Speaker 1: We as humans were scared that we were going to
Speaker 1: unleash some kind of monster. What were the consequences of
Speaker 1: us genetically engineering things? I mean, more recently, we've had
Speaker 1: similar debates about crispers, And maybe you've heard that there
Speaker 1: was even a case where a Chinese scientist used crisper
Speaker 1: to genetically engineer a baby, a human that has really
Speaker 1: really big ethical questions, And this was happening only in bacteria,
Speaker 1: but it was the first time it had happened, and
Speaker 1: we were rightfully, really thinking carefully about what the consequences
Speaker 1: could be. For example, imagine you cloned a bacteria that
Speaker 1: contained genes that could break down petroleum, and then you
Speaker 1: unleashed that in an oil mining operation. You could really
Speaker 1: cause a lot of destruction. And what if that was
Speaker 1: just impossible to control and then you destroyed huge natural
Speaker 1: resources unintentionally intentionally for that matter. So those were the
Speaker 1: kinds of questions people were worried about.
Speaker 2: Or what if it helped the bactery organize and it
Speaker 2: crawled out of the vat and like extracted vengeance for
Speaker 2: all the brethren that we've tortured in order to extract
Speaker 2: incident from them.
Speaker 1: That's a great question, but I'm pretty sure about it.
Speaker 2: That's a very polite answer to a totally bonkers questionin
Speaker 2: you all should have seen her face.
Speaker 1: That didn't make it to the top ten list for
Speaker 1: discussion out of so lamar.
Speaker 3: Hi.
Speaker 2: I'm Daniel. I'm a particle physicist and a member of
Speaker 2: the White Senn Research Institute in Irvine, and today I'm
Speaker 2: going to be an extra big fan of biology.
Speaker 3: Hello, I'm Kelly Wiener Smith. Can I be like an
Speaker 3: adjunct at the White sin Research Institute?
Speaker 1: Like?
Speaker 3: Is that what friends are called?
Speaker 2: Come be a visiting professor? No problem? Yes, all right?
Speaker 3: Does that come with dinner?
Speaker 2: Dinner is a bonus? Yes? Plus you can add this
Speaker 2: as an extra affiliation on all of your papers to
Speaker 2: make you sound really.
Speaker 3: Smart, fantastic. I'm go to you. I'm gonna put it
Speaker 3: right on my CV. Have you ever done a show
Speaker 3: with your wife before?
Speaker 2: I have never done a podcast episode with Katrina, though
Speaker 2: I've had lots and lots of science conversations over the
Speaker 2: dinner table, so we definitely talked a lot about science
Speaker 2: and board our teenagers to death. But no, I don't
Speaker 2: think it's ever been recorded. So this is great for posterity.
Speaker 3: Well, and I'm excited because we have talked on the
Speaker 3: show often about how, you know, since she studies microbiome stuff,
Speaker 3: sometimes you find bags of poop in your freezer and
Speaker 3: stuff like that, and I feel like it's really important
Speaker 3: for people to like put a voice to those stories.
Speaker 3: And today that's gonna happen.
Speaker 2: You just want another poop in the freezer ally on
Speaker 2: the show to outvote me. That's what's going on here, really,
Speaker 2: I do.
Speaker 3: I want the gross votes to outnumber the people who
Speaker 3: are squeamish. And also I like, you know, pushing the
Speaker 3: envelope in the direction of gross so that I don't
Speaker 3: seem as gross, you know, Like, mostly I want Zach
Speaker 3: to realize how lucky he is. Yeah, that there's not
Speaker 3: bags of poop in the freezer like the dead bird.
Speaker 3: Not a big deal.
Speaker 2: All right, Well, welcome to the podcast where we pretend
Speaker 2: to be talking about science, but really we're doing marital therapy.
Speaker 3: Well, and on today's show, we're very lucky to have
Speaker 3: Katrina come on to talk to us about diabetes and
Speaker 3: the history of insulin production and the future of insulin production.
Speaker 3: And she was amazing. She had a lot of incredible insights.
Speaker 2: Yeah, I think a lot of people think they understand
Speaker 2: diabetes generally, but there's a lot of really fascinating biochemistry
Speaker 2: and a lot of nuance there, and a lot to
Speaker 2: understand about the daily life of somebody with diabetes. And
Speaker 2: it's kind of amazing that until about one hundred years ago,
Speaker 2: diabetes was a death sentence. You got diabetes and you
Speaker 2: were dead a couple years later. And now because of
Speaker 2: amazing biologists, we can save the lives of all those kids,
Speaker 2: and people like my wife can grow up and be
Speaker 2: like a professor and had kids and live a full life.
Speaker 2: It's really kind of an amazing testament to what science
Speaker 2: can do.
Speaker 3: And I'm not going to release any spoilers here, but
Speaker 3: there were at least two things she talked about where
Speaker 3: I was like, I thought I knew and I was
Speaker 3: totally wrong. And so I think we're gonna have a
Speaker 3: good episode of sort of dispelling rumors or myths about diabetes.
Speaker 2: All right, Well, then, without further ado, let's welcome my
Speaker 2: favorite scientist at the whites And Research Institute. So then
Speaker 2: today it's my great pleasure to welcome to the podcast.
Speaker 2: Co president of the White Sun Research Institute and winner
Speaker 2: of the whites In Research Prize as Professor Katrina whites
Speaker 2: In at uc Irvine Katriina, Welcome to the podcast.
Speaker 1: Thank you.
Speaker 3: I'm so excited you're here.
Speaker 1: I didn't even know about those awards, but I will.
Speaker 2: I guess I'll go update your CV right now.
Speaker 3: Update your tenure packet, all the things.
Speaker 2: Yeah, but we did just invite Chain onto the podcast
Speaker 2: to joke around with her. We invited her on because
Speaker 2: she's a deep expert in today's topic.
Speaker 3: So today we're talking about bioengineering bacteria, we're talking about diabetes,
Speaker 3: we're talking about lydia villa comarov and it's going to
Speaker 3: be an amazing conversation and we're super excited to have
Speaker 3: you here.
Speaker 1: Thank you.
Speaker 3: So by the end of the episode, we're going to
Speaker 3: get to bacteria producing pharmaceutical components. But let's start by
Speaker 3: talking about diabetes. What are the mechanisms underlying diabetes.
Speaker 1: Well, that's a really good question, and actually even just
Speaker 1: using the word diabetes already doesn't give you quite enough
Speaker 1: information to be able to answer that question, because there's
Speaker 1: two really different forms of diabetes. I guess we could
Speaker 1: go back to ancient times when the word first arose,
Speaker 1: and in that time we understood that sugar was involved
Speaker 1: and that not being able to process sugar was involved.
Speaker 1: We've actually known that for hundreds of years, so you
Speaker 1: could think of glucose as maybe the first biomarker. There
Speaker 1: were really interesting ways that people would detect that someone
Speaker 1: had diabetes. It's actually diabetes melitis, and the words mean
Speaker 1: that you're losing water due to sugar. And people would
Speaker 1: take urine and put it out to see if the
Speaker 1: ants were attracted to it. They would taste the urine
Speaker 1: to see if it was sweet, and that would give
Speaker 1: them a clue that you had this wasting disease where
Speaker 1: your body couldn't process sugar. And like, probably the first
Speaker 1: thing that pops into mind when you think of diabetes
Speaker 1: in modern times is it's associated with obesity, But actually
Speaker 1: diabetes is a wasting disease. It means that you can't
Speaker 1: get energy from sugar and you actually starve to death
Speaker 1: while drowning with lots of sugar in your blood. So
Speaker 1: I think that's just actually really amazing and usually counterintuitive.
Speaker 1: When I'm teaching, I sometimes show images of the children
Speaker 1: who would die from diabetes before the insulin was discovered,
Speaker 1: and they are emaciated because they're unable to get any
Speaker 1: energy from the sugar that they're eating. So to back up,
Speaker 1: I mean, there's two main kinds of diabetes. The first one,
Speaker 1: type one diabetes for a while even called juvenile diabetes,
Speaker 1: is when your immune system kills the cells in your
Speaker 1: pancreas that make insulin, so you're no longer able to
Speaker 1: access sugar. So you eat sugar. It gets into your blood,
Speaker 1: but the key that allows the sugar to be used
Speaker 1: by your cells is just totally missing.
Speaker 2: And so you're saying, insulin is that key. Insulin is
Speaker 2: a thing that takes sugar from your blood and into
Speaker 2: your cells exactly.
Speaker 1: Insulin is a protein like ham, but it's acting like
Speaker 1: a little it's a little robot. It's a little key
Speaker 1: that actually summons the transporters that help glucose get into
Speaker 1: your cell up to the surface and then the gates
Speaker 1: open and the sugar can get into the cells. Without that,
Speaker 1: the sugar just sits in your blood and the cells starve.
Speaker 3: Is there a toxic effect of the sugar building up
Speaker 3: as well? Or is it just that you're starving? Is
Speaker 3: the main problem the long term?
Speaker 1: The sugar in your blood is super toxic. But those
Speaker 1: are kind of like decade long problems. So if you're
Speaker 1: dealing with starving in the course of weeks or months,
Speaker 1: then the decade long problem of too much sugar in
Speaker 1: your blood is just not something to worry about. But yes, hope,
Speaker 1: too much sugar in your blood is definitely toxic. And
Speaker 1: I think that's the part that's more famous about diabetes
Speaker 1: right now, because most diabetes in our time, ninety percent
Speaker 1: of diabetes is what we called type two diabetes, and
Speaker 1: it can be lifestyle associated, but amazingly, it's actually more genetic.
