Insulin (featuring Dr. Katrine Whiteson)

Daniel and Kelly chat with Dr. Katrine Whiteson about diabetes, the history of insulin production, and Dr. Lydia Villa-Komaroff. See omnystudio.com/listener https://omnystudio.com/listener for privacy information.

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Daniel Whiteson?

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• 1:38Speaker 04

  We, as humans, were scared that we were gonna unleash some kind of monster. What were the consequences of us genetically engineering things? I mean, more recently, we've had similar debates about CRISPRs. And maybe you've heard that there was even a case where a Chinese scientist used CRISPR to genetically engineer a baby, a human. That has really, really big ethical questions. And this was happening only in bacteria, but it was the first time it had happened. And we were rightfully, really thinking carefully about what the consequences could be. For example, imagine you cloned a bacteria that contained genes that could break down petroleum. And then you unleashed that in an oil mining operation.

• 2:22Speaker 04

  You could really cause a lot of destruction. And what if that was just... Impossible to control and then you destroyed huge natural resources unintentionally or intentionally for that matter. So those were the kinds of questions people were worried about.

• 2:37Daniel Whiteson?

  Or what if it helped the bacteria organize and it crawled out of the vat and like extracted vengeance for all the brethren that we've tortured in order to extract insulin from them?

• 2:46Speaker 04

  That's a great question, but I'm pretty sure they didn't talk about it.

• 2:49Daniel Whiteson?

  That's a very polite answer to a totally bonkers question, Katrina.

• 2:54Daniel Whiteson?

  Y'all should have seen her face.

• 2:56Speaker 04

  That didn't make it to the top 10 list for discussion at a Silmar.

• 3:13Daniel Whiteson?

  Hi, I'm Daniel. I'm a particle physicist and a member of the Whiteson Research Institute in Irvine. And today I'm going to be an extra big fan of biology.

• 3:22Kelly Weinersmith?

  Hello, I'm Kelly Weiner Smith. And can I be like an adjunct at the Whiteson Research Institute? Like, is that what friends are called?

• 3:30Daniel Whiteson?

  Come be a visiting professor. No problem. Absolutely. Yes.

• 3:34Kelly Weinersmith?

  All right. Does that come with dinner?

• 3:38Daniel Whiteson?

  Dinner is a bonus. Yes. Plus, you can add this as an extra affiliation on all of your papers to make you sound really smart.

• 3:44Kelly Weinersmith?

  Fantastic. I'm gonna, yeah, I'm gonna put it right on my CV. Have you ever done a show with your wife before?

• 3:50Daniel Whiteson?

  I have never done a podcast episode with Katrina, though I've had lots and lots of science conversations over the dinner table. So we definitely talked a lot about science and bored our teenagers to death. But no, I don't think it's ever been recorded. So this is great for posterity.

• 4:06Kelly Weinersmith?

  Well, and I'm excited because we have talked on the show often about how, you know, since she studies microbiome stuff, sometimes you find bags of poop in your freezer and stuff like that. And I feel like it's really important for people to like, put a voice to those stories. And today, that's gonna happen.

• 4:21Daniel Whiteson?

  You just want another poop in the freezer ally on the show to outvote me. That's what's going on here, really.

• 4:26Kelly Weinersmith?

  I do. I want the gross votes to outnumber the like, people who are squeamish. And also, I like, you know, pushing the envelope in the direction of gross so that I don't seem as gross, you know? Like, mostly, I want Zach to realize how lucky he is. Yeah, that there's not bags of poop in the freezer. Like, the dead bird, not a big deal.

• 4:44Daniel Whiteson?

  All right. Well, welcome to the podcast where we pretend to be talking about science, but really, we're doing marital therapy.

• 4:52Kelly Weinersmith?

  Well, on today's show, we're very lucky to have Katrina come on to talk to us about diabetes and the history of insulin production and the future of insulin production. And she was amazing. She had a lot of incredible insights.

• 5:05Daniel Whiteson?

  Yeah, I think a lot of people think they understand diabetes generally, but there's a lot of really fascinating biochemistry and a lot of nuance there and a lot to understand about the daily life of somebody with diabetes. And it's kind of amazing that until about 100 years ago, diabetes was a death sentence. You got diabetes and you're dead a couple of years later. And now, because of amazing biologists, we can save the lives of all those kids and people like my wife can grow up and be like a professor and have kids and live a full life. It's really kind of an amazing testament to what science can do.

• 5:36Kelly Weinersmith?

  And I'm not going to release any spoilers here, but there were at least two things she talked about where I was like, I thought I knew and I was totally wrong. And so I think we're going to have a good episode of sort of dispelling rumors or myths about diabetes.

• 5:51Daniel Whiteson?

  All right. Well, then, without further ado, let's welcome my favorite scientist at the Weitzin Research Institute.

• 6:00Daniel Whiteson?

  So then today's my great pleasure to welcome to the podcast, co-president of the Weitzin Research Institute and winner of the Weitzin Research Prize, Associate Professor Katrina Weitzin at UC Irvine. Katrina, welcome to the podcast.

• 6:14Speaker 04

  Thank you.

• 6:15Kelly Weinersmith?

  I'm so excited you're here.

• 6:19Speaker 04

  I didn't even know about those awards, but I will, I guess I'll gladly accept them.

• 6:22Daniel Whiteson?

  Yeah, go update your CV right now.

• 6:27Kelly Weinersmith?

  Update your tenure packet, all the things.

• 6:29Speaker 04

  Definitely.

• 6:32Daniel Whiteson?

  But we didn't just invite Katrina to the podcast to jerk around with her. We invited her on because she's a deep expert in today's topic.

• 6:39Kelly Weinersmith?

  So today, we're talking about bioengineering bacteria. We're talking about diabetes. We're talking about Lydia Villa Komaroff, and it's going to be an amazing conversation. And we're super excited to have you here.

• 6:51Speaker 04

  Thank you.

• 6:52Kelly Weinersmith?

  So by the end of the episode, we're going to get to bacteria-producing pharmaceutical components. But let's start by talking about diabetes. What are the mechanisms underlying diabetes?

• 7:03Speaker 04

  Well, that's a really good question. And actually, even just using the word diabetes already doesn't give you quite enough information to be able to answer that question, because there's two really different forms of diabetes. I guess we could go back to ancient times when the word first arose. And in that time, we understood that sugar was involved and that not being able to process sugar was involved. We've actually known that for hundreds of years. So you could think of glucose as maybe the first biomarker. There were really interesting ways that people would detect that someone had diabetes. It's actually diabetes mellitus, and the words mean that you're losing water due to sugar. And people would take urine and put it out to see if the ants were attracted to it. They would

• 7:47Speaker 04

  taste the urine to see if it was sweet, and that would give them a clue that you had this wasting disease where your body couldn't process sugar. And like, probably the first thing that pops into mind when you think of diabetes in modern times is it's associated with obesity. But actually, diabetes is a wasting disease. It means that you can't get energy from sugar, and you actually starve to death while drowning with lots of sugar in your blood. So I think that's just actually really amazing and usually counterintuitive. When I'm teaching, I sometimes show images of the children who would die from diabetes before the insulin was discovered. And they are emaciated because they're unable to get any energy from the sugar that they're eating. So to back up, I mean, there's two main kinds

• 8:29Speaker 04

  of diabetes. The first one, type 1 diabetes, for a while, it was even called juvenile diabetes, is when your immune system kills the cells in your pancreas that make insulin. So you're no longer able to access sugar. So you eat sugar, it gets into your blood, but the key that allows the sugar to be used by your cells is just totally missing.

• 8:49Daniel Whiteson?

  And so you're saying insulin is that key. Insulin is the thing that takes sugar from your blood and into your cells?

