Latest / Daniel and Kelly’s Extraordinary Universe / Insulin (featuring Dr. Katrine Whiteson)

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Insulin (featuring Dr. Katrine Whiteson) · Daniel and Kelly’s Extraordinary Universe

• 0:05
  Speaker 1: We as humans were scared that we were going to
• 0:08
  Speaker 1: unleash some kind of monster. What were the consequences of
• 0:12
  Speaker 1: us genetically engineering things? I mean, more recently, we've had
• 0:16
  Speaker 1: similar debates about crispers, And maybe you've heard that there
• 0:19
  Speaker 1: was even a case where a Chinese scientist used crisper
• 0:23
  Speaker 1: to genetically engineer a baby, a human that has really
• 0:27
  Speaker 1: really big ethical questions, And this was happening only in bacteria,
• 0:32
  Speaker 1: but it was the first time it had happened, and
• 0:34
  Speaker 1: we were rightfully, really thinking carefully about what the consequences
• 0:37
  Speaker 1: could be. For example, imagine you cloned a bacteria that
• 0:42
  Speaker 1: contained genes that could break down petroleum, and then you
• 0:46
  Speaker 1: unleashed that in an oil mining operation. You could really
• 0:50
  Speaker 1: cause a lot of destruction. And what if that was
• 0:52
  Speaker 1: just impossible to control and then you destroyed huge natural
• 0:58
  Speaker 1: resources unintentionally intentionally for that matter. So those were the
• 1:02
  Speaker 1: kinds of questions people were worried about.
• 1:03
  Speaker 2: Or what if it helped the bactery organize and it
• 1:05
  Speaker 2: crawled out of the vat and like extracted vengeance for
• 1:09
  Speaker 2: all the brethren that we've tortured in order to extract
• 1:12
  Speaker 2: incident from them.
• 1:13
  Speaker 1: That's a great question, but I'm pretty sure about it.
• 1:16
  Speaker 2: That's a very polite answer to a totally bonkers questionin
• 1:21
  Speaker 2: you all should have seen her face.
• 1:23
  Speaker 1: That didn't make it to the top ten list for
• 1:25
  Speaker 1: discussion out of so lamar.
• 1:40
  Speaker 3: Hi.
• 1:41
  Speaker 2: I'm Daniel. I'm a particle physicist and a member of
• 1:43
  Speaker 2: the White Senn Research Institute in Irvine, and today I'm
• 1:46
  Speaker 2: going to be an extra big fan of biology.
• 1:49
  Speaker 3: Hello, I'm Kelly Wiener Smith. Can I be like an
• 1:52
  Speaker 3: adjunct at the White sin Research Institute?
• 1:54
  Speaker 1: Like?
• 1:55
  Speaker 3: Is that what friends are called?
• 1:57
  Speaker 2: Come be a visiting professor? No problem? Yes, all right?
• 2:01
  Speaker 3: Does that come with dinner?
• 2:05
  Speaker 2: Dinner is a bonus? Yes? Plus you can add this
• 2:07
  Speaker 2: as an extra affiliation on all of your papers to
• 2:10
  Speaker 2: make you sound really.
• 2:11
  Speaker 3: Smart, fantastic. I'm go to you. I'm gonna put it
• 2:13
  Speaker 3: right on my CV. Have you ever done a show
• 2:16
  Speaker 3: with your wife before?
• 2:17
  Speaker 2: I have never done a podcast episode with Katrina, though
• 2:19
  Speaker 2: I've had lots and lots of science conversations over the
• 2:23
  Speaker 2: dinner table, so we definitely talked a lot about science
• 2:26
  Speaker 2: and board our teenagers to death. But no, I don't
• 2:30
  Speaker 2: think it's ever been recorded. So this is great for posterity.
• 2:33
  Speaker 3: Well, and I'm excited because we have talked on the
• 2:35
  Speaker 3: show often about how, you know, since she studies microbiome stuff,
• 2:39
  Speaker 3: sometimes you find bags of poop in your freezer and
• 2:41
  Speaker 3: stuff like that, and I feel like it's really important
• 2:43
  Speaker 3: for people to like put a voice to those stories.
• 2:46
  Speaker 3: And today that's gonna happen.