Speaker 1: It's more inherited to get type two diabetes. So about
Speaker 1: ninety percent of the diabetes in the world right now
Speaker 1: emerges usually later in life, and it's not because you
Speaker 1: don't have insulin. You could actually have plenty of insulin,
Speaker 1: it's just not working very well, so your body is
Speaker 1: resistant to the use of the insulin. That's associated with
Speaker 1: metabolic syndrome, but actually can be quite genetic. You can
Speaker 1: be a very healthy, thin looking person and still get
Speaker 1: type two diabetes. So that's also a bit of a
Speaker 1: misnomertis always assume it's associated with lifestyle, but in the
Speaker 1: case of type two diabetes, if it is arising because
Speaker 1: of obesity, you can reverse it if you eat less carbs,
Speaker 1: exercise more, and in general it don't overload the system
Speaker 1: that depends on insulin. You can resensitize your body to
Speaker 1: the insulin that it can make, and you can also
Speaker 1: take medicines that make the insulin more effective.
Speaker 2: All right, so let me recap for the non biologists.
Speaker 2: You eat a ham sandwich, your body turns some of
Speaker 2: that into sugar, puts it into your blood, but then
Speaker 2: your cells and your body, like your muscles, can't access
Speaker 2: it from your blood without insulin, this thing that takes
Speaker 2: it from the blood into the cells. And type one
Speaker 2: diabetes is when your body kills the cells to produce insulin,
Speaker 2: so you just don't have it. Type two is when
Speaker 2: you still have insulin, but because of some metabolic things,
Speaker 2: it's not working as well, or it's just not.
Speaker 1: As effective, or you just don't have enough. Yeah, that's
Speaker 1: about right. There's a lot of nuances you will not
Speaker 1: be surprised to hear. For example, your brain, which uses
Speaker 1: about twenty percent of the glucus in your body, doesn't
Speaker 1: really depend on insulin in the same way. So I
Speaker 1: find that kind of amazing that your brain is just
Speaker 1: like this constant machine that's using a lot of the
Speaker 1: sugar in your blood. It's like the main reason it's
Speaker 1: so important that our blod glucose levels are maintained at
Speaker 1: a certain level, otherwise your brain doesn't function. So that's
Speaker 1: kind of independent of the insulin. And then there's other
Speaker 1: really cool exceptions, like your muscles, especially during exercise, they're
Speaker 1: extra sensitive to being able to get glucose in. So
Speaker 1: there are extreme examples, Like there's a story about a
Speaker 1: guy one hundred years ago before there was really insulin,
Speaker 1: who kept himself alive with like a really crazy exercise
Speaker 1: regiment and he had like amazing muscle mass and he
Speaker 1: kind of like extended his capacity to metabolize his diet
Speaker 1: even though he didn't have much insulin. So it's kind
Speaker 1: of interesting we didn't do more of that, but on average, yeah,
Speaker 1: without insulin, your blood will be full of sugar and
Speaker 1: your cells will be starving. And if you look at
Speaker 1: a picture of a kid who died from type one
Speaker 1: diabetes before nineteen twenty one, when insulin was discovered, they
Speaker 1: look emaciated, which is just terrible so.
Speaker 2: You're starving, but your blood is filled with sugar and
Speaker 2: your pea is filled with sugar. You just don't have
Speaker 2: access to it. So it's like being hungry at a buffet.
Speaker 2: It's crazy.
Speaker 1: Yeah, exactly.
Speaker 3: Do you know this story of how we discovered insulin.
Speaker 1: Yeah, I mean, there's actually a lot of really good
Speaker 1: stories around that. It was a slow process like science
Speaker 1: often is, because we got a lot of important clues
Speaker 1: even maybe half a century before the discovery of insulin,
Speaker 1: Like we knew for a long time, hundreds of years
Speaker 1: that it was related to glucose. So then by the
Speaker 1: eighteen eighties in Germany, there were scientists who figured out
Speaker 1: that if you removed the pancreas from a dog, it
Speaker 1: would cause essentially the symptoms of diabetes.
Speaker 2: What were they doing. Were they just like taking random
Speaker 2: organs out of dogs one at a time to see
Speaker 2: what happens, Like, let's see what happens that dogs don't
Speaker 2: have a heart. Oh that didn't work very well.
Speaker 1: Yeah, I guess that's not diabetes related. Good question. I mean,
Speaker 1: you know it could be that like some unlucky dog
Speaker 1: got kicked by a cow or hit by There weren't
Speaker 1: cars in those days, but hit by a horse.
Speaker 3: I guess we did do some pretty awful things to
Speaker 3: animals in the past. It wouldn't surprise me if there
Speaker 3: were a series of experiments we were like, how do
Speaker 3: they do without this? How about without that?
Speaker 2: In the past, biologists are still doing horrible things to animals,
Speaker 2: and the name of science.
Speaker 3: We have to go through complicated protocols and institutions and
Speaker 3: prove that those animals are needed for scientific discovery these days.
Speaker 3: But that could be a whole different episode.
Speaker 2: Unless you want to do experiments on your own children,
Speaker 2: in which case you don't have to ask an IRB,
Speaker 2: but you should ask your husband.
Speaker 1: But if you're the parent, you could also ask yourself,
Speaker 1: especially if it's like something very low risk. This is
Speaker 1: a case where I could try to look up the
Speaker 1: eighteen eighty nine story that I have in my brain
Speaker 1: about the pancreas. But anyway, somehow they realized that there
Speaker 1: was a connection between pancreas being missing and diabetes. So
Speaker 1: then that sounds like the kind of thing where it
Speaker 1: shouldn't have taken more than a couple of months to
Speaker 1: go from knowing it was the pancreas to extracting insulin
Speaker 1: from the pancreas so that you could save all these
Speaker 1: kids who were dying from diabetes. But it wasn't until
Speaker 1: nineteen twenty one, twenty two that we finally extracted insulin
Speaker 1: from the pancreas. A lot of that time went to
Speaker 1: figuring out how to purify the insulin protein away from
Speaker 1: all the other digestive enzymes and proteins that are also
Speaker 1: produced by the pancreas. So you know, your pancreas is
Speaker 1: this organ that's there to help you digest stuff. One
Speaker 1: of its main jobs is to produce proteins that break
Speaker 1: down our food, and those are also made of protein.
Speaker 1: So basically the pancreas is full of stuff that destroys insulin,
Speaker 1: since insulin is also a protein, so like separating those
Speaker 1: things away from each other. It took forty years or
Speaker 1: thirty years. That's a really hard thing to do. Now,
Speaker 1: that's the kind of thing we're really good at, but
Speaker 1: in those days we had to invent a bunch of
Speaker 1: techniques to get good at that.
Speaker 2: It's amazing to me how recently we have like any
Speaker 2: idea what big organs in our body do. Like before that,
Speaker 2: we're just like we don't know this is just a
Speaker 2: blob of meat like stuff that seems to be important.
Speaker 1: What I think is amazing is that when we don't
Speaker 1: know what something does, we assume it's irrelevant. So like
Speaker 1: we're always saying that the spleen and the appendix, for example,
Speaker 1: serve no purpose. You know, you listen to them telling
Speaker 1: you in the hospital when you're getting your appendix out, like, hey,
Speaker 1: you don't need this, It'll be no big deal. I
Speaker 1: find that really funny that when we don't understand something,
Speaker 1: we just say it's irrelevant. Like that is definitely not true.
Speaker 1: In the case of the appendix, having your appendix there
Speaker 1: as a reservoir for gut bacteria is like the difference
Speaker 1: between life and death. To be able to recede your
Speaker 1: gut microbiome and be protected from infection in the future.
Speaker 1: That was like clearly important enough that we developed an
Speaker 1: organ and hung onto it, you know, and.
Speaker 3: The evidence for that is really good now, right, that
Speaker 3: that is the appendix's role to hold onto those bacteria.
Speaker 1: I mean, it's a hypothesis that's hard to prove, right
Speaker 1: because it's very context dependent. But if you think about
Speaker 1: the context of human history, that seems like a very
Speaker 1: relevant context.
Speaker 2: It's biology. So the answer is it depends.
Speaker 3: It's true. It's true. So they opened up the pancreas,
Speaker 3: they've been able to divide out the different proteins that
Speaker 3: are in there. How do you get from art I've
Speaker 3: divided out the proteins to actually treating the disease. Was
Speaker 3: that a pretty easy step?
Speaker 1: That's a real cool question. And this all happened at
Speaker 1: a university. It was at the University of Toronto, and
Speaker 1: there was a medical student there that summer, Best, and
Speaker 1: he was working with a lab supervisor, Banting. So Banting
Speaker 1: and Best are the famous team who discovered insulin that
Speaker 1: summer in Toronto. The second they had it purified out,
Speaker 1: they started treating a dog who had had their pancreas
Speaker 1: taken out, and they were able to keep a dog
Speaker 1: alive for a couple of months using the dog insulin extract,
Speaker 1: which was pretty crude. In the meantime, they also worked
Speaker 1: on better purifying insulin from cows and that's when they
Speaker 1: started considering using it to treat a child. And they
Speaker 1: actually moved to this really quickly.
Speaker 3: Interesting.
