Episode Transcript Aarati: 0:11 Hi everyone, and welcome back to the Smart Tea Podcast, where we talk about the lives of scientists and innovators who shape the world. Good morning, Arpita. Arpita: 0:20 Good morning, Aarati. We are recording this on a Saturday morning, and I'm surprised Aarati's awake. Aarati: 0:29 I am so not a morning person. It's pretty early for me to be talking to people. Arpita: 0:35 I want to state for the record that 9 a. m. was Aarati's idea. I did not push that, and I was very surprised. I was like, oh shit, like I will definitely be awake, but I Aarati: 0:46 was, Arpita: 0:46 am Aarati: 0:47 I was also like, okay, she wants to know what time I will be awake, so what time is not embarrassing for me to say. Like, Is it really embarrassing if I say like 10 o'clock, 11 o'clock? It's not morning anymore. So Arpita: 1:05 was, that was really funny for me. I was like, oh, okay, like, wow, okay, let's do it. Aarati: 1:09 Yeah. Arpita: 1:11 Like on a Saturday, Like, I'll wake up, but I usually have, like, a slow morning, you know, I'll, like, wake up, I'll, like, make some coffee, I'll, sit on the couch, read my Kindle. Aarati: 1:21 Yeah. Just relax. Arpita: 1:23 if you can see what's happening here. Aarati: 1:25 Oh wow. Oh my goodness. Is that Poppy? Arpita: 1:29 This is Poppy. Poppy, you wanna say hi to the camera? Um, Aarati: 1:32 Yeah. I can tell by the orange fur and beautiful green eyes. Arpita: 1:36 Can you hear her purring? Aarati: 1:38 Yeah, she's so cute. Oh my goodness. So content Arpita: 1:42 she does this every day. And so usually most of my day working from home is sitting in this chair with this blanket, this cat. Aarati: 1:51 God, that sounds amazing. Arpita: 1:53 And I'm like, at one point, like if I ever get a new job in which I actually have to go into work, like, I don't know if I'm going to be able to handle that Aarati: 2:01 Yeah, Arpita: 2:02 Like, it's going to be a downgrade, right? Aarati: 2:03 I have the same exact thing. Just, do we really have to meet in person cause then I have to get all dressed up... Arpita: 2:09 That's what I mean, much effort. Aarati: 2:12 And also I think part of it is my brain, like, I need to work on tasks half an hour at a time, like, so need to do work, and then I need to go cook something, and come back and do work, and then go make tea or something, and like, you know? Arpita: 2:26 I'm fully with you. Aarati: 2:27 It makes me so productive. Arpita: 2:28 I agree with you. I don't know if I would do well in an office setting at this point. I'm also just like, do I know how to talk to people still? Aarati: 2:37 Same. Arpita: 2:38 Do I know how to have like a deskmate? Aarati: 2:41 Yes. Do I know how to have a conversation? Do I know how to like Arpita: 2:45 be a normal coworker? Aarati: 2:46 Yes. Arpita: 2:48 I don't know if I can. Aarati: 2:49 Yeah, I don't think, I don't think I can either mm god. I've been, um, waking up early anyway this week a lot because I've been putting together this workshop, for tech people and. anyone else who's interested about science communication basically. Um, so we've been like planning this, these workshop sessions and then we've been having them early in the morning because some people are like from Europe and some people are from the east coast and so we want to find a time that everyone is kind of available and can attend and it's been pretty good. It's been like we've had pretty good turnout and everything but yeah, partly because I'm like, yeah, okay. I've been Recently Arpita: 3:28 You can wake up early. Yeah. Aarati: 3:30 anyway. Get going. Arpita: 3:32 That's funny. Aarati: 3:33 Yes. Arpita: 3:34 Well, I'm very proud of you. Aarati: 3:35 No, thank you so much. Anyway, I wonder who you're talking about today. Are they a morning or night person? Do you know? Mm Arpita: 3:43 wow. Great question. If I had to hypothesize, I would say this person is a morning person, but you know what? I could be wrong. A lot of really intelligent productive people are night people. So who knows really? Today we're talking about Svetlana Mosjov. Um, Aarati: 4:00 Another Russian? Arpita: 4:00 She is Macedonian. Aarati: 4:01 Oh, Macedonian, Arpita: 4:05 Yeah, another Eastern European. But I am very excited to talk about her she is one of the scientists who was involved in discovering GLP-1, which is Semaglutide, which is Ozempic and Wegovy and all of these like weight loss medications, which are huge Aarati: 4:24 Mm hmm. Arpita: 4:24 you know, guess like current events because it's created a ton of revenue for pharmaceutical companies and all these like celebrities are taking it. And I just find it very fascinating in general because it started out as something to help people with diabetes and then turned into this like weight loss, wonder drug. Um, but this is a really interesting story about how this came to be. So I'm really excited to talk to you about her. Aarati: 4:54 I'm excited because last year I was working with Boston Medical University and I made a series of videos with them about GLP 1 medications, like Ozempic. Arpita: 5:08 Oh, cool. Aarati: 5:08 Yeah, And so we just made a bunch of videos explaining to patients how to use it basically, just like, you know, how to store it and how to inject yourself and things like that. It was a lot of fun, but it was It was, it was cool. Yeah. So I'm excited to hear about, I, I know kind of like, now I know how to inject yourself with the medication... Arpita: 5:30 Ok yeah, that was not of my research. Aarati: 5:32 Yeah. I don't, I don't know anything about how it got started or Svetlana herself. So I'm excited to hear about it. Arpita: 5:39 Great. Okay. Let's hop it. So Svetlana was born in Skopje, which is in Northern Macedonia, and she was born when it was formerly Yugoslavia. So she grew up in the 50s in Eastern Europe and loved, you know, going out in nature and was very scientifically curious, her family moved to Belgrade and she loved physics and chemistry and loved lab class and experiments where, you know, you've got to combine two different things to create a third thing that was brand new. Um, and so Yugoslavia after their war, uh, had a really great education system where they encourage students to. Get an education regardless of their gender, which was pretty great for how early this was. So she got a degree in chemistry, from the university of Belgrade. So she had a very good early start. Um, I should caveat by saying this, that Svetlana is very much still alive. So in terms of like biography, a lot of like this early stuff was fairly limited. So a lot of the things about her personal life and, um, I don't know, the way you would, like, read a biography about Aarati: 7:01 Mm hmm. Arpita: 7:02 someone who is no longer with us is a little bit