• 2:48
  Speaker 2: You just want another poop in the freezer ally on
• 2:50
  Speaker 2: the show to outvote me. That's what's going on here, really,
• 2:53
  Speaker 2: I do.
• 2:53
  Speaker 3: I want the gross votes to outnumber the people who
• 2:56
  Speaker 3: are squeamish. And also I like, you know, pushing the
• 3:00
  Speaker 3: envelope in the direction of gross so that I don't
• 3:02
  Speaker 3: seem as gross, you know, Like, mostly I want Zach
• 3:05
  Speaker 3: to realize how lucky he is. Yeah, that there's not
• 3:08
  Speaker 3: bags of poop in the freezer like the dead bird.
• 3:10
  Speaker 3: Not a big deal.
• 3:11
  Speaker 2: All right, Well, welcome to the podcast where we pretend
• 3:13
  Speaker 2: to be talking about science, but really we're doing marital therapy.
• 3:19
  Speaker 3: Well, and on today's show, we're very lucky to have
• 3:21
  Speaker 3: Katrina come on to talk to us about diabetes and
• 3:25
  Speaker 3: the history of insulin production and the future of insulin production.
• 3:29
  Speaker 3: And she was amazing. She had a lot of incredible insights.
• 3:32
  Speaker 2: Yeah, I think a lot of people think they understand
• 3:33
  Speaker 2: diabetes generally, but there's a lot of really fascinating biochemistry
• 3:37
  Speaker 2: and a lot of nuance there, and a lot to
• 3:39
  Speaker 2: understand about the daily life of somebody with diabetes. And
• 3:42
  Speaker 2: it's kind of amazing that until about one hundred years ago,
• 3:45
  Speaker 2: diabetes was a death sentence. You got diabetes and you
• 3:48
  Speaker 2: were dead a couple years later. And now because of
• 3:51
  Speaker 2: amazing biologists, we can save the lives of all those kids,
• 3:54
  Speaker 2: and people like my wife can grow up and be
• 3:56
  Speaker 2: like a professor and had kids and live a full life.
• 3:59
  Speaker 2: It's really kind of an amazing testament to what science
• 4:02
  Speaker 2: can do.
• 4:03
  Speaker 3: And I'm not going to release any spoilers here, but
• 4:05
  Speaker 3: there were at least two things she talked about where
• 4:07
  Speaker 3: I was like, I thought I knew and I was
• 4:10
  Speaker 3: totally wrong. And so I think we're gonna have a
• 4:12
  Speaker 3: good episode of sort of dispelling rumors or myths about diabetes.
• 4:17
  Speaker 2: All right, Well, then, without further ado, let's welcome my
• 4:20
  Speaker 2: favorite scientist at the whites And Research Institute. So then
• 4:27
  Speaker 2: today it's my great pleasure to welcome to the podcast.
• 4:30
  Speaker 2: Co president of the White Sun Research Institute and winner
• 4:34
  Speaker 2: of the whites In Research Prize as Professor Katrina whites
• 4:38
  Speaker 2: In at uc Irvine Katriina, Welcome to the podcast.
• 4:41
  Speaker 1: Thank you.
• 4:42
  Speaker 3: I'm so excited you're here.
• 4:45
  Speaker 1: I didn't even know about those awards, but I will.
• 4:48
  Speaker 2: I guess I'll go update your CV right now.
• 4:54
  Speaker 3: Update your tenure packet, all the things.
• 4:57
  Speaker 2: Yeah, but we did just invite Chain onto the podcast
• 5:01
  Speaker 2: to joke around with her. We invited her on because
• 5:03
  Speaker 2: she's a deep expert in today's topic.
• 5:06
  Speaker 3: So today we're talking about bioengineering bacteria, we're talking about diabetes,
• 5:11
  Speaker 3: we're talking about lydia villa comarov and it's going to
• 5:14
  Speaker 3: be an amazing conversation and we're super excited to have
• 5:17
  Speaker 3: you here.
• 5:18
  Speaker 1: Thank you.
• 5:19
  Speaker 3: So by the end of the episode, we're going to
• 5:21
  Speaker 3: get to bacteria producing pharmaceutical components. But let's start by
• 5:26
  Speaker 3: talking about diabetes. What are the mechanisms underlying diabetes.