Speaker 1: I would say that would still happen today because it
Speaker 1: would definitely be a life or death circumstance. We still
Speaker 1: have these compassionate use exemptions from the FDA, the Food
Speaker 1: and Drug Administration. In fact, I use those for our
Speaker 1: phage therapy trials, where if somebody has no other options,
Speaker 1: we'll allow you to do with something more experimental. But
Speaker 1: that means that this like lab guy, a med student
Speaker 1: who was certainly not a professional at making medicines, was
Speaker 1: just taking this extract they made in the lab. And
Speaker 1: the first boy they treated was a Canadian boy at
Speaker 1: the hospital at the University of Toronto. He was fourteen
Speaker 1: and he was wasting away because he didn't have any insulin,
Speaker 1: and he went from being very very ill with very
Speaker 1: high blood sugar to doing much better, like within hours,
Speaker 1: and then really soon after that. There's an image that
Speaker 1: I think is super iconic to anybody who knows about
Speaker 1: the discovery of insulin, and it's an image of a
Speaker 1: nurse with a cart and maybe a doctor next to them,
Speaker 1: and the story goes that they went into this ward
Speaker 1: of the hospital that had thirty comatose children with type
Speaker 1: one diabetes, and the parents were there, and then they
Speaker 1: injected this very experimental cocktail they had made in the
Speaker 1: lab into those thirty kids and they all woke up,
Speaker 1: and you know, that was a really big moment in
Speaker 1: science and must have been amazing for the parents who
Speaker 1: really had no reason to hope their kids had any
Speaker 1: chance of getting better.
Speaker 2: I mean, if your kid is wasting away and the
Speaker 2: doctor says, hey, we're going to inject this experimental dog
Speaker 2: organ juice into your kid, you might just be like, yes,
Speaker 2: do anything please?
Speaker 1: Right? Yeah, exactly.
Speaker 2: But how did we know that dog pancreas would produce
Speaker 2: dog insulin which humans could use. Isn't it possibility that
Speaker 2: like dog insulin could be different from human insulin.
Speaker 1: Yeah, that's a really good point. I mean, I guess
Speaker 1: we tried it and learned in the moment that first
Speaker 1: fourteen year old was injected with insulin, we figured that out.
Speaker 1: And we now know that the insulins across animals have
Speaker 1: really shared features. So you know, animals that have guts
Speaker 1: also have insulin basically, so insulin is very conserved. This system,
Speaker 1: which might seem quite delicate, is being used across the
Speaker 1: animal kingdom, and in general, the insulins are pretty exchangeable, so.
Speaker 2: You could like extract insulin from a hummingbird and use
Speaker 2: it on a person.
Speaker 1: Well, hummingbird. Wow, you'd need a lot of hummingbirds. That's
Speaker 1: a good question, but yeah, I think so. There was
Speaker 1: actually a Czech couple, Eva and Victor Saxel, who fled
Speaker 1: Nazi occupied Czechoslovakia in nineteen forty. She was teaching English
Speaker 1: in Shanghai when her symptoms of diabetes developed when she
Speaker 1: was around nineteen or twenty years old. By then, highly
Speaker 1: purified insulin from cows was available in the pharmacies of Shanghai,
Speaker 1: and people were living pretty healthy lives in the nineteen
Speaker 1: forties when they had access to insulin. But then when
Speaker 1: the Japanese occupied, those pharmacies shut down and Eva was
Speaker 1: in a really tough spot. How was she going to
Speaker 1: survive without access to insulin from pharmacies. And so this
Speaker 1: is really an amazing tale of survival because Eva and
Speaker 1: Victor they actually figured out they got their hands on
Speaker 1: a book showing the method that Banting and Best had
Speaker 1: developed for purifying insulin out of the pancreas. They didn't
Speaker 1: have dogs or cows, but they figured out that they could.
Speaker 1: They were knitting socks and selling them to get money
Speaker 1: to buy water buffalo pancreases, and first they figured out
Speaker 1: how to get the water buffalo insulin for Eva, but
Speaker 1: they actually made enough to sustain hundreds of people with
Speaker 1: diabetes in the ghetto of Shanghai. So hundreds of people
Speaker 1: survived for the years of World War two depending on
Speaker 1: the insulin that Eva and her husband were purifying out
Speaker 1: of the water buffalo pancreas. It's really amazing.
Speaker 3: Oh that's interesting.
Speaker 1: There's another story like that in Chile of a husband
Speaker 1: who learned how to extract insulin from any kind of animal,
Speaker 1: and he was helping his wife survive. And I think
Speaker 1: the issue actually was that she would develop immunity to
Speaker 1: one kind of insulin, and not because of the insulin itself,
Speaker 1: but the extract is never pure, so she basically would
Speaker 1: develop allergies to the extract. So then he would move
Speaker 1: on to another kind of animal. And I think she
Speaker 1: didn't have access to pharmaceutical grade insulin, so he was
Speaker 1: helping her survive that way.
Speaker 2: Because insulin doesn't cure diabetes, right, it just helps get
Speaker 2: the sugar across the cells. Right now, you need a
Speaker 2: constant supply of insulin, right, Like, how long will the
Speaker 2: type one diabetic live if insulin supply just gets shut off.
Speaker 1: Yeah, just a couple days, And so you hear those
Speaker 1: stories about the kids wasting away over the course of
Speaker 1: a year or two. And that's at the beginning of
Speaker 1: the disease when they still make some insulin. But somebody
Speaker 1: who has developed long term type one diabetes and has
Speaker 1: been dependent on insulin for a long time, they literally
Speaker 1: have no insulin. And then it's not actually a matter
Speaker 1: of starvation, like you wouldn't live long enough to starve
Speaker 1: with type one diabetis and no insulin, because your blood
Speaker 1: sugar would go very high. And then you go into
Speaker 1: a state that's called ketosis, where your body starts producing
Speaker 1: key tones, basically wasting away your muscles to get energy,
Speaker 1: and that process produces a lot of acid, and you
Speaker 1: basically die from the acid in your blood. It's like
Speaker 1: when you hit the wall in a marathon and you
Speaker 1: don't have any more glucose from your liver and muscles.
Speaker 1: Your liver and muscles have glycogen stores, and so then
Speaker 1: your body turns to breaking down the protein of your
Speaker 1: muscles to get energy, and that process produces keytnes, which
Speaker 1: are acidic, and then you die from the acid in
Speaker 1: your blood.
Speaker 2: So we can survive if we extract insulin from these
Speaker 2: poor animals. But that's a destructive process, right You can't
Speaker 2: extract insulin from a dog without killing the dog, or
Speaker 2: can you?
Speaker 1: The way it's done, as far as I know, has
Speaker 1: always been destructive. And so I mean, this could lead
Speaker 1: us to another interesting conversation about like, well, okay, we
Speaker 1: made this discovery, so then how did we actually produce
Speaker 1: enough insulin to keep the diabetics of the world alive
Speaker 1: who need it every couple hours, you know, not just days.
Speaker 3: And that seems like a great topic to ponder, And
Speaker 3: we'll return to it after the break and we're back.
Speaker 3: And so we had just finished discussing how it had
Speaker 3: been figured out how you can extract the insulin protein
Speaker 3: from deceased animals, and now we're talking about starting to
Speaker 3: scale up so that we can provide this in an
Speaker 3: industrial sort of way.
Speaker 2: I have another question before we talk about industrial production
Speaker 2: of insulin, which is a naive question, like if it's
Speaker 2: about the pancreas producing insulin and your pancreas is not
Speaker 2: making one, why can't you do a pancreas transplant, like
Speaker 2: we can do a heart transplant or a kidney transplant
Speaker 2: or other kinds of transplants. And why can't I just
Speaker 2: get the pancreas from a human corpse and put it
Speaker 2: into a diabetic and cure their diabetes.
Speaker 1: You can do that actually, and you know, Canada has
Speaker 1: been so important in all these diabetes developments and the
Speaker 1: Edmonton Protocol was developed also in Canada. Point is, yes,
Speaker 1: you can transplant a pancreas into a person, but then
Speaker 1: you have to give them immunosuppressants. In order to survive
Speaker 1: after an organ transplant, you have to take immunosuppressive drugs,
Speaker 1: which mean that your risk of cancer and infectious disease
Speaker 1: become very high. So to do that to a young
Speaker 1: person who otherwise has a healthy life expectancy is dooming
Speaker 1: them to a less healthy and shorter life.
Speaker 3: I assume who would you do that for.
Speaker 1: Then there's one context where it happens a lot, which
Speaker 1: is really cool, which is if you have kidney failure,
Speaker 1: which is also more common in people with diabetes, and
Speaker 1: doing a kidney transplant, you can do a tandem transplant
Speaker 1: of kidney and pancreas, and you have to take the
Speaker 1: immunister presence anyway for the kidney transplant, so then you
Speaker 1: get a bonus of no longer being diabetic, which is
Speaker 1: great because it also protects the kidney. So that's a
Speaker 1: really cool procedure, which is pretty common that people get
Speaker 1: a kidney and a pancreas transplant together.
Speaker 2: All right, So if you don't get a pancreas transplant,
Speaker 2: you need your steady supply of insulin. And we were saying,
Speaker 2: we don't want to just keep killing dogs in order
Speaker 2: to in order to extract the insulin from their pancreas,
Speaker 2: or rats of China or whatever, So then tell us
Speaker 2: about how we produce insulin without killing all of our
Speaker 2: furry friends.
Speaker 1: Well, for many years between around nineteen twenty something and
Speaker 1: the nineteen eighties, we relied on animals that we produce
Speaker 1: for food, so cows and pigs were our main source
Speaker 1: of insulin for all those years, and so that scaled up.