different. Yes. So, yeah, Aarati: 7:07 That makes sense, yeah. The research will be different, um, people won't have written, like, a whole thing about her life and commemorating her and remembering her yet, you Arpita: 7:17 Yet, exactly. She's very much alive, very much with us. And so, um, yeah, so like the research is a little bit different. The bulk of this focuses on, you know, her adult life and her work. So just caveating the fact that we are very quickly barreling through our youth Okay, so then She immigrated to the U. S. for graduate school at Rockefeller University, and once she got here, she was very drawn to Bruce Merrifield's lab, and she joined as the first female graduate student. And Bruce would later go on to win a Nobel Prize for his very efficient method of synthesizing peptides. And so she was basically in a chem lab. So during her graduate work, she focused on glucagon. So glucagon is a hormone that is released by your pancreas as a check on insulin. So when you eat, you experience an increase in blood glucose, and then your pancreas releases insulin to help lower it. Glucagon does the opposite. So when your blood glucose dips too low, your body uses glucagon to then release glycogen stores in your liver and other parts of your body to make sure that your blood glucose doesn't drop too low. Did you learn the, um, did you learn the, uh, mnemonic for that in grad school where it's like, glucose is gone, so it's gluca gone, and sometimes that's why it releases? Aarati: 8:46 Oh no! I don't think I've, I don't think I learned that one. I think I've kind of associated glucagon as like the hunger hormone kind of you know, but I didn't, I didn't have like a pneumonic device that would have been so helpful. Arpita: 9:00 Glucose is gone, glucagone. Aarati: 9:02 That's so useful. Yeah. I don't know why I didn't think of it myself, too. It's like right there. Arpita: 9:09 I know, it's literally right there. It's like barely a mnemonic. It's like actually the word. Aarati: 9:13 wonder That's how they came up with it. Arpita: 9:15 I have no idea. Aarati: 9:16 That like the amount of creativity that scientists have. Arpita: 9:20 That's actually fact. Like, um, god, this is escaping me. What is the green stain we use for everything? The, um, Aarati: 9:27 GFP? Arpita: 9:27 GFP? yeah. Where it's like literally green fluorescent protein. It's like, we couldn't think of anything. We were just like, it's green and it's fluorescent And it's a Aarati: 9:38 have RFP for red fluorescent, and then YFP, and then we have all the FPs. All the fluorescent proteins, yeah. But then, you know, on the other hand, I, we, like, I read science papers, but, I read science papers where they're, like, literally making stuff up. They're just like, oh, we're calling this behavior, like, rotating to left, or R T L, and then they use R T L for the entire paper, and I'm like, is that really necessary to abbreviate that or create a whole separate word for something that already exists, you know? Arpita: 10:13 I feel like a lot of times in papers, maybe this is not true. I also get really grumpy when like unnecessary things are acronymized. I don't know. That's not a real word, but like we do not need an acronym for everything. Um, because if you're like skimming a paper and you miss the part where they define it. You're like, what is R T like, what does that mean? Like, and then you have to like, then you have to exactly, they need to like, command F and like find where they'd mentioned it the first time and then go back up. It's so dumb. But I wonder if papers do that because a lot of journals have word count limits. Aarati: 10:50 Probably! Which I also think is stupid, because I'm like, everything is online, like, what is the Arpita: 10:58 Why do you care? Aarati: 11:00 Why does it matter, everything's online now, it, it literally doesn't matter, Arpita: 11:05 It literally doesn't matter. And then they. They link all like the supplementary information anyway. So I'm like, if the table that I need is in supplementary information, like, why do you not just like put it all in one place so I can just scroll to the bottom and find your tables? Aarati: 11:20 Yeah. Or just link it somehow. I mean, we're so behind the times in some of these cases. I don't know. It's just so frustrating and then it just impedes people accessing that kind of knowledge because you don't want to read the paper then if it becomes too frustrating to read, you're just like, it's such a barrier to understanding and learning. Arpita: 11:42 And like no one, most normal people are not out here reading an entire paper start to finish. Like that is Aarati: 11:51 Yeah. Arpita: 11:51 point of a paper. Aarati: 11:52 Abstract conclusion, maybe a little in the Arpita: 11:54 Right, like, maybe and also, like, usually I have a specific question. If I'm looking at a paper. I have a specific thing that I'm trying to understand. I don't care about your methods. I don't care. I don't care. I just want to know. I'm looking for this one data point. Aarati: 12:09 Yeah you're looking for like, Figure 3b... Arpita: 12:12 Exactly. I'm like, I your Table 2, like, row three. Like that's what I need. Aarati: 12:17 what I need. I need that one data point Arpita: 12:20 And if I have to scroll up looking for all your damn acronyms, like I'm going to be Aarati: 12:24 yeah, yeah, you've made this whole job, like, half an hour when it should have been five minutes. It's Arpita: 12:30 Oh, Aarati: 12:31 so frustrating. Anyway, we've gotten on a very big tangent. Arpita: 12:34 Now that we've gone on our big soapbox about how Aarati: 12:37 we Arpita: 12:37 hate journals. Um, now I have to find my place again. Aarati: 12:40 Yeah. How did we get on this topic? Arpita: 12:42 I don't know. Glucagon? Oh yeah, glucose Yes. Aarati: 12:46 Glucose is gone. That's so far back. Arpita: 12:50 We, yeah, we were, we're on page, we're on page one of this Aarati: 12:54 Oh my God. Okay. See like in the mornings you have all this energy and I'm grumpy and it's like not a good combination. Arpita: 13:03 I know maybe we should go back to post lunch recording when both of us like, you know, like leveled out. Aarati: 13:11 Yeah, where you're tired and I'm happy. Oh my God. Oh, God. Arpita: 13:15 Okay. Let me, Let let me find my place again. Yes. Okay. So in people with type two diabetes, their blood glucose levels get too high because they have insulin resistance. So that means that when insulin is released, their blood glucose levels actually don't really respond that well. So then it remains high instead of being lowered by insulin. So There's this hypothesis that if you suppress glucagon, and then you prevent increased levels of blood glucose, this could actually help with treating type 2 diabetes. However, this was difficult