convenient to you can uh propagate it and grow up huge amounts of this worm the mutant um but what happens when the eggs uh the embryos hatch inside the the other and so they do what's called mattress. They eat they eat their way out. So no killing yeah maybe there's a less uh maybe there's a more benign word for it anyway. Um yeah they actually yes I don't know too much about um different types of cancer but for my is cancer just the um just the jeez is it the duplication of cells but it doesn't normally stop. So could we could micro RNA turn whatever is duplicating it off? Very good question. Yeah. Yeah.
063Um, super good question. Um, could micronise in cancer? So, there's actually a lot known about this. Um, but there's, you know, huge amount still to know. Um, certain micronas have been identified as what's called tumor suppressors, which means if they're expressed, they can suppress the tumor. But what happens in the tumor is the tumor evolves a way to silence that microna gene. Right? So these would be micrones for example that are expressed during normal development when this when your tissue differentiates. So they are driving differentiation and controlling genes involved differentiation. So the tumor you know just evolves shutting off these genes like that that tumor suppressors and the micronates are some of them are tumor suppressors. So the therapeutic notion would be let's see if we can deliver the microna back in some synthetic form
064you know chemically synthesized or or otherwise and to try to override the proliferative machinery you know by putting a natural repressor in there. Yeah. You want to shout? Yeah I'll just shout. Oh yeah. So when a gene sequence starts producing a micro RNA that is a suppressor of another RNA is that microRNA producing perpetuity or will eventually that shut down because some other process on other phases the microRNA exists right as part of development but then eventually it goes away because it's just no longer yeah yeah your insight is really spot on lot some micronese will be turned on at a particular time to drive differentiation say certain tissue but then later it needs to go away to permit something else to happen. So these micronas are produced from from a gene that encodes them
065and that gene can be regulated up and down on and off. So the microna can go up and then go down you know or some micrones start out very high and then get shut off. Other micronas be surprisingly steady and express in many many cell types and pretty much steady you know so they can be seemingly not a switch but maybe some kind of just sort of a buffer or damper you know they just go away or they have to get degraded or they get diluted by cell division or yeah that's a very active area of study um Katie McJunkan studies this you know and so it's Um yeah, not a lot of them about some micronese are very very stable. Others get shut off at a certain time and people are super curious about
066what are the machinery that can identify that microna from all the others and and turn it turn it off. I I heard that there's like refreshments somewhere. I think that's you probably should go. Yeah, absolutely. Because we can still talk and you can answer questions and so forth. Um, there are cookies and there's coffee and there's water. Um, tea tea in the cafeteria. I mean, I didn't know if this was a time for it. I just wanted to make sure we didn't forget. Let's do this.