Speaker 1: In the nineteen twenties. There were two main companies that emerged,
Speaker 1: and there's lots of stories about how the patents all
Speaker 1: worked out, but basically Eli Lilly in Indiana became the
Speaker 1: US leader in producing insulin, and Novo Nordisk in Denmark
Speaker 1: became the European leader and making insulin. Currently there's a
Speaker 1: third producer, so Nofi, they're French. Ninety percent of the
Speaker 1: insulin in the world is still produced by those three companies.
Speaker 1: And initially all their insulin was coming from animals, and
Speaker 1: so you would get pig pancreas or cow pancreas from butchers.
Speaker 1: It became a very refined process, and I think it
Speaker 1: took you know, a crazy amount of pig pancreas. I mean,
Speaker 1: you know, it was like a thousand pounds of pancreas
Speaker 1: would would lead to one pound of insulin being produced.
Speaker 1: It took a lot of purification and so and we
Speaker 1: kept that going, and this supply was quite widespread and
Speaker 1: a lot of people's lives were sustained with that insulin.
Speaker 1: I don't think we could have kept scaling up. So
Speaker 1: it's very good we had an early and amazing advance
Speaker 1: and changing how we produced insulin around the eighties. But yeah,
Speaker 1: for all those years we were collecting pigs and cow
Speaker 1: pancreas from butcher an extracting insulin from there. And actually
Speaker 1: we know a few people like Daniel, our friend Mones.
Speaker 1: His mom she worked at Nova NOORDESK and she was
Speaker 1: one of the people who developed those procedures, or at
Speaker 1: least she was involved, I know in extracting insulin from pigs.
Speaker 1: A lot of people were involved in making that happen.
Speaker 2: I wonder if that was complicated for some folks, like
Speaker 2: people who were vegetarians but diabet and then they had
Speaker 2: to essentially use this animal product. Or what if you
Speaker 2: were like Hindu and didn't want to use cow insulin,
Speaker 2: or your Muslim and you didn't want to use pig insulin. Yeah,
Speaker 2: could people like choose which animal it came from.
Speaker 1: Yeah? I never had to use animal insulin myself, so
Speaker 1: I don't know, but yes, I think you could choose
Speaker 1: which animal source it came from. That was part of
Speaker 1: the what you knew about the product. That's one very
Speaker 1: big issue. Another big issue is that people would typically
Speaker 1: develop sensitivities or allergies to it over time, and then
Speaker 1: it would be less effective. It was a solution in
Speaker 1: many ways, and there are people who lived for decades
Speaker 1: taking and cow insulin, but it wasn't as easy to
Speaker 1: keep that going your whole life because a lot of
Speaker 1: people developed sensitivities like allergies, you mean.
Speaker 2: Like your immune system is responding because it's like, hey,
Speaker 2: this is a cow product, not something from inside the body.
Speaker 1: Yeah, I don't even think it was the insulin itself.
Speaker 1: And despite all the purification I just talked about, I
Speaker 1: think it was hard to remove everything allergenic about it,
Speaker 1: so then you would develop immunity.
Speaker 3: Were there any concerns about diseases passing from pigs and
Speaker 3: cows to people or the purification process or to cleared
Speaker 3: that out.
Speaker 1: That's a really cool question, and there were actually concerns.
Speaker 1: I don't think we even knew about it at the time,
Speaker 1: but now there's a lot of concern about preon diseases,
Speaker 1: and so actually diabetics are sometimes excluded from blood donation
Speaker 1: and other kind of organ transplant because of concern for
Speaker 1: preon diseases, especially coming from cows. So yeah, people who
Speaker 1: have been having a lot of animal products like that,
Speaker 1: in theory could have been exposed to preon diseases, which
Speaker 1: I think were less and at that time, also because
Speaker 1: of agricultural practices, like I think preon diseases became more
Speaker 1: common towards the end of the twentieth century because we
Speaker 1: were doing all this like feed animal waste, like chopped
Speaker 1: up animal bits to the animals themselves, and that would
Speaker 1: kind of concentrate the chances of preon diseases developing. And
Speaker 1: that's better now. We know not to do that now.
Speaker 3: And so you indicated in the nineteen eighties something changed.
Speaker 3: What was the thing that changed.
Speaker 1: Well, it's so amazing to me that this happened as
Speaker 1: early as it did in the eighties. But we actually
Speaker 1: figured out how to produce human insulin by fermenting it
Speaker 1: in bacteria and sometimes yeast by the early eighties, and
Speaker 1: so this was connected to the first genetically engineered organisms.
Speaker 1: In the fifties and sixties, we made the discovery of DNA.
Speaker 1: We understood the central dogma that DNA was the storage
Speaker 1: material of biology and that it was a blueprint for
Speaker 1: producing RNA and then protein insulin is a protein. You know,
Speaker 1: it was only a decade or maybe twenty years after
Speaker 1: we understood that that we were really making use of
Speaker 1: that information, which I think is really cool. So by
Speaker 1: the seventies, the hotbed of a lot of this activity
Speaker 1: was California and also Boston. People were starting to clone
Speaker 1: and like they were starting to be able to, like,
Speaker 1: you know, use little molecular scissors to chop out a
Speaker 1: piece of DNA from a bacteria and replace it with
Speaker 1: another piece of DNA that encoded something you were interested in.
Speaker 1: And so it's kind of interesting to me to think
Speaker 1: about how these molecular biologists who were more like theoreticians
Speaker 1: about the biology almost these weren't like doctors who were
Speaker 1: thinking about solutions so much. But they're like, Hey, I
Speaker 1: wonder what a good important protein to try to clone
Speaker 1: would be. And they're like, hey, insulin. A lot of
Speaker 1: people need that. Let's try that. And so one of
Speaker 1: the first things that was involved in these early cloning
Speaker 1: projects just to demonstrate, like, hey, can we clone stuff
Speaker 1: in bacteria was insulin and so in the seven we
Speaker 1: started to do that kind of cloning. And then around
Speaker 1: the mid seventies there was this moment where everyone realized, like,
Speaker 1: oh my god, what are we doing. If I, like
Speaker 1: complete these experiments, have I just created something that could
Speaker 1: go on and replicate and cause a lot of destruction.
Speaker 1: And so there was actually a meeting in a Sillamart, California.
Speaker 1: I think it was around nineteen seventy seven. We all
Speaker 1: know this meeting, the Silamar meeting about the safety of
Speaker 1: genetic engineering basically, and maybe one hundred and fifty people
Speaker 1: were there, mostly scientists, but politicians too, and they had
Speaker 1: a real look in the mirror, like what are we
Speaker 1: doing and is this safe? And everybody halted their work
Speaker 1: until the meeting so that we could decide what to do.
Speaker 1: And during that meeting there were a lot of discussion
Speaker 1: about whether it was okay, and in the end there
Speaker 1: were rules around what you were allowed to do, but
Speaker 1: it was decided that you could indeed proceed with cloning,
Speaker 1: especially under controlled circumstances. So the project for cloning insulin
Speaker 1: was one of the ones that halted until after that meeting,
Speaker 1: and then once the decision was made that it was
Speaker 1: okay to proceed, then the scientists continued with their cloning projects.
Speaker 1: And so I think it was about around nineteen seventy eight,
Speaker 1: which is also the year I was born, that the
Speaker 1: first insulin cloning project was completed.
Speaker 3: So when I hear the word clone, I think of
Speaker 3: like copying and pasting and organism.
Speaker 1: Mm hmm.
Speaker 3: Is it you're essentially copying and pasting bacteria that now
Speaker 3: have the human insulin gene. Is that the right way
Speaker 3: to think about it?
Speaker 1: Yeah, exactly, So the human insulin gene was copied and
Speaker 1: pasted into a bacteria, and then they asked the bacterial
Speaker 1: cell to grow and produce the insulin. Now, I just
Speaker 1: made it sound really simple like there was just only
Speaker 1: one thing that had to be copied in But to
Speaker 1: be honest, a lot of genetic engineering had to happen
Speaker 1: so that the insulin could be produced. They had to
Speaker 1: make sure that all the ingredients were there, that it
Speaker 1: was in a spot that the bacterial sell again its
Speaker 1: own needs, was producing this protein. You know, it's not
Speaker 1: like the bacteria needed the insulin, So they had to
Speaker 1: kind of rewire some of the metabolic pathways to force
Speaker 1: that to happen. So, to be honest, it was a
Speaker 1: combination of real savvy and luck that insulin could be
Speaker 1: produced that way. A lot of bacteria don't have the
Speaker 1: right tools for making other kinds of modifications to proteins
Speaker 1: that are common in eukaryotic cells, and so the fact
Speaker 1: that they could do that a little bit was luck.
Speaker 1: And when we look back at which bacteria were initially
Speaker 1: chosen for some of these cloning projects, they were just random,
Speaker 1: Like the most common Ecoli, the kind of bacteria this
Speaker 1: was done and is called ecoli assure Shia coli. And
Speaker 1: there's this really famous strain of E. Coli ecol I
Speaker 1: K twelve that was the one that was used in
Speaker 1: this project. And E. Coli K twelve was isolated from
Speaker 1: a Stanford patient who had some kind of infectious disease.
Speaker 1: I think diphtheria just randomly taken from this person's gut,
Speaker 1: and then it happened to have properties that were good
Speaker 1: for cloning. Like I have equal IK twelve in my lab.
Speaker 1: All biologists no equal IK twelve, but it's just like
Speaker 1: a random Standford patient from the nineteen twenties ecoli.
Speaker 2: I have some basic questions about how this works, like
Speaker 2: why are we using bacteria? Is it just like the
Speaker 2: simplest unit that we think we could still genetically engineer.