• 8:54Speaker 04

  Exactly. Insulin is a protein like ham, but it's acting like it's a little robot, it's a little key that actually summons the transporters that help glucose get into your cell up to the surface. And then the gates open and the sugar can get into the cells. Without that, the sugar just sits in your blood and the cells starve.

• 9:15Kelly Weinersmith?

  Is there a toxic effect of the sugar building up as well? Or is it just that you're starving is the main problem?

• 9:21Speaker 04

  The long term, the sugar in your blood is super toxic, but those are kind of like decade long problems. So if you're dealing with starving in the course of weeks or months, then the decade long problem of too much sugar in your blood is just not something to worry about. But yes, too much sugar in your blood is definitely toxic. And I think that's the part that's more famous about diabetes right now. Because most diabetes in our time, 90% of diabetes is what we call type two diabetes. And it can be lifestyle associated, but amazingly, it's actually more genetic. It's more inherited to get type two diabetes. So about 90% of the diabetes in the world right now emerges usually later in life. And it's not because you don't have insulin. You could actually have plenty of insulin.

• 10:05Speaker 04

  It's just not working very well. So your body is resistant to the use of the insulin. That's associated with metabolic syndrome, but actually can be quite genetic. You can be a very healthy, thin looking person and still get type two diabetes. So that's also a bit of a misnomer to always assume it's associated with lifestyle. But in the case of type two diabetes, if it is arising because of obesity, you can reverse it. If you eat less carbs, exercise more, and in general, don't overload the system that depends on insulin, you can resensitize your body to the insulin that it can make. And you can also take medicines that make the insulin more effective.

• 10:43Daniel Whiteson?

  All right, so let me recap for the non-biologists. You eat a ham sandwich, your body turns some of that into sugar, puts it into your blood. But then your cells in your body, like your muscles, can't access it from your blood without insulin, this thing that takes it from the blood and into the cells. And type one diabetes is when your body kills the cells to produce insulin, so you just don't have it. And type two is when you still Still have insulin, but because of some metabolic things, it's not working as well, or it's just not as effective.

• 11:12Speaker 04

  Or you just don't have enough. Yeah, that's about right. There's a lot of nuances that you will not be surprised to hear. For example, your brain, which uses about 20% of the glucose in your body, doesn't really depend on insulin in the same way. So I find that kind of amazing that your brain is just like this constant machine that's using a lot of the sugar in your blood. It's like the main reason it's so important that our blood glucose levels are maintained at a certain level. Otherwise, your brain doesn't function. So that's kind of independent of the insulin. And then there's other really cool exceptions, like your muscles, especially during exercise, they're extra sensitive to being able to get glucose in. So there are extreme examples, like there's a story about a guy 100 years ago,

• 11:53Speaker 04

  before there was really insulin, who kept himself alive with like a really crazy exercise regimen. And he had like amazing muscle mass and he kind of like extended his capacity to metabolize his diet, even though he didn't have much insulin. So it's kind of interesting. We didn't do more of that. But on average, yeah, without insulin, your blood will be full of sugar and your cells will be starving. And if you look at a picture of a kid who died from type 1 diabetes before 1921, when insulin was discovered, they look emaciated, which is just terrible.

• 12:22Daniel Whiteson?

  So you're starving, but your blood is filled with sugar and your pee is filled with sugar. You just don't have access to it. So it's like being hungry at a buffet. It's crazy.

• 12:31Speaker 04

  Yeah, exactly.

• 12:32Kelly Weinersmith?

  Do you know the story of how we discovered insulin?

• 12:35Speaker 04

  Yeah, I mean, there's actually a lot of really good stories around that. It was a slow process like science often is, because we got a lot of important clues, even maybe a half a century before the discovery of insulin. Like, we knew for a long time, hundreds of years, that it was related to glucose. So then by the 1880s in Germany, there were scientists who figured out that if you removed the pancreas from a dog, it would cause essentially the symptoms of diabetes.

• 13:02Daniel Whiteson?

  What were they doing? Were they just like taking random organs out of dogs one at a time to see what happens? Like, let's see what happens if dogs don't have a heart. Oh, that didn't work very well.

• 13:10Speaker 04

  Yeah, I guess that's not diabetes related. Good question. I mean, you know, it could be that like some unlucky dog got kicked by a cow or hit by, there weren't cars in those days, but hit by a horse, I guess.

• 13:21Kelly Weinersmith?

  We did do some pretty awful things to animals in the past. It wouldn't surprise me if there were a series of experiments. We were like, how do they do without this? How about without that?

• 13:30Daniel Whiteson?

  In the past, biologists are still doing horrible things to animals in the name of science.

• 13:33Kelly Weinersmith?

  We have to go through complicated protocols and institutions and prove that those animals are needed for scientific discovery these days, but that could be a whole different episode.

• 13:43Daniel Whiteson?

  Unless you want to do experiments on your own children, in which case you don't have to ask an IRB, but you should ask your husband.

• 13:50Speaker 04

  But if you're the parent, you could also ask yourself, especially if it's like something very low risk.

• 14:00Speaker 04

  This is a case where I could try to look up the 1889 story that I have in my brain about the pancreas. But anyway, somehow they realized that there was a connection between pancreas being missing and diabetes. So then that sounds like the kind of thing where it shouldn't have taken more than a couple of months to go from knowing it was the pancreas to extracting insulin from the pancreas so that you could save all these kids who were dying from diabetes. But it wasn't until 1921, 22, that we finally extracted insulin from the pancreas. A lot of that time went to figuring out how to purify the insulin protein away from all the other digestive enzymes and proteins that are also produced by the pancreas.

• 14:43Speaker 04

  So, you know, your pancreas is this organ that's there to help you digest stuff. One of its main jobs is to produce proteins that break down our food. And those are also made of protein. So basically, the pancreas is full of stuff that destroys insulin, since insulin is also a protein. So like separating those things away from each other, it took 40 years or 30 years. That's a really hard thing to do. Now that's the kind of thing we're really good at, but in those days, we had to invent a bunch of techniques to get good at that.

• 15:12Daniel Whiteson?

  It's amazing to me how recently we have like any idea what big organs in our body do. Like before that, we were just like, we don't know, this is just. A blob of meat like stuff that seems to be important.

• 15:23Speaker 04

  What I think is amazing is that when we don't know what something does, we assume it's irrelevant. So like, we're always saying that the spleen and the appendix, for example, serve no purpose. Like, you know, you listen to them telling you in the hospital and you're getting your appendix out like, hey, you don't need this. It'll be no big deal. I find that really funny that when we don't understand something, we just say it's irrelevant. Like, that is definitely not true. In the case of the appendix, having your appendix there as a reservoir for gut bacteria is like the difference between life and death, to be able to reseed your gut microbiome and be protected from infection in the future. That was like clearly important enough that we developed an organ and hung on to it, you know?

• 16:01Kelly Weinersmith?

  And the evidence for that is really good now, right? That that is the appendix's role to hold on to those bacteria?

• 16:06Speaker 04

  I mean, it's a hypothesis that's hard to prove, right? Because it's very context dependent. But if you think about the context of human history, that seems like a very relevant context.

• 16:15Daniel Whiteson?

  It's biology, so the answer is it depends.

• 16:19Kelly Weinersmith?

  It's true. It's true. So they opened up the pancreas. They've been able to divide out the different proteins that are in there. How do you get from, all right, I've divided out the proteins to actually treating the disease? Was that a pretty easy step?

• 16:32Speaker 04

  That's a really cool question, and this all happened at a university. It was at the University of Toronto, and there was a medical student there that summer, Best. And he was working with a lab supervisor, Banting. So Banting and Best are the famous team who discovered insulin that summer in Toronto. The second they had it purified out, they started treating a dog who had had their pancreas taken out. And they were able to keep a dog alive for a couple of months using the dog insulin extract, which was pretty crude. In the meantime, they also worked on better purifying insulin from cows. And that's when they started considering using it to treat a child. And they actually moved to this really quickly.