• 5:30
  Speaker 1: Well, that's a really good question, and actually even just
• 5:33
  Speaker 1: using the word diabetes already doesn't give you quite enough
• 5:36
  Speaker 1: information to be able to answer that question, because there's
• 5:40
  Speaker 1: two really different forms of diabetes. I guess we could
• 5:44
  Speaker 1: go back to ancient times when the word first arose,
• 5:47
  Speaker 1: and in that time we understood that sugar was involved
• 5:50
  Speaker 1: and that not being able to process sugar was involved.
• 5:53
  Speaker 1: We've actually known that for hundreds of years, so you
• 5:55
  Speaker 1: could think of glucose as maybe the first biomarker. There
• 5:58
  Speaker 1: were really interesting ways that people would detect that someone
• 6:01
  Speaker 1: had diabetes. It's actually diabetes melitis, and the words mean
• 6:06
  Speaker 1: that you're losing water due to sugar. And people would
• 6:09
  Speaker 1: take urine and put it out to see if the
• 6:12
  Speaker 1: ants were attracted to it. They would taste the urine
• 6:15
  Speaker 1: to see if it was sweet, and that would give
• 6:17
  Speaker 1: them a clue that you had this wasting disease where
• 6:20
  Speaker 1: your body couldn't process sugar. And like, probably the first
• 6:23
  Speaker 1: thing that pops into mind when you think of diabetes
• 6:26
  Speaker 1: in modern times is it's associated with obesity, But actually
• 6:30
  Speaker 1: diabetes is a wasting disease. It means that you can't
• 6:33
  Speaker 1: get energy from sugar and you actually starve to death
• 6:35
  Speaker 1: while drowning with lots of sugar in your blood. So
• 6:38
  Speaker 1: I think that's just actually really amazing and usually counterintuitive.
• 6:41
  Speaker 1: When I'm teaching, I sometimes show images of the children
• 6:44
  Speaker 1: who would die from diabetes before the insulin was discovered,
• 6:48
  Speaker 1: and they are emaciated because they're unable to get any
• 6:51
  Speaker 1: energy from the sugar that they're eating. So to back up,
• 6:54
  Speaker 1: I mean, there's two main kinds of diabetes. The first one,
• 6:58
  Speaker 1: type one diabetes for a while even called juvenile diabetes,
• 7:02
  Speaker 1: is when your immune system kills the cells in your
• 7:04
  Speaker 1: pancreas that make insulin, so you're no longer able to
• 7:07
  Speaker 1: access sugar. So you eat sugar. It gets into your blood,
• 7:11
  Speaker 1: but the key that allows the sugar to be used
• 7:13
  Speaker 1: by your cells is just totally missing.
• 7:15
  Speaker 2: And so you're saying, insulin is that key. Insulin is
• 7:17
  Speaker 2: a thing that takes sugar from your blood and into
• 7:19
  Speaker 2: your cells exactly.
• 7:21
  Speaker 1: Insulin is a protein like ham, but it's acting like
• 7:25
  Speaker 1: a little it's a little robot. It's a little key
• 7:27
  Speaker 1: that actually summons the transporters that help glucose get into
• 7:32
  Speaker 1: your cell up to the surface and then the gates
• 7:36
  Speaker 1: open and the sugar can get into the cells. Without that,
• 7:39
  Speaker 1: the sugar just sits in your blood and the cells starve.
• 7:42
  Speaker 3: Is there a toxic effect of the sugar building up
• 7:44
  Speaker 3: as well? Or is it just that you're starving? Is
• 7:47
  Speaker 3: the main problem the long term?
• 7:49
  Speaker 1: The sugar in your blood is super toxic. But those
• 7:51
  Speaker 1: are kind of like decade long problems. So if you're
• 7:54
  Speaker 1: dealing with starving in the course of weeks or months,
• 7:58
  Speaker 1: then the decade long problem of too much sugar in
• 8:00
  Speaker 1: your blood is just not something to worry about. But yes, hope,
• 8:04
  Speaker 1: too much sugar in your blood is definitely toxic. And
• 8:06
  Speaker 1: I think that's the part that's more famous about diabetes
• 8:08
  Speaker 1: right now, because most diabetes in our time, ninety percent
• 8:12
  Speaker 1: of diabetes is what we called type two diabetes, and
• 8:16
  Speaker 1: it can be lifestyle associated, but amazingly, it's actually more genetic.