to study because synthesizing glucagon was pretty challenging. However, in this lab, in Bruce Merrifield's lab, he was really focusing on synthesizing peptides and synthesizing proteins and Svetlana in this lab finally got it to work. So she was able to synthesize glucagon. Aarati: 14:13 Oh, nice. And this when she's still a grad student or postdoc or something. Arpita: 14:18 She's a grad student. Aarati: 14:19 Okay. Arpita: 14:20 So while she's a grad student. Svetlana met her future husband, um, an immunologist, Michel Nussenzweig. Aarati: 14:29 Good job. Arpita: 14:30 Thank you. Uh, and so he was, um, working on an MD PhD, uh, at NYU, and then he was doing his PhD at Rockefeller as well. Aarati: 14:42 Wait, he's doing an MD, PhD at NYU? Arpita: 14:45 Sorry, he, just his MD and then his PhD at Rockefeller. Aarati: 14:50 Okay, because I was just like, oh my god, I've heard of MD PhD, which I think is already amazing and incredible, but is he doing an MD PhD PhD, like a double PhD? Arpita: 15:01 no, no. No, sorry, MD Aarati: 15:03 MD Arpita: 15:03 PhD, and he's studying at both NYU and Rockefeller. Aarati: 15:08 Got it. Arpita: 15:08 That's how they met. Aarati: 15:09 Got it. Arpita: 15:10 So he was very cute. And when she would be stressed writing her dissertation and working on experiments, he would come to her office and lab and bring her food and hot cups of tea. And Aarati: 15:22 Oh my amazing. Adorable. Arpita: 15:25 And so by the end of her PhD in 1978, she wrote her thesis on glucagon synthesis, and then she stayed in Bruce's lab as a postdoc to like refine these techniques a little bit more. And then a few years later in the early eighties, her husband, Michel started residency at MGH in Boston. So they both relocated to Boston and Svetlana joined the Endocrine Department as an adjunct instructor. So in this new role, she became the head of a new facility that would specifically synthesize peptides for the endocrine scientists. So, that was really her job was to synthesize these peptides, which then she would send off to all the labs that were using these for their experiments. So though this was like really important work, it wasn't very time consuming. So it gave her a lot of freedom to pursue her own research. So she had one lab bench and she didn't really have a lot of funding. She had pretty limited funding. So she was only able to hire one technician but with these limited resources, she knew that she wanted to study this mysterious peptide that was called Glucagon-like peptide 1, which we now know as GLP 1. So GLP-1 had been recently discovered in another MGH endocrinologist lab, Joel Habener and he and his lab were studying key hormones, including glucagon in anglerfish pancreases. And they apparently like pulled these anglerfish out from the Boston Harbor. Aarati: 16:56 Wait, they pulled the anglerfish out of Boston Harbor to study in the lab? Arpita: 17:01 Correct. Aarati: 17:02 Whose job is that? Is that the scientist's job also, to go trap fish? Arpita: 17:06 You would know that it was some like undergrad, like some unfortunate like child who was forced to go out onto the docks. Aarati: 17:14 Some intern. Arpita: 17:15 Literally. Aarati: 17:16 Like high school intern, who's like, we need more fish for the lab, go catch them at six in the morning. Arpita: 17:22 Literally. So they dissected and froze the fish pancreas islet cells. So those are like the specific cells that produce insulin and glucagon. And they were searching for the DNA inside and then they ultimately cloned a gene called proglucagon which they thought was actually the thing that was synthesizing GLP 1. Aarati: 17:46 I wonder why they were using anglerfish? Arpita: 17:48 I don't even know. Anglerfish aren't really a model organism. Aarati: 17:52 Yeah. Yeah. It's an interesting choice to study glucagon also, like insulin and glucagon in a fish, like, I don't Arpita: 18:03 know. I don't even know what the model organisms are for studying like pancreas or like endocrine related stuff. Like, I don't, I don't know. I don't know what model organisms are. It's a good question. Are you Googling it? Aarati: 18:16 Yeah. I see a lot of stuff about zebrafish. Arpita: 18:20 So then why didn't they just buy some zebrafish? Aarati: 18:22 Yeah, because we had the I'm just wondering, because like, I studied worms, right? Like, nematodes, and we had this whole list of reasons as to why they're the greatest model organism ever. Like, they're transparent and they have, like, these little tiny brains, which makes them really easy to study, um, and they self replicate basically, which is fantastic if you find one mutant, you can make thousands more without having to breed them and like do all these cross genetic stuff. It's pretty amazing. So, yeah, I'm sure, I'm sure the anglerfish community is also like, anglerfish are the greatest model organism ever. Arpita: 18:57 Are anglerfish a model organism though, or are they just like fish that exist? Aarati: 19:01 Are they just fish that exist? And we, and this lab just decided to study them. Arpita: 19:07 Yeah. Aarati: 19:07 Yeah. I'm sure there must be a reason. Somebody tell us. Somebody tell us the reason why fish are the greatest model organism. Arpita: 19:14 This like lab went on to win like a buttload of prizes, which is like really not a spoiler. I feel like we kind of knew but like clearly they did something Aarati: 19:23 Yeah. Yeah. Okay. Sorry. yeah. There's, they're using anglerfish to study islets, right? Islets and pancreas, in the pancreas. Arpita: 19:32 The islet cells in the pancreas. Yes. So in 1982, just before Svetlana got to MGH, they reported that this gene, proglucagon, encoded a large precursor protein that the body then cleaved to form glucagon. So this kind of reaction is pretty common in protein synthesis in the body. You have like a much larger peptide that is synthesized and then gets kind of broken down into these smaller things that then go on to have effects on your specific cells. Aarati: 20:04 Yeah, it's almost like refining it in a way this really big thing and then it just you shave it down a little bit to make it the perfect fit like wood cutting. or something. Arpita: 20:13 Exactly. That's a great analogy. So GLP-1's amino acid sequence also shares some features with gastric inhibitory peptide or GIP. which at the time, GIP was the only known member of a distinct category of hormones called incretins. So Incretins are produced by the gut and they kind of kickstart the pancreas into releasing insulin. And because they do that, scientists thought that it could make them really useful for studying and then even maybe like treating or curing type two diabetes. But in the studies for GIP, it ended up being kind of disappointing. Using it in humans resulted in