• 17:14Kelly Weinersmith?

  Interesting.

• 17:15Speaker 04

  I would say that would still happen today because it would definitely be a life or death circumstance. We still have these compassionate use exemptions from the FDA, the Food and Drug Administration. In fact, I use those for our phage therapy trials where if somebody has no other options, we'll allow you to do something more experimental. But that means that this like lab guy, med student, who was certainly not a professional at making medicines. Was just taking this extract they made in the lab and the first boy they treated was a Canadian boy at the hospital at the University of Toronto. He was 14 and he was wasting away because he didn't have any insulin. And he went from being very, very ill with very high blood sugar to doing much better,

• 17:59Speaker 04

  like within hours. And then really soon after that, there's an image that I think is super iconic to anybody who knows about the discovery of insulin. And it's an image of a nurse with a cart and maybe a doctor next to them. And the story goes that they went into this ward of the hospital that had 30 comatose children with type one diabetes and the parents were there. And then they injected this very experimental cocktail they had made in the lab into those 30 kids and they all woke up. And, you know, that was a really big moment in science and must have been amazing for the parents who really had no reason to hope their kids had any chance of getting better.

• 18:38Daniel Whiteson?

  I mean, if your kid is wasting away and the doctor says, hey, we're going to inject this experimental dog organ juice into your kid, you might just be like, yes, do anything, please, right?

• 18:47Speaker 04

  Yeah, exactly.

• 18:48Daniel Whiteson?

  But how did we know that dog pancreas would produce dog insulin, which humans could use? Isn't there a possibility that like dog insulin could be different from human insulin?

• 18:57Speaker 04

  Yeah, that's a really good point. I mean, I guess we tried it and learned that in the moment that first 14 year old was injected with insulin, we figured that out. And we now know that the insulins across animals have really shared features. So, you know, animals that have guts also have insulin, basically. So insulin is very conserved. The system, which might seem quite delicate, is being used across the animal kingdom. And in general, the insulins are pretty exchangeable.

• 19:28Daniel Whiteson?

  So you could like extract insulin from a hummingbird and use it on a person?

• 19:31Speaker 04

  Hummingbird, wow, you'd need a lot of hummingbirds. That's a good question, but um, yeah, I think so. There was actually a Czech couple, Eva and Victor Saxel, who fled Nazi occupied Czechoslovakia in nineteen forty. She was teaching English in Shanghai when her symptoms of diabetes developed when she was around nineteen or twenty years old. By then, highly purified insulin from cows was available in the pharmacies of Shanghai. And people were living pretty healthy lives in the nineteen forties when they had access to insulin. But then, when the Japanese occupied, those pharmacies shut down and Eva was in a really tough spot. How was she going to survive without access to insulin from pharmacies? And so this is really an amazing tale of survival.

• 20:15Speaker 04

  Because Eva and Victor, they actually figured out, they got their hands on a book showing the method that Banting and Best had developed for purifying insulin out of the pancreas. They didn't have dogs or cows, but they figured out that they could, they were knitting socks and selling them to get money to buy water buffalo pancreases. And first, they figured out how to get the water buffalo insulin for Eva, but they actually made enough to sustain hundreds of people with diabetes in the ghetto of Shanghai. So hundreds of people survived for the years of World War Two, depending on the insulin that Eva and her husband were purifying out of the water buffalo pancreas. It's really amazing.

• 20:52Kelly Weinersmith?

  Oh, that's interesting.

• 20:54Speaker 04

  There's another story like that in Chile of a husband who learned how to extract insulin from any kind of animal. And he was helping his wife survive. And I think the issue actually was that she would develop immunity to one kind of insulin. And not because of the insulin itself, but the extract is never pure. So she basically would develop allergies to the extract. So then he would move on to another kind of animal. And I think she didn't have access to pharmaceutical grade insulin. So he was helping her survive that way.

• 21:21Daniel Whiteson?

  Because insulin doesn't cure diabetes, right? It just helps get the sugar across the cells right now. You need a constant supply of insulin, right? Like, how long will a type one diabetic live if insulin supply? Just gets shut off.

• 21:33Speaker 04

  Yeah, just a couple of days. And so you hear those stories about the kids wasting away over the course of a year or two, and that's at the beginning of the disease when they still make some insulin. But somebody who has developed long term type one diabetes and has been dependent on insulin for a long time, they literally have no insulin. And then it's not actually a matter of starvation. Like, you wouldn't live long enough to starve with type one diabetes and no insulin, because your blood sugar would go very high. And then you go into a state that's called ketosis, where your body starts producing ketones, basically wasting away your muscles to get energy. And that process produces a lot of acid. And you basically die from the acid in your blood. It's like when you hit the wall in a marathon, and you don't have any more glucose from your

• 22:18Speaker 04

  liver and muscles. Your liver and muscles have glycogen stores. And so then your body turns to breaking down the protein of your muscles to get energy. And that process produces ketones, which are acidic. And then you die from the acid in your blood.

• 22:30Daniel Whiteson?

  So we can survive if we extract insulin from these poor animals. But that's a destructive process, right? You can't extract insulin from a dog without killing the dog, or can you?

• 22:39Speaker 04

  The way it's done, as far as I know, has always been destructive. And so, I mean, this could lead us to another interesting conversation about like, well, okay, we made this discovery. So then how did we actually produce enough insulin to keep the diabetics of the world alive, who need it every couple hours, you know, not just days?

• 22:56Kelly Weinersmith?

  And that seems like a great topic to ponder. And we'll return to it after the break.

• 23:10Speaker 01

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• 24:54Kelly Weinersmith?

  And we're back. And so we had just finished discussing how it had been figured out how you can extract the insulin protein from deceased animals. And now we're talking about starting to scale up so that we can provide this in an industrial sort of way.

• 25:07Daniel Whiteson?

  I have another question before we talk about industrial production of insulin, which is a naive question. Like, if it's about the pancreas producing insulin, and your pancreas is not making one, why can't you do a pancreas transplant? Like, we can do a heart transplant, or a kidney transplant, or other kinds of transplants. Why can't I just get the pancreas from a human corpse and put it into a diabetic and cure their diabetes?

• 25:28Speaker 04

  You can do that, actually, and you know, Canada has been so important in all these diabetes developments and the Edmonton Protocol was developed also in Canada. Point is, yes, you can transplant a pancreas into a person, but then you have to give them immunosuppressants.

• 25:43Daniel Whiteson?

  Hmm.

• 25:43Speaker 04

  In order to survive after an organ transplant, you have to take immunosuppressive drugs, which mean that your risk of cancer and infectious disease become very high. So to do that to a young person who otherwise has a healthy life expectancy is dooming them to a less healthy and shorter life.

• 26:00Daniel Whiteson?

  I see.

• 26:01Kelly Weinersmith?

  Who would you do that for, then?

• 26:02Speaker 04

  There's one context where it happens a lot, which is really cool, which is if you have kidney failure, which is also more common in people with diabetes, and you're doing a kidney transplant, you can do a tandem transplant of kidney and pancreas, and you have to take the immunosuppressants anyway for the kidney transplant. So then you get a bonus of no longer being diabetic, which is great because it also protects the kidney. So that's a really cool procedure, which is pretty common that people get a kidney and a pancreas transplant together.

• 26:30Daniel Whiteson?

  All right, so if you don't get a pancreas transplant, then you need a steady supply of insulin. And we were saying, we don't want to just keep killing dogs in order to, in order to extract insulin from their pancreas, or rats of China, or whatever. So then, tell us about how we produce insulin without killing all of our furry friends.