Speaker 2: Why can't we genetically engineer dogs to make human insulin?
Speaker 1: I mean, I think we were using bacteria thinking that
Speaker 1: that would be a really great way to scale up
Speaker 1: and not have a combination of ethics and safety and
Speaker 1: just production. How great is it if the same way
Speaker 1: you brew beer you can brew insulin. You know, that
Speaker 1: was the thinking. We're good at producing things with bacteria.
Speaker 1: Yogurt beer beer is mostly yeast, but still bread. We
Speaker 1: have microbial fermentation for food production really down, So the
Speaker 1: idea was to pivot that towards making medicines.
Speaker 2: I see, so bacteria can't make cute puppy eyes, care
Speaker 2: about growing them up and slaughtering them all for our.
Speaker 1: Insulin, sure, I mean that's one way of looking at it.
Speaker 1: But also just from a purely energy climate and finance perspective,
Speaker 1: bacteria are very efficient, so you know it's going to
Speaker 1: be quick and.
Speaker 3: Much more short generation times.
Speaker 1: Yes, exactly, E Coli double in twenty minutes. I still
Speaker 1: think that a batch of insulin is not an overnight process,
Speaker 1: like I think even in modern insulin production factories it
Speaker 1: probably takes like a month or two to go from
Speaker 1: the overnight culture of the bacteria producing the insulin to
Speaker 1: like all of the different processing steps. Insulin is a
Speaker 1: really complicated protein because it's so you know, powerful, which
Speaker 1: you know, with great power comes great responsibility. Too much
Speaker 1: insulin can very quickly kill you in our own bodies.
Speaker 1: Our insulin is produced in an inactive form, and it
Speaker 1: has to be cleaved to become active. And so the
Speaker 1: insulin that's produced in the bacteria initially also is in
Speaker 1: that inactive form, and then all that processing that would
Speaker 1: normally happen in someone's body has to happen in the
Speaker 1: factory so that the form that you inject is already active.
Speaker 1: So there's a lot of complex steps there. And if
Speaker 1: you were to try to take it out of puppies,
Speaker 1: I think that would be way less effective. I mean,
Speaker 1: the number of cows we needed to produce enough insulin
Speaker 1: to support humanity was becoming untenable. Like there weren't enough
Speaker 1: cows to make all the insulin, even though we have
Speaker 1: a crazy appetite for meat and beef, but we still
Speaker 1: couldn't probably sustain all the diabetics who needed insulin.
Speaker 2: And why do we need to build this in a
Speaker 2: life form anyway? Like we know how to do chemistry,
Speaker 2: I mean I don't, but some people do. Why can't
Speaker 2: you just like stick the atoms together and build this
Speaker 2: thing out of little lego pieces, you know, synthesize the
Speaker 2: thing in the lab.
Speaker 1: Yeah, I like that idea. And there is a thing
Speaker 1: called cell free extract production that people sometimes use these days.
Speaker 1: I think it just is convenient and handy that these
Speaker 1: bacteria in a way are great little factories. They already
Speaker 1: know how to make copies of themselves. So I think
Speaker 1: from an efficiency perspective, I mean, how great is it
Speaker 1: that the bacteria you just give them a little glucose
Speaker 1: and they go figure all that stuff out for themselves.
Speaker 1: Otherwise you'd have to manufacture thousands and thousands of different
Speaker 1: components that the bacteria otherwise just build for themselves, and.
Speaker 2: They're self replicating, which is much more than our grad
Speaker 2: students can do.
Speaker 1: I mean, to be honest, to the way we produce
Speaker 1: a lot of the things you might consider putting into
Speaker 1: a sell free artificial manufacturing process, we'd probably get them
Speaker 1: from microbial production to a lot of the things that
Speaker 1: we produce that way we do with the help of microps.
Speaker 2: Like cheese. I don't think I want to eat lab
Speaker 2: synthesized cheese either. We actually have a friend who was
Speaker 2: working on plant free food and he give us a
Speaker 2: taste from like chemically synthesized butter, and it wasn't good. No,
Speaker 2: I didn't like it. No mascrecy, but it wasn't better.
Speaker 2: But what I have one more question, simple, which is
Speaker 2: you talk about inserting these genes into the bacteria to
Speaker 2: make it do its thing, which makes it feel like
Speaker 2: the bacteria is some sort of computer and you're just
Speaker 2: like changing the program and you're like, hey, can you
Speaker 2: make this instead of that? Is it as simple as that?
Speaker 2: Can you go a little bit into the detail of
Speaker 2: like how do we know how to write this code?
Speaker 2: And then how do we take the code and actually
Speaker 2: put it into the genome? Right, it's not as simple
Speaker 2: as like logging into the bacteria and editing the files.
Speaker 2: You need to actually like put it into the DNA.
Speaker 2: How do we know how to do any of that?
Speaker 1: Yeah? What a good question. I'm not sure I know
Speaker 1: all the answers, but I can tell you that one
Speaker 1: of the first proteins that we ever even figured out
Speaker 1: what the sequence of it was was insulin. And so
Speaker 1: that's at the protein level, like the sequence of amino
Speaker 1: acids that you need to make insulin, that's what makes
Speaker 1: insulin insulin. From there, the protein sequence could have lots
Speaker 1: of different DNA sequences that lead to the same protein
Speaker 1: sequence because we have redund and see in the genetic code.
Speaker 1: So usually you have three nucleotide bases encoding an amino
Speaker 1: acid for a protein sequence, and there's many combinations of
Speaker 1: DNA that would lead to the right sequence for the protein.
Speaker 1: I actually don't know how they chose what DNA sequence
Speaker 1: to initially clone into the E. Coli. In theory, it
Speaker 1: could be that they just this is not how they
Speaker 1: did it because they didn't have the right tools to
Speaker 1: do this. But in theory, it could be that they
Speaker 1: were just like, oh, well, we know what protein sequence
Speaker 1: we want, so therefore any of these bajillion different DNA
Speaker 1: sequences will work, So we'll just artificially synthesize one of
Speaker 1: those and do it from there. We could do that today.
Speaker 1: That's actually pretty easy thing to do. I've often thought
Speaker 1: about that, Like, if you knew something you wanted to produce,
Speaker 1: you could synthesize the piece of DNA and send it
Speaker 1: to a yogurt manufacturer anywhere in the world, and they
Speaker 1: could make vast quantities of a protein that you were
Speaker 1: interested in if you could get the cells to cooperate.
Speaker 1: I mean, there's a few things that would be hard
Speaker 1: about it, but yeah, I think they must have known
Speaker 1: this sequence for human DNA and then physically got in
Speaker 1: their hands on that and chopped it out and then
Speaker 1: like physically we use the word ligation, it just means
Speaker 1: like pasting it into the bacteria, and it wasn't just that,
Speaker 1: And a lot of this happened also with the company Genentech.
Speaker 1: I'm sure that many people know more about this history
Speaker 1: than I do. But some of it is proprietary, right
Speaker 1: because it was happening at a company, some of it anyway.
Speaker 1: And so they cloned the human DNA sequence, copied it
Speaker 1: into the bacterial cell, and just fired the bacteria up
Speaker 1: to produce it.
Speaker 3: So now you've got the bacteria with the code, and
Speaker 3: you figured out how to get them to be running
Speaker 3: that code all the time, so they're making more insulin. Yeah,
Speaker 3: is that insulin accumulating inside the bacteria or do they
Speaker 3: excrete it? How do we get it after that?
Speaker 1: That's a really good question, and I think there's actually
Speaker 1: several ways you could do that, and I would not
Speaker 1: be surprised if both of those options are happening in
Speaker 1: various factories in the world right now. One way it
Speaker 1: can happen often when a bacterial cell is confronted with
Speaker 1: like a crazy amount of something it doesn't quite know
Speaker 1: what to do with, it pumps it into a little
Speaker 1: compartment called a vacuole, and it just like makes little
Speaker 1: pouches of it. That's my understanding for the main thing
Speaker 1: that happens is that you get these little pouches of
Speaker 1: the vacuoles from the cells, and then the next step
Speaker 1: is to pop the cells, pull out all those vacuoles,
Speaker 1: and then get the insulin from there. So I'm pretty
Speaker 1: sure that's the main way that it's done these days
Speaker 1: from E. Coli. Not all insulin is made in bacteria
Speaker 1: and ecoli. There's I think maybe twenty or thirty percent
Speaker 1: of the insulin that's manufactured in the world is in
Speaker 1: yeast and sachromics service. And then it's going to be
Speaker 1: yet another process. And so yeah, theory, you could make
Speaker 1: the cell excrete the insulin into the liquid, which might
Speaker 1: make your process easier, but since insulin's a protein and
Speaker 1: it can get broken down by enzymes that eat proteins,
Speaker 1: in a way, you might be better off having it
Speaker 1: be in a protected pouch that you could just pull
Speaker 1: those aside and get the insulin out.
Speaker 3: I don't think I've thought before about the complicated process
Speaker 3: of acquiring this stuff after the bacteria has made it.
Speaker 3: Like I guess i'd imagine, like you know, you skim
Speaker 3: the top and there's the insulin and you stick it
Speaker 3: into needles. But yeah, I mean extracting all of those vacules, Yeah,
Speaker 3: and popping them doesn't sound like easy work.
Speaker 1: No, that's a sophisticated process. And then the protein sequence
Speaker 1: still contains extra bits that make it inactive on purpose,
Speaker 1: so that it's not in our bodies. We don't want
Speaker 1: it to be active exactly when it's produced. It's like
Speaker 1: unleashed and activated very intentionally, So to get it to
Speaker 1: be in that active form takes yet more steps.