very little effects in changes in insulin levels. And this ended up being kind of a bust for Joel Habener's lab. So Joel and Svetlana wondered whether GLP-1 would be different and if it actually would end up being an incretin. So one step towards finding out whether or not this was true was to see where in the body the active form of this peptide was being made. So this is the portion of the protein that when cleaved or cut off from the parent protein would become biologically active or actually have an effect on your cells. So Svetlana looked at the string of 37 amino acids that made up the mammalian GLP 1 sequence. And based on the similarity of the sequence to glucagon, she hypothesized that a stretch of 31 amino acids between the spot seven to 37 within the larger GLP-1 peptide might be an incretin. Aarati: 21:57 So the GLP 1 peptide has like, how many did you say? Um, 37 similar amino acids to glucagon? Arpita: 22:08 37 amino acids total. And then. Aarati: 22:11 amino acids total. Arpita: 22:12 And then because she was looking at the sequence, and she was like, these 31, so spots 7 to 37, um, seem similar to glucagon. And so she was like, this might be, like, she's just hypothesizing that this might be the sequence that is most interesting. Aarati: 22:30 Right. Okay. And so because of that, it is possible that GLP 1 will act in a similar way to glucagon to release sugar stores from the body. Arpita: 22:40 So, she had this hypothesis that it was spot 7 to 37, and then she had to prove whether or not that was true. So, to see whether the 7 to 37 fragment was present in the intestines, she used an antibody to search for it. So she first made a lot of GLP 1 like the protein itself and injected rabbits with different segments of her GLP 1 peptide. And then she waited two months for the antibodies to proliferate in their blood. So she basically, the antibodies here are kind of functioning as a tag or a marker to help you see whether or not that's present in the blood. So she's kind of chopping up this bigger peptide into smaller segments and testing different parts of it, even though her hypothesis is 7 to 37 and seeing which tags are present and which bits of this biologically active protein are present in the blood. Aarati: 23:33 Oh, so she made like a range of antibodies that all recognized different parts of the peptide. It wasn't just one antibody. Oh, okay. Arpita: 23:43 her. So she has an idea that it's this specific segment, but as a good Aarati: 23:48 as a good Arpita: 23:48 scientist... She, Aarati: 23:49 yeah, she's gonna test, she's gonna test all the regions. Yeah. Good job. Okay. Very thorough. Arpita: 23:57 Very thorough. Um, and so she then collects, uh, so she's doing this in rabbits. I don't know why we moved from anglerfish to rabbits, no idea, but she Aarati: 24:09 At least it's a mammal, so I'm happier with rabbits, or like, not happier, but you know what I mean. Like, it makes more sense. Arpita: 24:17 This next part made me laugh. Um, so she collected blood from one of the neck arteries in the rabbits and then isolated the antibodies. And she said in an interview that this experience working with the rabbits made her dislike working with lab animals because it made her feel like she needed to go home and take a shower. And I was like, Literally, yes. Aarati: 24:36 Yes. yes. Yeah, that's, that's why I always stopped at worms. Worms are like, microscopic I can't even touch them. I never got to even flies. I was like stuck, stuck at the worms. Oh my gosh. I can't imagine rabbits. They're so cute too. I mean, she was just withdrawing their blood, right? So Arpita: 24:59 There's no sacking, but I mean, I'm, I'm sure she eventually sacks them, but I mean, I You Aarati: 25:03 to, but yeah. Oh yeah. But I totally get that. Arpita: 25:07 I totally get it. It made me laugh. So two floors below her, Joel and his team are beginning to look at the biology of GLP 1. So in 1984, the lab got a new postdoc. His name was Daniel Drucker, who was looking to identify which specific cell types were producing GLP 1. Um, so like looking at the islet cells, but like which one specifically. Um, and Daniel was an MD and an endocrinologist. He had never worked in a lab before, so he struggled a little bit when he got there. Aarati: 25:43 Yeah. It's, I think people actually think that doctors know a lot more science than they do, like, you know, Arpita: 25:51 Or like Aarati: 25:52 very, Arpita: 25:52 bench research. Aarati: 25:53 Yeah, like, bench research and stuff, and it's like, it's very different, that's why our whole field exists of, like, medical communications, because doctors don't have the time to go into all the research, And they need something, like, really quick, and easy to digest on the limited amount of time they have. Arpita: 26:10 Yeah, it's, it's true. So he struggles a little bit. Um, and Daniel then asks Svetlana if she wants to collaborate. And Svetlana told him that she'd already produced antibodies to different stretches of GLP 1 and, like, she has a specific way to detect its presence in the intestines. So Joel's lab and Daniel, uh, joined forces with her to use her detecting methods to track different stretches of GLP 1 peptide in various rat tissues. So they've somehow moved on to rats. Aarati: 26:46 Okay. Just across all the model organisms. Arpita: 26:48 know. Aarati: 26:49 model organisms, the better. Arpita: 26:50 So Svetlana found that the 7 to 37 stretch of GLP 1 was the active portion, which is exactly what she had hypothesized, which was in rats. So this data, uh, were published in a joint paper, um, that listed Svetlana first and Joel last, and it's now considered a landmark in the field of GLP 1s. So the next question was whether the 7 to 37 form of GLP was biologically active. So that means, does it actually trigger insulin release in the pancreas? So we know that this is like the segment of GLP 1 that's actually doing the work, like there's ancillary proteins around it, like we know now this is the bit that we really care about. But is it the actual peptide that is now triggering the release of insulin in the pancreas? Aarati: 27:45 Oh yes. Is it actually doing the thing? Yeah. Arpita: 27:48 actually doing the thing? Yeah, exactly. I know I was trying really hard not to get into the weeds of protein research. Hopefully this is making sense. Aarati: 27:58 Yeah. I think it is. Arpita: 28:00 so using Svetlana's synthesized GLP 1, Daniel led a study showing that GLP 1 did actually prompt insulin secretion in a line of rat pancreatic islet cells. So now that they've shown this, they want to test its effects in a whole organ. So Joel contacts a friend, an endocrinologist named Gordon Weyer, who developed a rat pancreas model. And this is an organoid. Aarati: 28:32 Oh, okay. Yes, you're