• 26:46Speaker 04

  Well, for many years, between around nineteen twenty something and the nineteen eighties, we relied on animals that we produced for food. So cows and pigs were our main source of insulin for all those years. And so that scaled up in the nineteen twenties. There were two main companies that emerged, and there's lots of stories about how the patents all worked out. But basically, Eli Lilly in Indiana became the US leader in producing insulin, and Novo Nordisk in Denmark became the European leader in making insulin. Currently, there's a third producer, Sanofi, they're French. Ninety percent of the insulin in the world is still produced by those three companies. And initially, all their insulin was coming from animals.

• 27:27Speaker 04

  And so you would get pig pancreas or cow pancreas from butchers. It became a very refined process, and I think it took, you know, a crazy amount of Pig pancreas, I mean, you know, it was like a thousand pounds of pancreas would really would lead to one pound of insulin being produced. It took a lot of purification. And so, and we kept that going and the supply was quite widespread and a lot of people's lives were sustained with that insulin. I don't think we could have kept scaling up. So it's very good. We had a early and amazing advance in changing how we produce insulin around the eighties. But yeah, for all those years, we were collecting pigs and cow pancreas from the butcher and extracting

• 28:12Speaker 04

  insulin from there. And actually, we know a few people like Daniel, our friend Moens, his mom, she worked at Nova Nordisk and she was one of the people who developed those procedures, or at least she was involved, I know, in extracting insulin from pigs. A lot of people were involved in making that happen.

• 28:30Daniel Whiteson?

  I wonder if that was complicated for some folks, like people who were vegetarians, but diabetic, and then they had to essentially use this animal product. Or what if you were like Hindu and didn't want to use cow insulin, or you're Muslim and you didn't want to use pig insulin? Could people like choose which animal it came from?

• 28:46Speaker 04

  Yeah, I never had to use animal insulin myself, so I don't know. But yes, I think you could choose which animal source it came from. That was part of the, what you knew about the product. That's one very big issue. Another big issue is that people would typically develop sensitivities or allergies to it over time. And then it would be less effective. It was a solution in many ways. And there are people who lived for decades taking pig and cow insulin, but it wasn't as easy to keep that going your whole life, because a lot of people develop sensitivities like allergies.

• 29:17Daniel Whiteson?

  You mean like your immune system is responding because it's like, hey, this is a cow product, not something from inside the body?

• 29:23Speaker 04

  Yeah, I don't even think it was the insulin itself. And despite all the purification I just talked about, I think it was hard to remove everything allergenic about it. So then you would develop immunity.

• 29:34Kelly Weinersmith?

  Were there any concerns about diseases passing from pigs and cows to people, or the purification process sort of cleared that out?

• 29:41Speaker 04

  That's a really cool question, and there were actually concerns. I don't think we even knew about it at the time, but now there's a lot of concern about prion diseases. And so actually, diabetics are sometimes excluded from blood donation and other kind of organ transplant because of concern for prion diseases, especially coming from cows. So yeah, people who have been having a lot of animal products like that, in theory, could have been exposed to prion diseases, which I think were less common at that time, also because of agricultural practices. Like, I think prion diseases became more common towards the end of the 20th century because we were doing all this, like, feed

• 30:22Speaker 04

  animal waste, like chopped up animal bits to the animals themselves, and that would kind of concentrate the chances of prion diseases developing, and that's better now. We know not to do that now.

• 30:35Kelly Weinersmith?

  And so you indicated in the 1980s, something changed. What was the thing that changed?

• 30:40Speaker 04

  Well, it's so amazing to me that this happened as early as it did in the 80s, but we actually figured out how to produce human insulin by fermenting it in bacteria and sometimes yeast by the early 80s. And so this was connected to the first genetically engineered organisms. In the 50s and 60s, we made the discovery of DNA. We understood the central dogma that DNA was the storage material of biology and that it was a blueprint for producing RNA and then proteins. Insulin is a protein. You know, it was only a decade or maybe 20 years after we understood that, that we were really making use of that information, which I think is really cool.

• 31:21Speaker 04

  So by the 70s, the hotbed of a lot of this activity was California and also Boston. People were starting to clone and like they were starting to be able to like, you know, use little molecular scissors to chop out a piece of DNA from a bacteria and replace it with another piece of DNA that encoded something you were interested in. And so it's kind of interesting to me to think about how these molecular biologists, who are more like theoreticians about the biology almost, these weren't like doctors who are thinking about solutions so much, but they're like, hey, I wonder what a good important protein to try to clone would be. And they're like, hey, insulin, a lot of people need that, let's try that. And so one of the first things that was involved

• 32:03Speaker 04

  in these early cloning projects, just to demonstrate like, hey, can we clone stuff in bacteria, was insulin. And so in the seventies, we started to do that kind of cloning. And then around the mid seventies, there was this moment where everyone realized like, oh, my God, what are we doing? If I like, complete these experiments, have I just created something that could go on and replicate and cause a lot of destruction? And so there was actually a meeting in Isilomar, California, I think it was around 1977. We all know this meeting, the Isilomar meeting about the safety of genetic engineering, basically. And maybe 150 people were there, mostly scientists, but politicians too. And they

• 32:44Speaker 04

  had a real like, look in the mirror, like, what are we doing? And is this safe? And everybody halted their work until the meeting so that we could like, decide what to do. And during that meeting, there were a lot of discussion about whether it was okay. And in the end, there were rules around what you were allowed to do, but it was decided that you could indeed proceed with cloning, especially under controlled circumstances. And so the project for cloning insulin was one of the ones that halted until after that meeting. And then, once the decision was made that it was okay to proceed, then the scientists continued with their cloning projects. And so I think it was about around

• 33:25Speaker 04

  1978, which is also the year I was born, that the first insulin cloning project was completed.

• 33:31Kelly Weinersmith?

  So when I hear the word clone, I think of like, copying and pasting an organism.

• 33:36Speaker 04

  Mm hmm.

• 33:37Kelly Weinersmith?

  You're essentially copying and pasting bacteria that now have the human insulin gene? Is that the right way to think about it?

• 33:43Speaker 04

  Yeah, exactly. So the human insulin gene was copied and pasted into a bacteria. And then they asked the bacterial cell to grow and produce the insulin. Now, I just made it sound really simple, like there was just only one thing that had to be copied in. But to be honest, a lot of genetic engineering had to happen so that the insulin could be produced. They had to make sure that all the ingredients were there, that it was in a spot that the bacterial cell against its own needs was producing this protein. You know, it's not like the bacteria needed the insulin. So they had to kind of rewire some of the metabolic pathways to force that to happen. So to be honest, it was a combination of real savvy and luck that insulin could be produced that way.

• 34:27Speaker 04

  A lot of bacteria don't have the right tools for making other kinds of modifications to proteins that are common in eukaryotic cells. And so the fact that they could do that a little bit was luck. And when we look back at which bacteria were initially chosen for some of these cloning projects, they were just random, like the most common E. coli, the kind of bacteria this was done in is called E. coli, Escherichia coli. And there's this really famous strain of E. coli, E. coli K12. That was the one that was used in this project. And E. coli K12 was isolated from a Stanford patient who had some kind of infectious disease, I think diphtheria, just randomly taken from this person's gut.

• 35:10Speaker 04

  And then it happened to have properties that were good for cloning. Like I have E. coli K12 in my lab. All biologists know E. coli K12, but it's just like a random Stanford patient from the 1920s. E. coli.

• 35:22Daniel Whiteson?

  I have some basic questions about how this works. Like, why are we using bacteria? Is it just like the simplest unit that we think we could still genetically engineer? Why can't we genetically engineer dogs to make? Human insulin.