Speaker 3: All right, awesome, So we're going to take a break now,
Speaker 3: and when we get back from the break, we're going
Speaker 3: to hear about lydia Villa Komorov's contribution to this field.
Speaker 3: All right, and we're back. So it's Women's History month.
Speaker 3: We're trying to feature some amazing women that most people
Speaker 3: have perhaps not heard of. And you agreed to come
Speaker 3: on the show and talk to us about lydia Villa Comarov.
Speaker 3: What was her contribution to this field.
Speaker 1: Well, lydia Villa Comorov was a grad student in the
Speaker 1: nineteen seventies during this era where we were just figuring
Speaker 1: out that we could clone bacteria. So not only did
Speaker 1: we understand the central dogma, the way that molecular biology
Speaker 1: is encoded. We were now starting to be able to
Speaker 1: manipulate it.
Speaker 3: Interesting, So a few.
Speaker 1: People had done anything in this area. Right around the
Speaker 1: time that doctor Villa Komarova finished her PhD from MIT
Speaker 1: in nineteen seventy five and she embarked on a really
Speaker 1: bold post doc at Harvard. It was to clone the
Speaker 1: human insulin gene into bacteria. It was so bold that
Speaker 1: Harvard actually asked them to stop. They paused the project
Speaker 1: for fear of ethical consideration for what the consequences of
Speaker 1: humans cloning things could be. So she actually continued her
Speaker 1: project at Cold Spring Harbor. There were lots of failures.
Speaker 1: I think that was a really tough post doc, but
Speaker 1: ultimately she succeeded. I think that was around nineteen seventy eight,
Speaker 1: and by the early eighties there was commercially available human
Speaker 1: insulin that had been synthesized in bacteria, and her project
Speaker 1: was to clone the gene for insulin into E. Coli,
Speaker 1: the bacteria. So she has a paper in PNAS, the
Speaker 1: Proceedings of the National Academy of Science, and in that
Speaker 1: paper she demonstrates that you can pull the insulin gene
Speaker 1: from humans, clone it into bacteria and get the bacterial
Speaker 1: cells to replicate. So it was a big step, not
Speaker 1: just that this was an idea, but that it could
Speaker 1: actually be done, and everyone had their eyes on this happening.
Speaker 1: It was considered risky and important enough that her project
Speaker 1: was halted as these considerations about the ethics were being
Speaker 1: discussed at the ASILAMAR meeting, and after the ASILAMAR meeting
Speaker 1: she was allowed to proceed. And it all happened very
Speaker 1: fast because her paper was already published in nineteen seventy eight,
Speaker 1: and I think the Assillamar meeting was only in nineteen
Speaker 1: seventy seven, So I bet that was intense. I bet
Speaker 1: she was working hard with.
Speaker 2: What ethics concerns do we have? Because, as we said earlier,
Speaker 2: bacteria can't make peppy eyes, so what are the ethical issues.
Speaker 1: It was a very new idea that humans could clone things,
Speaker 1: that we could decide what the DNA that a creature
Speaker 1: encoded was. And in some ways, I don't think it's
Speaker 1: different than agriculture, not just farming of crops, but I
Speaker 1: mean dog breeding or horse breeding or anything where you
Speaker 1: select for traits that you care about and then intentionally
Speaker 1: push a population towards having specific traits that we had
Speaker 1: always only done that in the context of selection, where
Speaker 1: all of the reproducing was happening by itself, or you know,
Speaker 1: what you might consider a natural way, in the sense
Speaker 1: that you were just like picking out the peas that
Speaker 1: had the color you were excited about and crossing those,
Speaker 1: and then you get more, and after hundreds of years
Speaker 1: you can't even recognize the organism compared to where it started.
Speaker 2: From the way we transformed corn from like a tiny
Speaker 2: little grain to this like hugely productive.
Speaker 1: Food, for example, exactly, or like watermelons, or you know
Speaker 1: something where watermelons weren't these like amazing, gicy, genormous fruits
Speaker 1: when we first found them, right, We cultivated that, and
Speaker 1: the consequences of the cultivation are obviously encoded in the
Speaker 1: genome and in some ways not really different than cloning
Speaker 1: something on purpose. In fact, we're not that good at cloning.
Speaker 1: Like cloning requires us as humans to decide what pieces
Speaker 1: of DNA belong in an organism, and we typically are
Speaker 1: kind of bad at that. It's interesting. I went to
Speaker 1: grad school in an era where rational design of proteins
Speaker 1: was really popular and a lot of people's projects were
Speaker 1: like looking at protein sequences and being like, oh, I
Speaker 1: think we should put an alanine there, and that's going
Speaker 1: to make this work better. That kind of thing, and
Speaker 1: typically it didn't actually work better. So in some ways,
Speaker 1: I think we've come to respect that evolution and allowing
Speaker 1: natural selection to happen is if in some ways, a
Speaker 1: more powerful way to pull off things you want to do.
Speaker 1: But you would never get insulin production through evolution. I mean,
Speaker 1: bacteria would never produce insulin. So it's actually a really
Speaker 1: great case for genetic engineering. It was a very cool
Speaker 1: problem that lydia Villa comorov took on because it was
Speaker 1: so effective and it really would never have happened without cloning.
Speaker 1: So your question was how did it come to be
Speaker 1: that this was an ethical problem? And the real issue
Speaker 1: was just that we as humans were scared that we
Speaker 1: were going to unleash some kind of monster. What were
Speaker 1: the consequences of us genetically engineering things? I mean, more recently,
Speaker 1: we've had similar debates about crispers, and you've heard that
Speaker 1: there is even a case where a Chinese scientist used
Speaker 1: Crisper to genetically engineer a baby, a human that has really,
Speaker 1: really big ethical questions, And this was happening only in bacteria,
Speaker 1: but it was the first time it had happened, and
Speaker 1: we were rightfully, really thinking carefully about what the consequences
Speaker 1: could be. For example, imagine you cloned a bacteria that
Speaker 1: contained genes that could break down petroleum, and then you
Speaker 1: unleashed that in an oil mining operation. You could really
Speaker 1: cause a lot of destruction. And what if that was
Speaker 1: just impossible to control and then you destroyed huge natural
Speaker 1: resources unintentionally or intentionally for that matter. So those were
Speaker 1: the kinds of questions people were worried about.
Speaker 2: Or what if it helped the bacteria organize and it
Speaker 2: crawled out of the vat and like extracted vengeance for
Speaker 2: all the brethren that we've tortured in order to extract
Speaker 2: insulin from them.
Speaker 1: That's a great question, but I'm pretty sure they didn't
Speaker 1: talk about it.
Speaker 2: That's a very polite answer to a totally bunkers question.
Speaker 2: You all should have seen her face.
Speaker 1: That didn't make it to the top ten list for
Speaker 1: discussion out of Solomar.
Speaker 2: I bet there were some science fiction writers there. They
Speaker 2: would have come up with that scenario. It didn't take
Speaker 2: me very long to think about it.
Speaker 3: I think there was a recent ant Solomar meeting that
Speaker 3: was sort of inspired by then prior meeting. So you
Speaker 3: mentioned the ethical issues associated with Crisper. Yeah, but I
Speaker 3: think they like literally had another Ansilomar meeting with like
Speaker 3: similar goals to figure out what direction.
Speaker 1: I think it's next month, Oh is it? Yeah? I
Speaker 1: think it's next week. I think you guys could have
Speaker 1: this episode coincide or we could look into that. That'd
Speaker 1: be cool. Yeah, because my friend Jen Martini was invited,
Speaker 1: but she couldn't go because she's teaching, and I know
Speaker 1: she doesn't start teaching until.
Speaker 3: Next week's I mean maybe we should have a whole
Speaker 3: episode on the ethical implications of Crisper too. That yeah,
Speaker 3: important and timely.
Speaker 2: So how ballsy was it for her to take on
Speaker 2: this project because if it didn't work, she could ended
Speaker 2: up with basically nothing, no result. I mean, this was
Speaker 2: like really swinging for a home run, wasn't it.
Speaker 1: Yeah, that's a really good question. It'd be fun to
Speaker 1: talk to the people who are around at that time.
Speaker 1: I don't think I would give this to a student
Speaker 1: as their only project. It does seem really risky. But yeah,
Speaker 1: if you look at the people involved, like who her
Speaker 1: bosses were and who their collaborators were. You know, they
Speaker 1: were used to taking on really big projects and hitting
Speaker 1: for home runs. So that's what you do in Boston, Yeah, exactly.
Speaker 3: So what came for her after this? So she did
Speaker 3: this amazing breakthrough, was the first person to do this
Speaker 3: amazing thing. What did she do after that?
Speaker 1: She stayed in science. Actually, she made a really good
Speaker 1: use of her science education, and she went on to
Speaker 1: work on not just insulin, but other hormones that are
Speaker 1: related to insulin. Some of them are called insulin like
Speaker 1: growth factors. It's a really complex field that I honestly
Speaker 1: couldn't tell you too much about what all the implications are,
Speaker 1: but I do know that she ran a lab and
Speaker 1: spent many years studying hormones that are related to insulin.