going to explain this more. Cause it sounds, I'm like imagining a pancreas floating in a little jar or something. Arpita: 28:39 That is in fact, exactly what it is. So it isn't an actual, so, okay, let's reverse. Okay. So now that they've shown that this happens basically in vitro, that this is, so that's the cells are kind of like by themselves in a vacuum, they are releasing the insulin that we are hypothesizing. So we're like looking at the cells by themselves. Now we're trying to see if this is happening in real life, basically, like, actually happening in the organs? Aarati: 29:13 Yeah. So we proved it in the petri dish. Yeah, we have a little Petri dish with cells. It's doing the thing. When we put GLP 1 in, or activate GLP 1 in these cells, they release insulin and we can test that because we can take the, you know, solution of cells and see how much insulin has been produced in the Petri dish. And now let's see if it actually happens in real life in a, in a animal. Arpita: 29:39 Exactly. So really they're like sequence of events. You can think of like starting very, very small. They're getting bigger and bigger and bigger. And so now they are in an organoid. So this friend, Gordon, has developed a three dimensional cluster of cells that are developed from pancreatic stem cells designed to mimic the functions of an organ. So it's not like an actual rat pancreas that was like excised and put into a dish. It is a cluster of cells that function together kind of like an So it's a, almost like a simulation that is manufactured. Aarati: 30:17 So he like, took pancreatic stem cells and kind of made them differentiate into not a full Arpita: 30:24 pancreas, Aarati: 30:25 but like.. Arpita: 30:26 A, quote unquote, pancreas Aarati: 30:28 A glob of cells that kind of act like a pancreas. Arpita: 30:31 Correct. Exactly. Correct. So if you think about if you were to just remove the entire pancreas, it is relying on, you know, nearby structures and other cells. It requires blood flow. It requires all of these things in order to function properly. So if you actually dissected a rat and put it, put their pancreas in a dish, it would kind of just be like tissue that doesn't really do anything. Aarati: 30:56 Yeah, Makes sense yeah. There's no arteries. There's no, yeah, yeah, that makes sense. Arpita: 31:02 So you're basically creating like a simulated little bit of it that you can manipulate in a dish. It's like one step above like a bunch of cells in a dish. Okay, so the organoid is stored in a plexiglass box, so you were right, and it's oxygenated at body temperature, and it's like this very controlled environment where researchers could measure the insulin levels minute by minute. Aarati: 31:28 Mm hmm. Arpita: 31:29 So Gordon injects the rat organoid with the synthesized GLP 1 and insulin output increased. So they started putting less and less peptide in, and they learned that even tiny amounts of GLP 1 had an effect. So Svetlana measured how much GLP was administered to confirm that the peptide aligned with the insulin response, and the two hormones go exactly up in parallel. So Administering GLP 1 release to a one to one release of insulin. Aarati: 32:03 So the more GLP 1 you administer, the more, insulin will be released, and the less GLP you administer, the less insulin will be released. Oh wow, so you can like exactly titer how much insulin, if you want this much insulin to be released, you have to put this much GLP in. That's really cool because I feel like that rarely happens in science, like it's always this huge mixed box of like 10 different factors that are... you know? Arpita: 32:29 And then you have to do some crazy stats to figure out what the relationship is. Aarati: 32:33 Exactly. That's so cool though. That's like so nice, the one to one ratio. Beautiful. I would be so excited. Arpita: 32:41 It's beautiful. So. Uh, she says in an interview that it was a beautiful experiment. She agrees with you. And the paper that they published in 1987 in the Journal of Clinical Investigation listed just three scientists. So Svetlana was first, Gordon was second, and Joel last. This work confirmed that GLP 1 was one of those very long sought after incretins. The MGH group was the first to start testing GLP 1 in humans. So Joel teamed up with a young MGH diabetes specialist, David Nathan, who infused the peptide into healthy people and people with diabetes. And GLP 1 prompted insulin release. just like it did in the organoid, um, when glucose levels rose. So for example, after you eat. So by the time David Nathan's paper was published in 1992, Svetlana had moved back to New York City. So she and her husband, Michel had moved two years earlier when he received a job at Rockefeller University. So they came back and at Rockefeller Svetlana joined the lab of an immunologist, and also a future Nobel laureate, Ralph Steinman as an assistant professor. And so her life is changing a little bit at this point. She has two young kids and is balancing being a working mother, but regardless as an assistant professor, she still is studying GLP-1 biology. Back in fish, unclear of fish, um, and she has funding from the National Science Foundation to do this work. So, meanwhile, back at MGH, work on GLP 1's effects in humans was moving forward with many different investigators. So we have a few new characters in the nineties, Jens Holst found out that unlike GIP, which was the failed peptide, GLP-1 could normalize blood sugar levels in people with diabetes. So just remembering that people in diabetes have very uncontrolled levels of blood glucose and normalizing that can be really huge for their treatment. Aarati: 34:49 Yeah. So GLP-1 is not just releasing insulin, but the insulin is actually working to normalize the blood sugar levels. Very, very important. Because what's the point of releasing insulin if it doesn't work for some reason? Arpita: 35:01 Exactly. And they also very interestingly found that in rat studies, GLP 1 also caused appetite loss. Aarati: 35:10 Yes. Now we're getting to, now we're starting to get to the beginnings of Arpita: 35:17 Okay, so put a pin in that we're going to come back to that. So though Svetlana was now at Rockefeller, and she's in New York. She took a lot of pride in her work that she did on GLP-1 at MGH so she was starting to wonder whether any patent applications had been filed. So she sent a few emails to Joel, which he never responded to. And a few years later in 1996, she mentioned this to a friend who worked at a biotech company who then looked it up and told her that there were actually a few patents that had been granted a few years earlier. So she looked these patents up and she found two 1992 patents was when the paper got published on a quote unquote fragment and quote unquote