• 35:35Speaker 04

  I mean, I think we were using bacteria, thinking that that would be a really great way to scale up and not have a combination of ethics and safety and just production. How great is it if the same way you brew beer, you can brew insulin, you know, that was the thinking. We we're good at producing things with bacteria. Yogurt, beer, well, your beer is mostly yeast, but still. Bread, we have microbial fermentation for food production really down. So the idea was to pivot that towards making medicines.

• 36:07Daniel Whiteson?

  I see. So bacteria can't make cute puppy eyes. So we don't care about growing them up and slaughtering them all for our insulin.

• 36:14Speaker 04

  Sure. I mean, that's one way of looking at it, but also just from a purely energy, climate and finance perspective. Bacteria are very efficient. So, you know, it's going to be quick and much more.

• 36:29Kelly Weinersmith?

  Short generation times?

• 36:31Speaker 04

  Yes, exactly. E. coli double in 20 minutes. I still think that a batch of insulin is not a overnight process. Like I think even in modern insulin production factories. It probably takes like a month or two to go from the overnight culture of the bacteria producing the insulin to like all of the different processing steps. Insulin is a really complicated protein because it's so, you know, powerful, which, you know, with great power comes great responsibility. Too much insulin can very quickly kill you. In our own bodies, our insulin is produced in an inactive form. And it has to be cleaved to become active. And so the insulin that's produced in the bacteria initially also is in that inactive form.

• 37:16Speaker 04

  And then all that processing that would normally happen in someone's body has to happen in the factory. So that the form that you inject is already active. So there's a lot of complex steps there. And if you were to try to take it out of puppies, I think that would be way less effective. I mean, the number of cows we needed to produce enough insulin to support humanity was becoming untenable. Like, there weren't enough cows to make all the insulin, even though we have a crazy appetite for meat and beef, but we still couldn't probably sustain all the diabetics who needed insulin.

• 37:46Daniel Whiteson?

  And why do we need to build this in a life form anyway? Like, we know how to do chemistry. I mean, I don't, but some people do. Why can't you just like stick the atoms together and build this thing out of little Lego pieces, you know, synthesize the thing in the lab?

• 38:00Speaker 04

  Yeah, I like that idea. And there is a thing called cell-free extract production that people sometimes use these days. I think it just is convenient and handy that these bacteria, in a way, are great little factories. They already know how to make copies of themselves. So I think from an efficiency perspective, I mean, how great is it that the bacteria, you just give them a little glucose and they go figure all that stuff out for themselves? Otherwise, you'd have to manufacture thousands and thousands of different components that the bacteria otherwise just build for themselves.

• 38:33Daniel Whiteson?

  Right. And they're self-replicating, which is much more than our grad students can do.

• 38:38Speaker 04

  I mean, to be honest, the way we produce a lot of the things you might consider putting into a cell-free artificial manufacturing process, we'd probably get them from microbial production to a lot of the things that we produce that way, we do with the help of microbes.

• 38:53Daniel Whiteson?

  Like cheese. I don't think I want to eat lab synthesized cheese either.

• 38:59Speaker 04

  I would.

• 39:01Daniel Whiteson?

  We actually have a friend who was working on plant-free food, and he gave us a taste of like chemically synthesized butter. And it wasn't good. No, I didn't like it. No.

• 39:11Speaker 04

  That's too bad.

• 39:11Daniel Whiteson?

  It was greasy, but it wasn't butter. But I have one more question, simple, which is, you talk about inserting these genes into the bacteria to make it do its thing, which makes it feel like the bacteria is some sort of computer and you're just like changing the program. And you're like, hey, can you make this instead of that? Is it as simple as that? Can you go a little bit into the detail of like, how do we know how to write this code? And then how do we take the code and actually put it into the genome? Home, right? It's not as simple as like logging into the bacteria and editing the files. You need to actually like put it into the DNA. How do we know how to do any of that?

• 39:44Speaker 04

  Yeah, what a good question. I'm not sure I know all the answers, but I can tell you that one of the first proteins that we ever even figured out what the sequence of it was was insulin. And so that's at the protein level, like the sequence of amino acids that you need to make insulin. That's what makes insulin insulin. From there, the protein sequence could have lots of different DNA sequences that lead to the same protein sequence because we have redundancy in the genetic code. So usually you have three nucleotide bases encoding an amino acid for a protein sequence. And there's many combinations of DNA that would lead to the right sequence for the protein.

• 40:24Speaker 04

  I actually don't know how they chose what DNA sequence to initially clone into the E. coli. In theory, it could be that they just, this is not how they did it because they didn't have the right tools to do this. But in theory, it could be that they were just like, oh, well, we know what protein sequence we want. So therefore, any of these bajillion different DNA sequences will work. So we'll just artificially synthesize one of those and do it from there. We could do that today. That's actually a pretty easy thing to do. I've often thought about that, like if you knew something you wanted to produce, you could synthesize the piece of DNA and send it to a yogurt manufacturer anywhere in the world and they could make vast quantities of a protein that you were interested in. If you could get the cells to cooperate, I mean, there's a few things that would be hard about it.

• 41:09Speaker 04

  But yeah, I think they must have known the sequence for human DNA and then physically gotten their hands on that and chopped it out. And then like physically, we use the word ligation. It just means like pasting it into the bacteria. And it wasn't just that. And a lot of this happened also with the company Genentech. I'm sure that many people know more about this history than I do, but some of it is proprietary, right? Because it was happening at a company. Some of it. Anyway, and so they cloned the human DNA sequence, copied it into the bacterial cell and just fired the bacteria up to produce it.

• 41:47Kelly Weinersmith?

  So now you've got the bacteria with the code and you've figured out how to get them to be running that code all the time. So they're making more insulin.

• 41:54Speaker 04

  Yeah.

• 41:54Kelly Weinersmith?

  Is that insulin accumulating inside the bacteria or do they excrete it? How do we get it after that?

• 42:01Speaker 04

  That's a really good question, and I think there's actually several ways you could do that. And I would not be surprised if both of those options are happening in various factories in the world right now. One way it can happen often when a bacterial cell is confronted with like a crazy amount of something it doesn't quite know what to do with, it pumps it into a little compartment called a vacuole and it just like makes little pouches of it. That's my understanding for the main thing that happens is that you get these little pouches of the vacuoles from the cells. And then the next step is to pop the cells, pull out all those vacuoles and then get the insulin from there. So I'm pretty sure that's the main way that it's done these days from E. coli. Not all insulin is made in bacteria and E. coli.

• 42:46Speaker 04

  There's I think maybe 20 or 30% of the insulin that's manufactured in the world is in yeast and Saccharomyces cerevisiae. And then it's going to be yet another process. And so yeah, in theory, you could make the cell excrete the insulin into the liquid, which might make your process easier. But since insulin is a protein and it can get broken down by enzymes that eat proteins, in a way, you might be better off having it be in a protected pouch so that you could just pull those aside and get the insulin out.

• 43:15Kelly Weinersmith?

  I don't think I've thought before about the complicated process of acquiring this stuff after the bacteria has made it. Like, I guess I'd imagine like, you know, you skim the top and there's the insulin and you stick it into needles. But yeah, I mean, extracting all of those vacuoles.

• 43:28Speaker 04

  Yeah.

• 43:28Kelly Weinersmith?

  And popping them doesn't sound like easy work.

• 43:30Speaker 04

  No, that's a sophisticated process. And then the protein sequence still contains extra bits that make it inactive on purpose so that it's not in our bodies, we don't want it to be active exactly when it's produced. It's like unleashed and activated very intentionally. So to get it to be in that active form takes yet more steps.

• 43:51Kelly Weinersmith?