• 8:20
  Speaker 1: It's more inherited to get type two diabetes. So about
• 8:23
  Speaker 1: ninety percent of the diabetes in the world right now
• 8:25
  Speaker 1: emerges usually later in life, and it's not because you
• 8:29
  Speaker 1: don't have insulin. You could actually have plenty of insulin,
• 8:32
  Speaker 1: it's just not working very well, so your body is
• 8:35
  Speaker 1: resistant to the use of the insulin. That's associated with
• 8:38
  Speaker 1: metabolic syndrome, but actually can be quite genetic. You can
• 8:41
  Speaker 1: be a very healthy, thin looking person and still get
• 8:43
  Speaker 1: type two diabetes. So that's also a bit of a
• 8:45
  Speaker 1: misnomertis always assume it's associated with lifestyle, but in the
• 8:50
  Speaker 1: case of type two diabetes, if it is arising because
• 8:52
  Speaker 1: of obesity, you can reverse it if you eat less carbs,
• 8:57
  Speaker 1: exercise more, and in general it don't overload the system
• 9:01
  Speaker 1: that depends on insulin. You can resensitize your body to
• 9:04
  Speaker 1: the insulin that it can make, and you can also
• 9:07
  Speaker 1: take medicines that make the insulin more effective.
• 9:09
  Speaker 2: All right, so let me recap for the non biologists.
• 9:12
  Speaker 2: You eat a ham sandwich, your body turns some of
• 9:15
  Speaker 2: that into sugar, puts it into your blood, but then
• 9:18
  Speaker 2: your cells and your body, like your muscles, can't access
• 9:21
  Speaker 2: it from your blood without insulin, this thing that takes
• 9:24
  Speaker 2: it from the blood into the cells. And type one
• 9:27
  Speaker 2: diabetes is when your body kills the cells to produce insulin,
• 9:30
  Speaker 2: so you just don't have it. Type two is when
• 9:32
  Speaker 2: you still have insulin, but because of some metabolic things,
• 9:36
  Speaker 2: it's not working as well, or it's just not.
• 9:38
  Speaker 1: As effective, or you just don't have enough. Yeah, that's
• 9:40
  Speaker 1: about right. There's a lot of nuances you will not
• 9:43
  Speaker 1: be surprised to hear. For example, your brain, which uses
• 9:46
  Speaker 1: about twenty percent of the glucus in your body, doesn't
• 9:49
  Speaker 1: really depend on insulin in the same way. So I
• 9:51
  Speaker 1: find that kind of amazing that your brain is just
• 9:53
  Speaker 1: like this constant machine that's using a lot of the
• 9:56
  Speaker 1: sugar in your blood. It's like the main reason it's
• 9:58
  Speaker 1: so important that our blod glucose levels are maintained at
• 10:01
  Speaker 1: a certain level, otherwise your brain doesn't function. So that's
• 10:05
  Speaker 1: kind of independent of the insulin. And then there's other
• 10:08
  Speaker 1: really cool exceptions, like your muscles, especially during exercise, they're
• 10:12
  Speaker 1: extra sensitive to being able to get glucose in. So
• 10:15
  Speaker 1: there are extreme examples, Like there's a story about a
• 10:18
  Speaker 1: guy one hundred years ago before there was really insulin,
• 10:21
  Speaker 1: who kept himself alive with like a really crazy exercise
• 10:24
  Speaker 1: regiment and he had like amazing muscle mass and he
• 10:27
  Speaker 1: kind of like extended his capacity to metabolize his diet
• 10:31
  Speaker 1: even though he didn't have much insulin. So it's kind
• 10:33
  Speaker 1: of interesting we didn't do more of that, but on average, yeah,
• 10:36
  Speaker 1: without insulin, your blood will be full of sugar and
• 10:39
  Speaker 1: your cells will be starving. And if you look at
• 10:41
  Speaker 1: a picture of a kid who died from type one
• 10:43
  Speaker 1: diabetes before nineteen twenty one, when insulin was discovered, they
• 10:46
  Speaker 1: look emaciated, which is just terrible so.
• 10:49
  Speaker 2: You're starving, but your blood is filled with sugar and
• 10:52
  Speaker 2: your pea is filled with sugar. You just don't have
• 10:54
  Speaker 2: access to it. So it's like being hungry at a buffet.