derivatives of GLP 1 that had the ability to prompt insulin secretion. And these are all the peptides that she had developed. Aarati: 36:04 But she's not the one with the patent. Arpita: 36:06 All of these patents listed Joel as the sole inventor. Aarati: 36:11 Oh my gosh, no way. Arpita: 36:13 Yeah. And so then Svetlana hired a patent law firm to help her fight for co inventor credit because Joel is not responding to any of her emails. Aarati: 36:22 Oh my gosh, he knew he did something shady. Arpita: 36:24 This is really interesting. So patent law is really tricky. So inventorship can be a really gray area since contributions are not always like very well defined. So for example, if you did an experiment that's like kind of different, and then it inspires me to invent something, do you get credit for that? Um, it's like unclear, but the law requires making a quote unquote, not insignificant contribution to the concept of the claim invention rather than simply carrying out the experiments. So it's really kind of where intellectual property law and patent law sort of overlaps. Like who actually gets the credit? Aarati: 37:03 Right. Yeah, because if my professor had the idea, and then I just carry out the idea, and I'm just like the pair of hands who did the actual experiment because they're the professor, you know? They get the patent because it was their idea. That makes It makes sense. Arpita: 37:21 To be clear, that is not what is happening in this situation. Svetlana absolutely the person who had the idea behind this, but that is kind of why this whole situation is tricky with her lawsuit. Um, so the fight with MGH's patent office went on for years. So, while this was happening, patents for the GLP 1 peptides were licensed to a pharmaceutical company, Novo Nordisk. Novo Nordisk immediately began drug development using this technology. So finally, this is almost like a decade later, between 2004 and 2006, MGH agreed to amend four patents to include Svetlana, and the United States Patent and Trademark Office accepted this change in inventorship, and now that she had patent in name, MGH agreed to award her one third of drug royalties with Joel getting the remaining two thirds. Aarati: 38:13 Good for her, for fighting for it for that long. Like, over a decade, that takes dedication, Arpita: 38:19 A long time. Aarati: 38:20 good for her. Like, yeah, get, get your credit, get, get your money. Arpita: 38:25 No, literally. Um, so a few years later, now we're in 2010, FDA approved the first Novo Nordisk GLP agonist drug called liraglutide, and it was sold under the brand name Victoza for diabetes. Aarati: 38:41 Yeah. I did four videos on Victoza. Arpita: 38:45 So she started getting some royalties, but then they stopped after just over a year because her first patent expired. So it took her so long to get her name on it that she actually didn't get to collect that many royalties on it. Aarati: 38:56 That sucks. Arpita: 38:57 And just like you, just like your sigh, I think she agreed with that. She was exhausted by this patent dispute. She was like, I just want to put all of this behind her. Aarati: 39:05 Yeah, screw this. Arpita: 39:07 In an interview, Joel mentions that he has regrets on how this patent story played out. He didn't think it would really matter that much or become this consequential or lucrative when he filed the patent. Aarati: 39:17 Then why didn't you tell her? Arpita: 39:19 I call bullshit. Aarati: 39:22 Like, you don't a big deal, then you should like, be like, Hey, I'm this thing. Do you just want to get in on it? Because it's no big deal. Arpita: 39:31 Yeah, I call BS that, but regardless, here we are. So as much as Svetlana was like ready for this GLP 1 story to be over, even though she really cared about the science, as we now know, GLP 1 was just getting started. So new versions of GLP-1 agonists were approved for diabetes. In clinical trials, insulin levels increased, which helped control diabetes symptoms. But as we found in rats, it also caused appetite loss. So whether it was desired or not participants these clinical trials began losing considerable weight. Aarati: 40:05 When I was doing the videos, I think I read that the mechanism of action for GLP 1 is such that it causes like nausea and that's kind of what leads to appetite loss. And so then if you take too much of it, you can actually induce vomiting and all these like really negative side effects. And so that's like one thing that patients who are taking GLP 1 medications kind of need to be aware of is that you can't just like take a whole bunch and expect like, Oh, I'm going to get these fantastic results because it might actually become more dangerous.. Arpita: 40:41 I'm not sure about vomiting and nausea, I'm interested in that, but I didn't. I was trying to find out the okay. Let me just read this part Aarati: 40:49 Yeah. Talk about the mechanism of action. Yeah. Talk, talk about how it works. Arpita: 40:53 So in just to back up a little bit in obese individuals, or even in type 2 diabetic individuals, the fat in your belly or visceral fats, this isn't the fat that's like right under your skin this is like deep fat that's around your organs. can cause inflammation inside of your body, which can contribute to the insulin resistance. And excess fat can accumulate in your liver and other tissues, which then interfere with the body's ability to respond to insulin signals after eating. As a result, if there are excess nutrients floating around and insulin isn't being produced adequately to bring this down, the body stores all these excess nutrients as lipids in adipose tissues. And then this causes a vicious cycle. So a GLP-1 agonist directly counters these effects. So GLP-1 agonists are used as, how do you say this word? S A T I E T Y. Satiety? Aarati: 41:55 Satiety? Arpita: 41:56 Satiety? Aarati: 41:57 I always said satiety. Arpita: 41:59 I don't actually think I like said it out loud. I was just reading this Aarati: 42:02 Hang on. I'm Googling it. Arpita: 42:04 I feel like it's satiety. Aarati: 42:05 Satiety. Arpita: 42:06 Okay, Aarati: 42:07 Satiety. That's what Google says. Arpita: 42:09 Great. So GLP 1 agonists are used as a satiety hormone in humans. So they act on the brain, which causes food from the stomach to empty slower than normal. So with more insulin in the blood from GLP 1 and less food leaving the stomach, overall blood glucose after eating is reduced. So in more recent research, GLP 1 agonists go far beyond satiety, may also change food preferences to become more healthy and even reduce a person's interest in alcohol, tobacco, and even opioids. And it was quickly apparent that the potential for this class of drugs is enormous and may be a paradigm shift, not only for the management of obesity, but for