  All right, awesome. So we're going to take a break now. And when we get back from the break, we're going to hear about Lydia Villacomarov's contribution to this field.

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• 45:55Kelly Weinersmith?

  All right, and we're back. So it's Women's History Month. We're trying to feature some amazing women that most people have, you know, perhaps not heard of. And you agreed to come on the show and talk to us about Lydia Villacomarov. What was her contribution to this field?

• 46:11Speaker 04

  Well, Lydia Villacomarov was a grad student in the 1970s during this era where we were just figuring out that we could clone bacteria. So not only did we understand the central dogma, the way that molecular biology is encoded, we were now starting to be able to manipulate it.

• 46:27Kelly Weinersmith?

  Interesting.

• 46:28Speaker 04

  So few people had done anything in this area right around the time that Dr. Villa Camarova finished her PhD from MIT in 1975. And she embarked on a really bold postdoc at Harvard. It was to clone the human insulin gene into bacteria. It was so bold that Harvard actually asked them to stop. They paused the project for fear of ethical considerations for what the consequences of humans cloning things could be. So she actually continued her project at Cold Spring Harbor. There were lots of failures. I think that was a really tough postdoc. But ultimately she succeeded. I think that was around 1978. And by the early eighties, there was commercially available human insulin that had been synthesized in bacteria.

• 47:12Daniel Whiteson?

  Right.

• 47:13Speaker 04

  And her project was to clone the gene for insulin into E. coli, the bacteria. So she has a paper in PNAS, the Proceedings of the National Academy of Science. And in that paper, she demonstrates that you can pull the insulin gene from humans, clone it into bacteria, and get the bacterial cells to replicate. So it was a big step, not just that this was an idea, but that it could actually be done. And everyone had their eyes on this happening. It was considered risky and important enough that her project was halted as these considerations about the ethics were being discussed at the Asilomar meeting.

• 47:56Speaker 04

  And after the Asilomar meeting, she was allowed to proceed. And it all happened very fast because her paper was already published in 1978. And I think the Asilomar meeting was only in 1977. So I bet that was intense. I bet she was working hard.

• 48:10Daniel Whiteson?

  What ethics concerns did we have? Because as we said earlier, bacteria can't make puppy eyes. So what are the ethical issues?

• 48:17Speaker 04

  It was a very new idea that humans could clone things, that we could decide what the DNA that a creature encoded was. And in some ways, I don't think it's different than agriculture, not just farming of crops, but I mean, dog breeding or horse breeding or anything where you select for traits that you care about. And then Intentionally push a population towards having specific traits. But we had always only done that in the context of selection, where all of the reproducing was happening by itself. Or, you know, what you might consider a natural way in the sense that you were just like picking out the peas that had the color you were excited about and crossing those.

• 48:58Speaker 04

  And then you get more and after hundreds of years, you can't even recognize the organism compared to where it started from.

• 49:05Daniel Whiteson?

  The way we transformed corn from like a tiny little grain to this like hugely productive food, for example.

• 49:10Speaker 04

  Exactly, or like watermelons or, you know, something where watermelons weren't these like amazing juicy ginormous fruits when we first found them, right? We cultivated that. And the consequences of the cultivation are obviously encoded in the genome. And in some ways, not really different than cloning something on purpose. In fact, we're not that good at cloning. Like cloning requires us as humans to decide what pieces of DNA belong in an organism. And we typically are kind of bad at that. It's interesting, I went to grad school in an era where rational design of proteins was really popular.

• 49:50Speaker 04

  A lot of people's projects were like looking at protein sequences and being like, oh, I think we should put an alanine there. And that's going to make this work better, that kind of thing. And typically it didn't actually work better. So in some ways, I think we've come to respect that evolution and allowing natural selection to happen is in some ways a more powerful way to pull off things you want to do. But you would never get insulin production through evolution. I mean, bacteria would never produce insulin. So it's actually a really great case for genetic engineering. It was a very cool problem that Lydia Villa Komarov took on because it was so effective. And it really would never have happened without cloning. So your question was, how did it come to be that this was an ethical problem?

• 50:35Speaker 04

  And the real issue was just that we as humans were scared that we were going to unleash some kind of monster. What were the consequences of us genetically engineering things? I mean, more recently, we've had similar debates about CRISPRs. And maybe you've heard that there was even a case where a Chinese scientist used CRISPR to genetically engineer a baby, a human. That has really, really big ethical questions. And this was happening only in bacteria, but it was the first time it had happened. And we were rightfully, really thinking carefully about what the consequences could be. For example, imagine you cloned a bacteria that contained genes that could break down petroleum.

• 51:18Speaker 04

  And then you unleashed that in an oil mining operation. You could really cause a lot of destruction. And what if that was just impossible to control? And then you destroyed huge natural resources unintentionally or intentionally for that matter. Those were the kinds of questions people were worried about.

• 51:36Daniel Whiteson?

  Or what if it helped the bacteria organize and it crawled out of the vat and like extracted vengeance for all the brethren that we've tortured in order to extract insulin from them?

• 51:46Speaker 04

  That's a great question, but I'm pretty sure they didn't talk about it.

• 51:48Daniel Whiteson?

  That's a very polite answer to a totally bonkers question, Katrina. Y'all should have seen her face.

• 51:55Speaker 04

  That didn't make it to the top 10 list for discussion, Ansel Lamarr.

• 51:59Daniel Whiteson?

  I bet. There were some science fiction writers there that would have come up with that scenario. It didn't take me very long to think about it.

• 52:04Kelly Weinersmith?

  I think there was a recent Ansel Lamarr meeting that was sort of inspired by that prior meeting. So you mentioned the ethical issues associated with CRISPR.

• 52:14Speaker 04

  Yeah.

• 52:15Kelly Weinersmith?

  But I think they like literally had another Ansel Lamarr meeting with like similar goals to figure out what direction.

• 52:21Speaker 04

  I think it's next month.

• 52:22Kelly Weinersmith?

  Oh, is it?

• 52:23Speaker 04

  Yeah, I think it's next month. Maybe you guys could have this episode coincide or we could look into that. That'd be cool. Yeah. Because my friend Jen Martini was invited, but she couldn't go because she's teaching. And I know she doesn't start teaching until next week.

• 52:33Kelly Weinersmith?

  Yeah. I mean, maybe we should have a whole episode on the ethical implications of CRISPR, too.

• 52:38Speaker 04

  Yeah.

• 52:39Kelly Weinersmith?

  That seems important and timely.

• 52:40Daniel Whiteson?

  So how ballsy was it for her to take on this project? Because if it didn't work, she could have ended up with basically nothing, no result. I mean, this was like really swinging for A home run, wasn't it?

• 52:50Speaker 04

  Yeah, that's a really good question. It'd be fun to talk to the people who were around at that time. I don't think I would give this to a student as their only project. It does seem really risky. But yeah, if you look at the people involved, like who her bosses were and who their collaborators were, you know, they were used to taking on really big projects and hitting for home runs, so.

• 53:11Kelly Weinersmith?

  That's what you do in Boston.

• 53:13Speaker 04

  Yeah, exactly.

• 53:16Kelly Weinersmith?

  So what came for her after this? So she did this amazing breakthrough, was the first person to do this amazing thing. What did she do after that?

• 53:24Speaker 04

  She stayed in science, actually. She made a really good use of her science education. And she went on to work on not just insulin, but other hormones that are related to insulin. Some of them are called insulin-like growth factors. It's a really complex field that I honestly couldn't tell you too much about what all the implications are. But I do know that she ran a lab and spent many years studying hormones that are related to insulin. And so she stayed in that field and she also really put a lot of energy into being a role model and a leader for other people who wanted to become scientists. She'd encountered definitely roadblocks herself, considering that most institutions wouldn't even accept women

• 54:08Speaker 04

  as applicants to graduate school when she was applying. And so she became a co-founding member of the Society for the Advancement of Chicanos and Hispanics and Native Americans in Science, or SACNAS. And that was back in the 1970s, and I actually didn't know that. I personally have had a lot of students who have been supported by SACNAS to go to conferences. They have meetings every year. I work at UC Irvine, which is a Hispanic-serving institution. And a lot of our students have gone to those meetings and had a really good time. So I think that's really cool. She founded that.