Speaker 1: And so she stayed in that field. And she also
Speaker 1: really put a lot of energy into being a role
Speaker 1: model and a leader for other people who wanted to
Speaker 1: become scientists. She'd encountered definitely roadblocks herself, considering that most
Speaker 1: institutions wouldn't even accept women as applicants to graduate school
Speaker 1: when she was applying, and so she became a co
Speaker 1: founding member of the Society for the Advancement of Chicanos
Speaker 1: and Hispanics and Native Americans and Science or SACNAS, And
Speaker 1: that was back in the nineteen seventies, and I actually
Speaker 1: didn't know that. I personally have had a lot of
Speaker 1: students who have been supported by SAKNAS to go to conferences.
Speaker 1: They have meetings every year. I work at UC Irvine,
Speaker 1: which is a Hispanic serving institution, and a lot of
Speaker 1: our students have gone to those meetings and had a
Speaker 1: really good time. So I think that's really cool she
Speaker 1: founded that.
Speaker 2: And why isn't she a zillionaire? I mean, I know
Speaker 2: that this technology is the foundation of like billions of
Speaker 2: dollars of annual profit for Nova Noordis and Eli Lilly.
Speaker 2: Why isn't she elon Musk?
Speaker 1: What a good question. I don't know the details of
Speaker 1: what kind of IP they tried to get for the
Speaker 1: technique that they developed. I also know that genen Tech
Speaker 1: was really involved, and so actually an important thing to
Speaker 1: say is that, you know, so her paper came out
Speaker 1: in nineteen seventy eight, she didn't keep up with this
Speaker 1: specific feel. I know that genen Tech was the company
Speaker 1: that really developed the possibility of producing insulin in bacteria.
Speaker 1: My sense is that what she did was proof of concept,
Speaker 1: I see, which was critical because it made people ready
Speaker 1: for the idea. But my guess is that genen Tech
Speaker 1: went on and developed the technology in its own specific
Speaker 1: way that could then have ip that stayed within the company.
Speaker 2: Isn't there like fast acting and long acting with insulin stuff.
Speaker 1: Her paper came out in nineteen seventy eight, and I
Speaker 1: know that by nineteen eighty two the Food and Drug
Speaker 1: Administration had approved human insulin to be given to people.
Speaker 1: I was diagnosed with type one diabetes in nineteen eighty
Speaker 1: four and I never took animal insulin. I only got
Speaker 1: the human insulin at that time. It was just the
Speaker 1: straight up human insulin sequence. It hadn't been modified to
Speaker 1: have new properties. But that's pretty amazing that we scaled
Speaker 1: that up for humanity that quickly. And so the insulins
Speaker 1: that I took with like regular insulin, is still produced
Speaker 1: today and I used it for twelve years, like multiple
Speaker 1: injections daily, And now if you go to Walmart, you
Speaker 1: can actually buy that kind of insulin for twenty five dollars.
Speaker 1: This is probably the most important thing I'm saying like
Speaker 1: ever anytime I have an audience, I say this because
Speaker 1: it could really save lives that you can buy regular
Speaker 1: human insulin at Walmart. It's intended for cats and dogs
Speaker 1: who have diabetes. But it's exactly the insulin that I
Speaker 1: used for many years, and it cost twenty five dollars
Speaker 1: and you don't need a prescription. It's just over the counter.
Speaker 1: You can just go to Walmart and buy this insulin
Speaker 1: and it's exactly the same bottle as the one that
Speaker 1: I used in the nineteen eighties. So, starting in the
Speaker 1: nineteen eight e we scaled up fermentation of human insulin
Speaker 1: to be available for all people. I wouldn't say access
Speaker 1: is perfect, but it's pretty good. Like there's definitely parts
Speaker 1: of the world where you can buy insulin at a
Speaker 1: pretty reasonable cost. I'm sure you've heard a lot about
Speaker 1: the cost of insulin, Like if you cross the border
Speaker 1: into Mexico, you can buy this insulin at a very
Speaker 1: reasonable cost too. It wasn't until the nineties that engineered
Speaker 1: insulins that have different kinetics, like they can be faster
Speaker 1: and slower. Those came out in the nineties. The slower
Speaker 1: insulins were available earlier, like the insulin you can buy
Speaker 1: at Walmart. There's a slower one too, that's called NPH,
Speaker 1: and that didn't require crazy bioengineering or I don't know,
Speaker 1: they've somehow figured that out way earlier.
Speaker 3: Why would you want faster and slower insulin, Well.
Speaker 1: The regular insulin it takes a few hours to become active.
Speaker 1: So the insulin exists in little trimers around zinc molecules
Speaker 1: in a dimer. So there's two zinc molecules that each
Speaker 1: have three insulin molecules attached to them, So there's six
Speaker 1: insulin molecules all hanging out together. You have to wait
Speaker 1: for them to dissociate because the insulin is only active
Speaker 1: as a monomer by itself, So when you inject regular insulin,
Speaker 1: you have to wait one hour for it to even
Speaker 1: start working at all, and it doesn't peak until three hours. Now,
Speaker 1: when you eat your food, it doesn't come in immediately either,
Speaker 1: But regular insulin is too slow for an average meal,
Speaker 1: so most people would have to either inject their insulin early,
Speaker 1: but that's kind of dangerous. Imagine you inject your insulin,
Speaker 1: but you're like your food is late, or you're on
Speaker 1: a walk and you forget to eat or you know,
Speaker 1: something like that. If your blood seger goes too low,
Speaker 1: you die from low blood sugar immediately. It's like the
Speaker 1: most common cause of death in people with type one diabetes.
Speaker 1: So that's really really something you have to be careful with.
Speaker 1: So having your insulin kinetics not really matching when you
Speaker 1: need the insulin is both for convenience and basic survival,
Speaker 1: really really important. There was a big arms race between
Speaker 1: Eli Lilly and Novonordisk in the nineties to rationally design
Speaker 1: insulins that had different properties, and they both succeeded in
Speaker 1: slightly different ways. And now you can buy insulin that
Speaker 1: falls apart more easily. Those dimers on the trimers of
Speaker 1: the zinc are not as stable, so they fall apart
Speaker 1: more quickly. And now when you inject the insulin, it
Speaker 1: starts to become active within minutes and peaks within an hour,
Speaker 1: which matches how people eat much better. So it's safer
Speaker 1: and a little bit easier to keep your blood sugar
Speaker 1: within range. But matching the kinetics of your food with
Speaker 1: the kinetics of your insulin is just a major challenge.
Speaker 3: So is it still the case that today people with
Speaker 3: diabetes need to be really careful about, like what kinds
Speaker 3: of insulin that they're injecting. Has it gotten easier over time?
Speaker 3: I feel like I heard once that there are these
Speaker 3: things that can attach to your body that sort of
Speaker 3: do all the measuring for you. What is it like today.
Speaker 1: Well, so there's been big changes both in how we
Speaker 1: deliver insulin and how we monitor blood sugar. So we
Speaker 1: haven't talked about blood sugar monitoring at all in any
Speaker 1: of this, but I'll bring up that, you know, we've
Speaker 1: known for centuries how to detect glucose and urine, but
Speaker 1: that's very old information. By the time the sugar hits
Speaker 1: your urine, that's like happened hours ago, and you can't
Speaker 1: really take that sample and demand quite in the same
Speaker 1: way as you can take a blood sample. So we
Speaker 1: started poking our fingers to get blood sugar measurements. Those
Speaker 1: devices started being available at home in the nineteen eighties
Speaker 1: and then for about ten or fifteen years. We now
Speaker 1: have these sensors that you can put a little sensor
Speaker 1: on your arm and you get blood sugar information every
Speaker 1: five minutes. So those sensors help you see what your
Speaker 1: blood sugar is. We also have both injections for insulin
Speaker 1: and also insulin pumps. So the pump will deliver insulin
Speaker 1: at rates that you tell it to give you the insulin.
Speaker 1: But none of this is happening without a lot of thought.
Speaker 1: There's not like a machine that just takes care of
Speaker 1: it for you. A lot of people when they see
Speaker 1: an insulin pump imagine like, oh, that must be so
Speaker 1: nice that like, oh, the AI is taking care of
Speaker 1: your bl chicker for you, And that's not the case
Speaker 1: at all. Insulin pumps just do what you tell them
Speaker 1: to do.
Speaker 3: That is what I imagined. Thanks for clarifying that.
Speaker 1: Even my doctors, like if I go to the eye doctor,
Speaker 1: they're like, oh, it must be some nice having your
Speaker 1: pump doing that for you. But I mean, no, the
Speaker 1: pump is not operating independently.
Speaker 2: And talk per a minute about why that's a hard problem.
Speaker 2: I mean, people might be thinking, well, you have a
Speaker 2: sense of that tells you how much glucose you have,
Speaker 2: and you have insulin which brings the glucose down. Why
Speaker 2: can't you just you know, fit a straight line to
Speaker 2: that and descide how much insulin I have? Why do
Speaker 2: you need a human brain in the loop there or
Speaker 2: why is it a hard problem.
Speaker 1: There's a lot of reasons it's a hard problem. A
Speaker 1: big one is that the way that we're giving the
Speaker 1: insulin just subcutaneously means that it's slow. So you know,
Speaker 1: when you eat, your pancreas is exactly in the right
Speaker 1: place at the right time, sensing the glucose as it's
Speaker 1: getting released from your digestion. So then not only do
Speaker 1: you get real time information, but you also have the
Speaker 1: insulin being delivered exactly where you need it. So when
Speaker 1: you take insulin subcutaneously, it takes like a good half
Speaker 1: an hour to dissolve and become active. I guess. Another
Speaker 1: really important thing to say is that the insulin's activity
Speaker 1: is affected by your own activity. So if you're exercising,
Speaker 1: the insulin that you're taking will do a lot more work.