• 10:57
  Speaker 2: It's crazy.
• 10:58
  Speaker 1: Yeah, exactly.
• 10:59
  Speaker 3: Do you know this story of how we discovered insulin.
• 11:02
  Speaker 1: Yeah, I mean, there's actually a lot of really good
• 11:04
  Speaker 1: stories around that. It was a slow process like science
• 11:07
  Speaker 1: often is, because we got a lot of important clues
• 11:10
  Speaker 1: even maybe half a century before the discovery of insulin,
• 11:13
  Speaker 1: Like we knew for a long time, hundreds of years
• 11:15
  Speaker 1: that it was related to glucose. So then by the
• 11:19
  Speaker 1: eighteen eighties in Germany, there were scientists who figured out
• 11:23
  Speaker 1: that if you removed the pancreas from a dog, it
• 11:26
  Speaker 1: would cause essentially the symptoms of diabetes.
• 11:29
  Speaker 2: What were they doing. Were they just like taking random
• 11:31
  Speaker 2: organs out of dogs one at a time to see
• 11:32
  Speaker 2: what happens, Like, let's see what happens that dogs don't
• 11:35
  Speaker 2: have a heart. Oh that didn't work very well.
• 11:37
  Speaker 1: Yeah, I guess that's not diabetes related. Good question. I mean,
• 11:41
  Speaker 1: you know it could be that like some unlucky dog
• 11:43
  Speaker 1: got kicked by a cow or hit by There weren't
• 11:46
  Speaker 1: cars in those days, but hit by a horse.
• 11:47
  Speaker 3: I guess we did do some pretty awful things to
• 11:50
  Speaker 3: animals in the past. It wouldn't surprise me if there
• 11:52
  Speaker 3: were a series of experiments we were like, how do
• 11:54
  Speaker 3: they do without this? How about without that?
• 11:56
  Speaker 2: In the past, biologists are still doing horrible things to animals,
• 11:59
  Speaker 2: and the name of science.
• 12:00
  Speaker 3: We have to go through complicated protocols and institutions and
• 12:04
  Speaker 3: prove that those animals are needed for scientific discovery these days.
• 12:08
  Speaker 3: But that could be a whole different episode.
• 12:09
  Speaker 2: Unless you want to do experiments on your own children,
• 12:11
  Speaker 2: in which case you don't have to ask an IRB,
• 12:14
  Speaker 2: but you should ask your husband.
• 12:17
  Speaker 1: But if you're the parent, you could also ask yourself,
• 12:19
  Speaker 1: especially if it's like something very low risk. This is
• 12:27
  Speaker 1: a case where I could try to look up the
• 12:29
  Speaker 1: eighteen eighty nine story that I have in my brain
• 12:31
  Speaker 1: about the pancreas. But anyway, somehow they realized that there
• 12:34
  Speaker 1: was a connection between pancreas being missing and diabetes. So
• 12:38
  Speaker 1: then that sounds like the kind of thing where it
• 12:41
  Speaker 1: shouldn't have taken more than a couple of months to
• 12:43
  Speaker 1: go from knowing it was the pancreas to extracting insulin
• 12:47
  Speaker 1: from the pancreas so that you could save all these
• 12:49
  Speaker 1: kids who were dying from diabetes. But it wasn't until
• 12:52
  Speaker 1: nineteen twenty one, twenty two that we finally extracted insulin
• 12:57
  Speaker 1: from the pancreas. A lot of that time went to
• 13:01
  Speaker 1: figuring out how to purify the insulin protein away from
• 13:05
  Speaker 1: all the other digestive enzymes and proteins that are also
• 13:08
  Speaker 1: produced by the pancreas. So you know, your pancreas is
• 13:11
  Speaker 1: this organ that's there to help you digest stuff. One
• 13:14
  Speaker 1: of its main jobs is to produce proteins that break
• 13:18
  Speaker 1: down our food, and those are also made of protein.
• 13:22
  Speaker 1: So basically the pancreas is full of stuff that destroys insulin,
• 13:26
  Speaker 1: since insulin is also a protein, so like separating those
• 13:29
  Speaker 1: things away from each other. It took forty years or
• 13:32
  Speaker 1: thirty years. That's a really hard thing to do. Now,
• 13:34
  Speaker 1: that's the kind of thing we're really good at, but
• 13:36
  Speaker 1: in those days we had to invent a bunch of
• 13:38
  Speaker 1: techniques to get good at that.