• 54:41Daniel Whiteson?

  And why isn't she a zillionaire? I mean, I know that this technology is the foundation of like billions of dollars of annual profit for Novo Nordisk and Eli Lilly. Why isn't she Elon Musk?

• 54:53Speaker 04

  What a good question. I don't know the details of what kind of IP they tried to get for the technique that they developed. I also know that Genentech was really involved. And so actually, an important thing to say is that, you know, so her paper came out in 1978. She didn't keep up with this specific field. I know that Genentech was the company that really developed the possibility of producing.

• 55:17Speaker 04

  Insulin and bacteria. My sense is that what she did was proof of concept.

• 55:22Daniel Whiteson?

  I see.

• 55:22Speaker 04

  Which was critical because it made people ready for the idea. But my guess is that Genentech went on and developed the technology in its own specific way that could then have IP that stayed within the company.

• 55:36Daniel Whiteson?

  Isn't there like fast acting and long acting insulin and stuff?

• 55:39Speaker 04

  Her paper came out in nineteen seventy eight and I know that by nineteen eighty two, the Food and Drug Administration had approved human insulin to be given to people. I was diagnosed with type one diabetes in nineteen eighty four and I never took animal insulin. I only got the human insulin. At that time, it was just the straight up human insulin sequence. It hadn't been modified to have new properties. But that's pretty amazing that we scaled that up for humanity that quickly. And so the insulins that I took with like regular insulin is still produced today. And I used it for twelve years, like multiple injections daily. And now if you go to Walmart, you can actually buy that kind of insulin for twenty five dollars.

• 56:21Speaker 04

  This is probably the most important thing I'm saying like ever. Anytime I have an audience, I say this because it could really save lives that you can buy regular human insulin at Walmart. It's intended for cats and dogs who have diabetes, but it's exactly the insulin that I used for many years. And it costs twenty five dollars and you don't need a prescription. It's just over the counter. You can just go to Walmart and buy this insulin. And it's exactly the same bottle as the one that I used in the nineteen eighties. So, starting in the nineteen eighties, we scaled up fermentation of human insulin to be available for all people. I wouldn't say access is perfect, but it's pretty good. Like, there's definitely parts of the world where you can buy insulin at a pretty reasonable cost.

• 57:06Speaker 04

  I'm sure you've heard a lot about the cost of insulin. Like, if you cross the border into Mexico, you can buy this insulin at a very reasonable cost, too. It wasn't until the nineties that engineered insulins that have different kinetics, like they can be faster and slower. Those came out in the nineties. The slower insulins were available earlier, like the insulin you can buy at Walmart. There's a slower one, too, that's called NPH, and that didn't require crazy bioengineering. Or, I don't know, they've somehow figured that out way earlier.

• 57:33Kelly Weinersmith?

  Why would you want faster and slower insulin?

• 57:36Speaker 04

  Well, the regular insulin, it takes a few hours to become active. So the insulin exists in little trimers around zinc molecules in a dimer. So there's two zinc molecules that each have three insulin molecules attached to them. So there's six insulin molecules all hanging out together. You have to wait for them to dissociate because the insulin is only active as a monomer by itself. So when you inject regular insulin, you have to wait one hour for it to even start working at all. And it doesn't peak until three hours. Now, when you eat your food, it doesn't come in immediately either. But regular insulin is too slow for an average meal. So most people would have to either inject their insulin early. But that's kind of dangerous.

• 58:21Speaker 04

  Imagine you inject your insulin, but your like food is late or you're on a walk and you forget to eat. Or, you know, something like that. If your blood sugar goes too low, you die from low blood sugar immediately. It's like the most common cause of death in people with type one diabetes. So that's really, really something you have to be careful with. So having your insulin kinetics not really matching when you need the insulin is both for convenience and basic survival, really, really important. There was a big arms race between Eli Lilly and Novo Nordisk in the nineties to rationally design insulins that had different properties. And they both succeeded in slightly different ways. And now you can buy insulin that falls apart more easily.

• 59:07Speaker 04

  Those uh, dimers on the trimers of the zinc are not as stable. So they fall apart more quickly. And now when you inject the insulin, it starts to become active within minutes and peaks within an hour, which matches how people eat much better. So it's safer and a little bit easier to keep your blood sugar within range. But matching the kinetics of your food with the kinetics of your insulin is just a major challenge.

• 59:32Kelly Weinersmith?

  So is it still the case that today people with diabetes need to be really careful about like what kinds of insulin that they're injecting? Has it gotten easier over time? I feel like I heard once that there are these things that can attach to your body that sort of do all the measuring for you. What is it like today?

• 59:48Speaker 04

  Well, so there's been big changes, both in how we deliver insulin and how we monitor blood sugar. So we haven't talked about blood sugar monitoring at all in any of this, but I'll bring up that, you know, we've known for centuries how to detect glucose in urine, but that's very old information. By the time the sugar hits your urine, that's like happened hours ago. And you can't really take that sample on demand quite in the same way as you can take a blood sample. So we started poking our fingers to get blood sugar measurements. Those devices started being available at home in the 1980s. And then for about 10 or 15 years, we now have these sensors that you can put a little sensor on your arm and you get blood sugar information every five minutes. So those sensors help you see what

• 1:00:32Speaker 04

  your blood sugar is. We also have both injections for insulin and also insulin pumps. So the pump will deliver insulin at rates that you tell it to give you the insulin. But none of this is happening without a lot of thought. There's not like a machine that just takes care of it for you. A lot of people, when they see an insulin pump, imagine like, oh, that must be so nice that like, oh, this the AI is taking care of your blood sugar for you. And that's not the case at all. Insulin pumps just do what you tell them to do.

• 1:01:01Kelly Weinersmith?

  That is what I imagined. Thanks for clarifying that.

• 1:01:04Speaker 04

  Even my doctors, like if I go to the eye doctor, they're like, oh, must be so nice having your pump doing that for you. But I mean, no, the pump is not operating independently.

• 1:01:13Daniel Whiteson?

  And talk for a minute about why that's a hard problem. I mean, people might be thinking, well, you have a sensor that tells you how much glucose you have and you have insulin, which brings the glucose down. Why can't you just, you know, fit a straight line to that and decide how much insulin to have? Why do you need a human brain in the loop there? Or why is it a hard problem?

• 1:01:30Speaker 04

  There's a lot of reasons it's a hard problem. A big one is that the way that we're giving the insulin just subcutaneously means that it's slow. So, you know, when you eat, your pancreas is exactly in the right place at the right time, sensing the glucose as it's getting released from your digestion. So then not only do you get real time information, but you also have the insulin being delivered exactly where you need it. So when you take insulin subcutaneously, it takes like a good half an hour to dissolve and become active. I guess another really important thing to say is that The insulin's activity is affected by your own activity. So if you're exercising, the insulin that you're taking will do a lot more work.

• 1:02:15Speaker 04

  And your own pancreas has more than one hormone. It has insulin and also glucagon. So it's a two-component system. Insulin drives your blood sugar down. Glucagon drives your blood sugar up. So what glucagon does is it releases the glycogen stores in your liver and muscle to raise your blood sugar. So if this dangerous thing starts to happen that your in- insulin drives your blood sugar too low, then the glucagon can pick it up from the floor and save your life. So you don't die from low blood sugar. Our insulin pumps don't have glucagon in them. Glucagon is a really delicate hormone. There's about a hundred companies out there engineering more stable glucagon. Maybe we'll have that soon, but right now the pumps just have insulin.