Speaker 1: And your own pancrease has more than one hormone. It
Speaker 1: has insulin and also glucagon, so it's a two component system.
Speaker 1: Insulin drives your blood sugar down, Glucagon drives your blood
Speaker 1: sugar up. So what glucagon does is it releases the
Speaker 1: glycogen stores in your liver and muscle to raise your
Speaker 1: blood sugar. So if this dangerous thing starts to happen
Speaker 1: that your insulin drives your blood sugar too low. Then
Speaker 1: the glucagon can pick it up from the floor and
Speaker 1: save your life so you don't die from low blood sugar.
Speaker 1: Our insulin pumps don't have glucagon in them. Glucagon is
Speaker 1: a really delicate hormone. There's about one hundred companies there
Speaker 1: engineering more stable glukug on. Maybe we'll have that soon,
Speaker 1: but right now the pumps just have insulin. There is
Speaker 1: a company that's trying to make a two component pump
Speaker 1: that also has glucagon, but anyway, that doesn't happen yet.
Speaker 1: So there's a number of reasons, like you could, in theory,
Speaker 1: use the glucose information, the old information you're getting from
Speaker 1: the sensor in your arm, and have that direct the
Speaker 1: dosing of the insulin from your pump. However, your pump
Speaker 1: doesn't know if you're about to go running, or if
Speaker 1: you are sick, or you know. The amount of insulin
Speaker 1: you need is affected by easily forty two factors that
Speaker 1: most of them can't be measured, and so you need
Speaker 1: your brain to synthesize all those factors and think through
Speaker 1: the decision of how much insulin you need, and.
Speaker 2: You don't trust chat GPT to make those decisions for
Speaker 2: you yet.
Speaker 1: I mean, I wouldn't mind like chatting with chat GPT
Speaker 1: about it and getting ideas, but I would definitely want
Speaker 1: to be the one who's the buck stops with me
Speaker 1: when it comes to that decision.
Speaker 2: All right, So then our last question is what do
Speaker 2: you see happening in the future, like in ten year
Speaker 2: and fifty years, in one hundred years, what's going to
Speaker 2: change about our treatment of diabetes or understanding of the
Speaker 2: biochemical processes.
Speaker 1: Well, there's biological and engineering fronts to talk about, and
Speaker 1: actually I should make a really big shout out to
Speaker 1: the group of people who are engineering devices. There's even
Speaker 1: groups of people who have built algorithms that do take
Speaker 1: the information from the glucose sensors and use it to
Speaker 1: dose the insulin. Sometimes they're called loopers. They're closing the loop.
Speaker 1: Many of those algorithms are open source, and people are
Speaker 1: having good results with better blood sugar control using those algorithms.
Speaker 1: It takes a really tech savvy person and somebody who
Speaker 1: you know. In my case, I go running every day
Speaker 1: and I don't think those algorithms take exercise into account
Speaker 1: in a way that works for me. So that's why
Speaker 1: I personally am not using the looping algorithms, although I'm interested.
Speaker 1: So if there's someone out there who's into looping, like,
Speaker 1: my mind is open. So there are people making really
Speaker 1: big progress on the algorithms, I think those are going
Speaker 1: to be a really big frontier that our algorithms are
Speaker 1: going to get better and better. Some of the major
Speaker 1: insulin pump companies have soft versions of those algorithms with
Speaker 1: a lot of safety on them, where they keep the
Speaker 1: average blood sugar values a little higher to give you
Speaker 1: a safety buffer. So that's starting to happen already. In fact,
Speaker 1: the pump I use has a soft algorithm like that that,
Speaker 1: especially for sleeping at night when there's not as many
Speaker 1: different changes going on, it can do a really good
Speaker 1: job of helping you keep your blood sugar in control.
Speaker 1: So that's already getting better. I'd say the engineering front
Speaker 1: will include better sensors, better algorithms. If we had glucagon,
Speaker 1: then that will also close the loop and help to
Speaker 1: make the measurements better overall, though, I mean, humans are
Speaker 1: really complex. Like one of my favorite results recently showed
Speaker 1: how people eating exactly the same meal one week apart
Speaker 1: and wearing a continuous glucose monitor had different blood sugar
Speaker 1: responses to the same meal, which I think highlights that
Speaker 1: challenge of why it has to be pretty thoughtful how
Speaker 1: you are dosing insulin even for the same meal and
Speaker 1: the same person. You can't assume it's going to work
Speaker 1: the same way each time. But then on the biology front,
Speaker 1: there's also really big progress. So we have been learning
Speaker 1: how to direct the program of stem cells and differentiating
Speaker 1: them into different kinds of cells that we can use
Speaker 1: for different kinds of medicine. There's a whole arm of
Speaker 1: research towards building pancreatic beta cells, the ones that secrete insulin,
Speaker 1: so that they could be transplanted. The first versions of
Speaker 1: these have required people to take immunosuppressants, just like for
Speaker 1: a pancreased transplant, so it didn't feel as exciting to me,
Speaker 1: but that's actually starting to get better, and there are
Speaker 1: efforts towards making hypoimmune, so like not giving an immune
Speaker 1: response cells, so that people could get transplants with these
Speaker 1: kind of cells and not have to take imminosuppressants and
Speaker 1: potentially have them work to control their blood sugar. I
Speaker 1: don't know, it's interesting to me to imagine trusting a
Speaker 1: little renegade group of cells to do that. But you know,
Speaker 1: that will get tested and we'll know a lot more
Speaker 1: those are. On the treatment front, there's another whole aspect
Speaker 1: to talk about, which is, you know, the way that
Speaker 1: type one diabetes develops, at least your immune system starts
Speaker 1: to attack your pancreas. This process can take a couple
Speaker 1: of years. A lot of people when they're diagnosed, imagine that.
Speaker 1: You know, oh, I got a cold and then I
Speaker 1: got diabetes, or I took finals and I was all
Speaker 1: stressed out and that caused my diabetes. But really it
Speaker 1: was just the straw that broke the camel's back. And
Speaker 1: this was a process that was going on for a
Speaker 1: couple of years, and then a stressful circumstance made you
Speaker 1: need more insulin, so then the system couldn't support you anymore.
Speaker 1: But now there's actually a treatment for people who are
Speaker 1: just starting to build the antibodies that are killing their
Speaker 1: pancreatic cells, and that treatment will basically target and slow
Speaker 1: down the immune process. It's called tea yield. And we
Speaker 1: actually have a friend whose son was caught early because
Speaker 1: he had a really savvy mom who understood what was
Speaker 1: going on, and she helped him get that treatment, and
Speaker 1: it's supposed to delay the onset of his type one
Speaker 1: diabetes for several years. So he's probably still on that path,
Speaker 1: but I could imagine us getting even better at that.
Speaker 1: And to be honest, the reason I became a microbiome
Speaker 1: scientist is that we know that the diagnosis of autoimmune
Speaker 1: diseases is becoming more and more frequent. EXAMA allergies, type
Speaker 1: one diabetes, a lot of autoimmune diseases are becoming more common,
Speaker 1: and we don't exactly know why. It's clearly a change
Speaker 1: in our immune development and the exposures we have in
Speaker 1: early life. And for example, most babies born in human
Speaker 1: history were breastfed and their guts became dominated by a
Speaker 1: biffidobacteria that's good at helping break down the breast milk fibers,
Speaker 1: and that's now missing from most people in the industrialized world.
Speaker 1: So there are big studies right now to try to
Speaker 1: reintroduce that biffodobacteria and see if it helps us reduce
Speaker 1: our incidence of autoimmune diseases. So the easiest disease to
Speaker 1: study is ezema in some ways because it emerges within
Speaker 1: the first year or so of life, and they're now
Speaker 1: are big studies using biffidobacteria to see if we can
Speaker 1: reduce those diseases. But there's also right now there's a
Speaker 1: big study in Europe across five countries with more than
Speaker 1: a thousand people who are from families who are a
Speaker 1: little bit more at risk for developing type one diabetes,
Speaker 1: and they're introducing that biffodobacteria. So it's going to take
Speaker 1: like probably ten years until we have the beginnings of
Speaker 1: the answer, because type one diabetes can happen in childhood
Speaker 1: or even adulthood. But we're gonna know if these changes
Speaker 1: in microbiome exposure that put us on a better immune
Speaker 1: development course could help to reduce the incidence of type
Speaker 1: one diabetes. So it might be akin to vaccination in
Speaker 1: the future that we intentionally develop our microbial exposures to
Speaker 1: direct the way our immune systems develop so we don't
Speaker 1: end up with all these autoimmune diseases.
Speaker 2: All right, Well, it sounds like a lot of potential
Speaker 2: progress and lots of different directions. I hope that young
Speaker 2: scientists out there are excited about working in all of
Speaker 2: these angles and taking big risks like Lydia did.
Speaker 3: Yeah, thanks for being on the show, kut Ri enough,
Speaker 3: that was awesome.
Speaker 1: Thank you.
Speaker 2: I'm going to nominate you for next year's White Sin
Speaker 2: Research Award as well, even that you've twenty five years ago.
Speaker 1: Now I'm going to nominate you. You. I mean, I
Speaker 1: think it's amazing that our society has produced all this
Speaker 1: insulin to keep so many people with diabetes alive. And
Speaker 1: we could do better with the access. But I mean,
Speaker 1: considering that it's like water for so many people to
Speaker 1: depend on the insulin, it's kind of amazing that we've
Speaker 1: kept these systems going.
Speaker 2: All right. Well, thanks very much, China, and thanks everybody
Speaker 2: for listening.
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