several other conditions. Aarati: 42:54 Wow. I didn't know all about alcohol, tobacco. Arpita: 42:57 That was a really recent paper that I read. I was honestly just a few months ago. But I also just wanted to mention that we think about hormones a lot of times as affecting just the organs around them, really hormones affect your entire body, including your brain. So it does make sense that when you think about a hormone like insulin, it is affecting your entire body. So it does make sense that it's acting on your brain and your brain telling your body that it's hungry. Aarati: 43:22 Yeah. Arpita: 43:23 Um, so I'm not sure about the nausea. I didn't read about nausea, but it really is also like, it's mostly focused on gastric emptying is what I read about. Aarati: 43:31 Oh, interesting. Yeah. Cause that was just one point that I remember making in the video that the, just the way that it works can induce nausea. And so you have to talk your doctor about, you know, Arpita: 43:44 doctor Aarati: 43:44 Yeah, because it was very much like a patient video. So it's like, talk to your doctor about finding the right, dosage and just be aware that these could be the side effects. Like, Arpita: 43:53 Exactly. Exactly. Aarati: 43:55 those commercials that have like, Yeah. like go on for like a minute Arpita: 44:00 okay. So now that we know what the mechanism is, uh, drugs like Wegovy and Ozempic have become really household names. Um, like mentioned, they have celebrity users and they have generated billions of dollars in profit for pharmaceutical companies and have resulted in international scientific acclaim for the researchers credited with discovering GLP 1. So, in 2017, Jens Holtz, Joel, and Daniel Drucker Jointly won the Harrington prize for innovation in medicine given by the American Society for Clinical Investigation and the Harrington Discovery Institute for their discovery of incretin hormones and for the translation of these findings into transformative therapies. Aarati: 44:44 Wait when was this? Arpita: 44:47 2017. Aarati: 44:47 2017. It's so recent. Oh my gosh. Arpita: 44:48 I know this is all very recent In 2020, the Warren Alpert foundation prize was awarded again to these three. And it's a very prestigious award that's given for biomedicine by Harvard. And Svetlana was again, left out. She got this news and she was incredibly hurt and disappointed. And especially scientific community awards are a really big way that credit is given in science, and they're often chosen based on nominations. So there is, I was reading like a press release on this and it's like, it's possible. That, and this doesn't make it okay, but it's possible that Svetlana, she continued to work on GLP 1, but because she didn't have her own lab, she didn't have her own funding, her, like, didn't have, like, those high profile publications the way that Joel did, for example, it's possible that she was just, like, simply less conspicuous than the three, and, like, wasn't immediately thought of. It doesn't make it okay. But it is just like a thought for like, because these are done by nominations. It was like the most high profile scientists in the field were the ones that were chosen. Aarati: 45:54 Yeah. But that's why I was asking you like, when did this happen? Like 2017 is so recent because I feel like now even more, there is such a push for acknowledging the women in STEM. And this seems like such an obvious way to do it. Like, you know, if a woman has made a great contribution, who cares the size of her lab, like, acknowledge that. Please give her her credit. Don't just leave her out because that's such a blow to not just her because she did so much work, but all women in STEM who are just like, okay, so if I make some great discovery some man's just gonna get, all the credit and all the patents and all the acknowledgements like come on, we're past that. Arpita: 46:34 I hate to tell you that this story gets worse. So, uh, then in 2021 the Gairdner award was given again to the three men. Um, so now we have three awards that were given just to them and Svetlana was left out. So at this point, GLP 1 was very much part of the zeitgeist and many Americans vocabulary. There was press conferences, interviews, and global recognition to those three with Svetlana left off very consistently. So any commentaries that journalists published, then aligned with the scientific prize winners, again, only listing Joel, Jens and Daniel and heavily exaggerated their contributions, right? Like now you have journalists being like, look at these people and look how like, blah, blah, blah. We're like talking about Ozempic and Wegovy. And Svetlana was mischaracterized as a quote unquote scientist in Joel's lab, even though she was in fact an independent researcher with her own funding who made this work and discovery possible. Aarati: 47:28 Okay. Now I'm also mad at the men too, because before I was just mad at the people who are giving out these nominations and these awards, but now I'm mad at the men too, for not like setting these journalists straight and being like, Hey, you should really be talking to Svetlana also. She did a lot. This wouldn't be a thing without her. And like, it's on them too to bring her into the fold, right? If they see that someone's being overlooked, like men do better too. I'm getting mad. Arpita: 47:54 So she also gets mad. Um, and she is an intensely private person. She had this whole bad experience with like the patent situation. She does not want to deal with this. Um, so she didn't actually start trying to get the story rectified until just last year in 2023. Other scientists at Rockefeller at Weill Cornell and MGH all spoke up and submitted correction requests to publications and press releases about her absence. So one of her close colleagues, Francis Barney said quote,"This is a story that has happened over and over again in science. There are no villains. You do not have to say that somebody hogged credit, but rather that she isn't getting the recognition that she deserves. End quote. Aarati: 48:32 Mm hmm. Arpita: 48:33 So though these corrections had the right intentions, they brought the mistake to the forefront of the public eye. So Joel, Daniel, and Jens all confirmed that Svetlana had important contributions and felt very sympathetic. And Joel said he, quote, wished that there was something that he could do, end quote. Aarati: 48:52 You literally could have, Like, what does that even mean? Like, you literally could have just opened your mouth and brought her name into the discussion. Arpita: 49:03 Understandably, Svetlana was very upset by this saying, quote, Of course they will say I deserve more recognition, but then they take the recognition that belongs to me and they assign it to themselves, end quote. Aarati: 