• 1:02:57Speaker 04

  There is a company that's trying to make a two-component pump that also has glucagon. But anyway, that doesn't happen yet. So there's a number of reasons, like you could, in theory, use the glucose information, the old information you're getting from the sensor in your arm, and have that direct the dosing of the insulin from your pump. However, your pump doesn't know if you're about to go running, or if you are sick, or you know, the amount of insulin you need is affected by easily forty-two factors that most of them can't be measured. And so you need your brain to synthesize all those factors and think through the decision of how much insulin you need.

• 1:03:35Daniel Whiteson?

  And you don't trust ChatGPT to make those decisions for you yet?

• 1:03:37Speaker 04

  I mean, I wouldn't mind like chatting with ChatGPT about it and getting ideas, but I would definitely want to be the one who's the buck stops with me when it comes to that decision.

• 1:03:47Daniel Whiteson?

  All right. So then our last question is, what do you see happening in the future? Like in ten years, in fifty years, in a hundred years? What's going to change about our treatment of diabetes or our understanding of the biochemical processes?

• 1:03:59Speaker 04

  Well, there's biological and engineering fronts to talk about. And actually, I should make a really big shout out to the group of people who are engineering devices. There's even groups of people who have built algorithms that do take the information from the glucose sensors and use Use it to dose the insulin. Sometimes they're called loopers. They're closing the loop. Many of those algorithms are open source and people are having good results with better blood sugar control using those algorithms. It takes a really tech savvy person. And somebody who, you know, in my case, I go running every day. And I don't think those algorithms take exercise into account in a way that works for me. So that's why I personally am not using the looping algorithms.

• 1:04:44Speaker 04

  Although I'm interested, so if there's someone out there who's into looping, like my mind is open. So there are people making really big progress on the algorithms. I think those are going to be a really big frontier that our algorithms are going to get better and better. Some of the major insulin pump companies have soft versions of those algorithms with a lot of safety on them where they keep the average blood sugar values a little higher to give you a safety buffer. So that's starting to happen already. In fact, the pump I use has a soft algorithm like that, that especially for sleeping at night when there's not as many different changes going on, it can do a really good job of helping you keep your blood sugar in control. So that's already getting better. I'd say the engineering front will include

• 1:05:27Speaker 04

  better sensors, better algorithms. If we had glucagon, then that will also close the loop and help to make the measurements better. Overall, though, I mean, humans are really complex. Like, one of my favorite results recently showed how people eating exactly the same meal one week apart and wearing a continuous glucose monitor had different blood sugar responses to the same meal, which I think highlights the challenge of why it has to be pretty thoughtful. How you are dosing insulin, even for the same meal and the same person, you can't assume it's going to work the same way each time. But then on the biology front, there's also really big progress. So we have been learning how to direct the program of stem cells

• 1:06:11Speaker 04

  and differentiating them into different kinds of cells that we can use for different kinds of medicine. There's a whole arm of research towards building pancreatic beta cells, the ones that secrete insulin. So that they could be transplanted. The first versions of these have required people to take immunosuppressants, just like for a pancreas transplant. So it didn't feel as exciting to me. But that's actually starting to get better. And there are efforts towards making hypoimmune, so like not giving an immune response cells. So that people could get transplants with these kind of cells and not have to take immunosuppressants and potentially have them work to control their blood sugar.

• 1:06:57Speaker 04

  I don't know, it's interesting to me to imagine trusting a little renegade group of cells to do that. But you know, that will get tested and we'll know a lot more. Those are on the treatment front. There's another whole aspect to talk about, which is, you know, the way that type one diabetes develops, at least your immune system starts to attack your pancreas. This process can take a couple of years. A lot of people, when they're diagnosed, imagine that, you know, oh, I got a cold and then I got diabetes. Or I took finals and I was all stressed out and that caused my diabetes. But really it was just the straw that broke the camel's back. And this was a process that was going on for a couple of years. And then a stressful circumstance made you need more insulin. So then the system couldn't support you anymore.

• 1:07:39Speaker 04

  But now there's actually a treatment for people who are just starting to build the antibodies that are killing their pancreatic cells. And that treatment will basically target and slow down the immune process. It's called TZILD. And we actually have a friend whose son was caught early because he had a really savvy mom who understood what was going on. And she helped him get that treatment. And it's supposed to delay the onset of his type one diabetes for several years. So he's probably still on that path. But I could imagine us getting even better at that. And to be honest, the reason I became a microbiome scientist is that we know that the diagnosis of autoimmune diseases is becoming more and more frequent.

• 1:08:24Speaker 04

  Eczema, allergies, type one diabetes, a lot of autoimmune diseases are becoming more common. And we don't exactly know why. It's clearly a change in our immune development and the exposures we have in early life. And for example, most babies born in human history were breastfed and their guts became dominated by a bifidobacteria that's good at helping break down the breastmilk fibers.

• 1:08:51Speaker 04

  And that's now missing from most people in the industrialized world. So there are big studies right now to try to reintroduce that bifidobacteria and see if it helps us reduce our incidence of autoimmune diseases. So the easiest disease to study is eczema in some ways because it emerges within the first year or so of life. And there now are big studies using bifidobacteria to see if we can reduce those diseases. But there's also, right now, there's a big study in Europe across five countries with more than a thousand people who are from families who are a little bit more at risk for developing type one diabetes. And they're introducing that bifidobacteria. So it's going to take like probably 10 years until we have the beginnings of the answer because type one diabetes can happen in childhood or even adulthood.

• 1:09:36Speaker 04

  But we're gonna know if these changes in microbiome exposure that put us on a better immune development course could help to reduce the incidence of type one diabetes. So it might be akin to vaccination in the future that we intentionally develop our microbial exposures to direct the way our immune systems develop so we don't end up with all these autoimmune diseases.

• 1:10:02Daniel Whiteson?

  All right. Well, it sounds like a lot of potential progress in lots of different directions. I hope that young scientists out there are excited about working in all of these angles and taking big risks like Lydia did.

• 1:10:13Kelly Weinersmith?

  Yeah, thanks for being on the show, Katrina. That was awesome.

• 1:10:16Speaker 04

  Thank you.

• 1:10:17Daniel Whiteson?

  I'm going to nominate you for next year's White's End Research Award as well. Even though you've won it five years in a row.

• 1:10:22Speaker 04

  No, I'm going to nominate you.

• 1:10:23Daniel Whiteson?

  No, no. Well, I'm voting for you.

• 1:10:25Kelly Weinersmith?

  You two are too cute.

• 1:10:26Speaker 04

  I mean, I think it's amazing that our society has produced all this insulin to keep so many people with diabetes alive. And we could do better with the access, but I mean, considering that it's like water for so many people to depend on the insulin, it's kind of amazing that we've kept these systems going.

• 1:10:45Daniel Whiteson?

  All right. Well, thanks very much, Katrina, and thanks, everybody, for listening.

• 1:10:56Kelly Weinersmith?

  Daniel and Kelly's Extraordinary Universe is produced by iHeartRadio. We would love to hear from you.

• 1:11:01Daniel Whiteson?

  We really would. We want to know what questions you have about this extraordinary universe.

• 1:11:07Kelly Weinersmith?

  We want to know your thoughts on recent shows, suggestions for future shows. If you contact us, we will get back to you.

• 1:11:13Daniel Whiteson?

  We really mean it. We answer every message. Email us at questions at danielandkelly.org.

• 1:11:20Kelly Weinersmith?

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• 1:11:29Daniel Whiteson?

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