49:14 Yeah. Oh my god. Arpita: 49:16 So Svetlana is very like, um, she's like very, um, Level, she's like, not rufflable and so this is like very outside of her personality, but she said in an interview with science magazine, quote,"It's fine. Let's just move on." Endquote. So, however, her colleague Francis said her attitude is always pragmatic. If everybody else is getting recognition, why not her? So finally, just last year, Cell and Nature issued a revised narrative of GLP 1's discovery to include her name. And later that year, the journal Science and the news outlet Stat published two lengthy profiles on her that finally told her side of the story. And just a few weeks ago, in this year, 2024, she was ordered the Tang Prize in biochemistry and was listed as one of 2024 Time Magazine's 100 Most Influential People. And since then, she's received an outpouring of support, especially from female scientists who similarly feel like their work has been sidelined. Aarati: 50:17 Yes. Arpita: 50:18 This all happened like literally just a couple of months ago when she's finally like, I, I, the reason I picked this story is because I saw a couple of articles about her and it was this female scientist who was left off of this amazing discovery that has like, really changed the way that think about this huge disease, diabetes, and also weight loss. And it's just become this whole, like, this almost like entity of like, Ozempic and Wegovy you know, like, we're hearing about this all the time. And the fact that something that is generating so much revenue, so much recognition has very pointedly left her off, I thought was crazy. And to your point in the year of our Lord 2024, like that is... Aarati: 51:01 Yeah. Arpita: 51:01 crazy. Aarati: 51:02 I'm so glad that we've moved that, that far, though. Like, 2017 doesn't seem that long ago, but at least, like, in those last seven years, we've made a lot of progress, it sounds like. So I'm happy about that, and hopefully we just continue from here on. Arpita: 51:18 I know it's like interesting though. Like if she hadn't actually spoken up for herself and said anything, like nothing would have changed. Because this narrative went on for several years and it was really just, you know, like less than a year ago that she was like, Hey, I actually contributed to this and you should include my name on this. And it took that long for the change to be affected and it took her speaking up for herself. So if she hadn't said anything... Aarati: 51:42 Especially when you said was, like, on all the papers, she was, like, the first author on all these papers, like, did no one do their research? And say, oh, who's the first author on this paper? Who's this Svetlana person? Maybe we should talk to her. Arpita: 51:56 I know. It's, it's really crazy. Um, and yeah, that kind of brings us up to today. So Svetlana is alive and well, she's in her mid seventies and she continues to live in New York with her family. But yeah, that's her story. And there's like, been some very interesting interviews with her where, you know, she talks about how she doesn't really get any... she doesn't get any revenue from any of its pharmaceutical companies because it is not actually GLP1 because they've done their own drug development based on that patent. So that's why we have semiglutide. Semi glutide is a analog of GLP1 because they've done their own proprietary, whatever. Um, it's extremely similar, but it's. Aarati: 52:41 Yeah. But they've modified it enough that it's Arpita: 52:45 Exactly. So she doesn't get any money from that. And her patents have all expired, but she maintains that she wasn't in it for the money. Like, she didn't really care about the money. What she cared about was being recognized adequately for the work and being represented to the equal extent that her male colleagues were so that she could set a precedent for, like, women who came after her. Like, that was what she really wanted. Wasn't in it for the money. Yeah, Aarati: 53:09 But still, the money would be nice. you know? Arpita: 53:12 I totally agree with you. Aarati: 53:14 Yes. Arpita: 53:15 The other thing that I found very interesting was, so her husband, Michel, is a also a very prominent scientist who does not really show up in the story very much. And looking him up he is a, like, a very accomplished scientist in his own right. But she very pointedly does not rely on him to throw his support behind her to be like,"Hey, like, I have a lot of clout in this academic community and you be paying attention to this person, Svetlana." Like, she very much wanted to do this on her own. she does not lean on him. Academic support, if that makes sense. Um, which is very interesting. And she mentions that she wants to make sure that their academic achievements and their work remains independent and they're not conflated with each other because then I think she becomes known as like, Michel's wife. And that's not wanted at all. Um, so obviously he's her husband and her partner and all of these things, but in terms of academic clout, she's not leaning on his, On his influence, which is very interesting. Aarati: 54:16 Yeah. And there's so many people out there also who are just like, whenever a woman makes it big, they always try to kind of equate her success, to a man, and be like, oh, the only reason she made it big, is because She's dating him or she's married to him and it's always a man It's always so I totally get that. Arpita: 54:36 Simone, Simone, Biles husband who plays in the NFL. He's not even very good. Aarati: 54:43 Yeah, exactly that. It's it's like she's this amazing amazing person in her own right. Let's not You know, include the man in this at all. Arpita: 54:53 Yeah. Um, but yeah, that's Svetlana's story and how GLP1s came to be. And they had quite an interesting story of trial and error. And she finally got the recognition she deserves. Aarati: 55:05 That's a great story. I'm so happy. It had somewhat happy ending. Arpita: 55:10 A somewhat happy ending. yeah, Yeah, Yeah, yeah, Aarati: 55:11 yeah, yeah Yeah, hopefully it becomes happier as the years go on. yeah, more and more recognition and, you know, um, but yeah, that was a great story. I didn't know any of that from making the videos last year. I hadn't really gone into the whole history of GLP great story. Arpita: 55:28 Thank you. Aarati: 55:31 Thanks for listening. If you have a suggestion for a story we should cover or thoughts you want to share about an episode, reach out to us at smarttpodcast. com. You can follow us on Instagram and Twitter at Smart Tea Podcast and listen to us on Spotify, Apple Podcasts, or wherever you get your podcasts. And leave us a rating or comment. It really helps us grow. New episodes are released every other Wednesday. See you next time!