• 13:39
  Speaker 2: It's amazing to me how recently we have like any
• 13:42
  Speaker 2: idea what big organs in our body do. Like before that,
• 13:45
  Speaker 2: we're just like we don't know this is just a
• 13:47
  Speaker 2: blob of meat like stuff that seems to be important.
• 13:50
  Speaker 1: What I think is amazing is that when we don't
• 13:52
  Speaker 1: know what something does, we assume it's irrelevant. So like
• 13:55
  Speaker 1: we're always saying that the spleen and the appendix, for example,
• 13:58
  Speaker 1: serve no purpose. You know, you listen to them telling
• 14:02
  Speaker 1: you in the hospital when you're getting your appendix out, like, hey,
• 14:04
  Speaker 1: you don't need this, It'll be no big deal. I
• 14:06
  Speaker 1: find that really funny that when we don't understand something,
• 14:08
  Speaker 1: we just say it's irrelevant. Like that is definitely not true.
• 14:11
  Speaker 1: In the case of the appendix, having your appendix there
• 14:14
  Speaker 1: as a reservoir for gut bacteria is like the difference
• 14:17
  Speaker 1: between life and death. To be able to recede your
• 14:20
  Speaker 1: gut microbiome and be protected from infection in the future.
• 14:23
  Speaker 1: That was like clearly important enough that we developed an
• 14:26
  Speaker 1: organ and hung onto it, you know, and.
• 14:27
  Speaker 3: The evidence for that is really good now, right, that
• 14:29
  Speaker 3: that is the appendix's role to hold onto those bacteria.
• 14:33
  Speaker 1: I mean, it's a hypothesis that's hard to prove, right
• 14:35
  Speaker 1: because it's very context dependent. But if you think about
• 14:38
  Speaker 1: the context of human history, that seems like a very
• 14:41
  Speaker 1: relevant context.
• 14:42
  Speaker 2: It's biology. So the answer is it depends.
• 14:46
  Speaker 3: It's true. It's true. So they opened up the pancreas,
• 14:50
  Speaker 3: they've been able to divide out the different proteins that
• 14:52
  Speaker 3: are in there. How do you get from art I've
• 14:54
  Speaker 3: divided out the proteins to actually treating the disease. Was
• 14:57
  Speaker 3: that a pretty easy step?
• 14:59
  Speaker 1: That's a real cool question. And this all happened at
• 15:02
  Speaker 1: a university. It was at the University of Toronto, and
• 15:05
  Speaker 1: there was a medical student there that summer, Best, and
• 15:09
  Speaker 1: he was working with a lab supervisor, Banting. So Banting
• 15:12
  Speaker 1: and Best are the famous team who discovered insulin that
• 15:15
  Speaker 1: summer in Toronto. The second they had it purified out,
• 15:19
  Speaker 1: they started treating a dog who had had their pancreas
• 15:23
  Speaker 1: taken out, and they were able to keep a dog
• 15:26
  Speaker 1: alive for a couple of months using the dog insulin extract,
• 15:30
  Speaker 1: which was pretty crude. In the meantime, they also worked
• 15:33
  Speaker 1: on better purifying insulin from cows and that's when they
• 15:36
  Speaker 1: started considering using it to treat a child. And they
• 15:39
  Speaker 1: actually moved to this really quickly.
• 15:41
  Speaker 3: Interesting.
• 15:42
  Speaker 1: I would say that would still happen today because it
• 15:44
  Speaker 1: would definitely be a life or death circumstance. We still
• 15:48
  Speaker 1: have these compassionate use exemptions from the FDA, the Food
• 15:51
  Speaker 1: and Drug Administration. In fact, I use those for our
• 15:53
  Speaker 1: phage therapy trials, where if somebody has no other options,
• 15:57
  Speaker 1: we'll allow you to do with something more experimental. But
• 16:00
  Speaker 1: that means that this like lab guy, a med student
• 16:04
  Speaker 1: who was certainly not a professional at making medicines, was
• 16:09
  Speaker 1: just taking this extract they made in the lab. And
• 16:11
  Speaker 1: the first boy they treated was a Canadian boy at
• 16:13
  Speaker 1: the hospital at the University of Toronto. He was fourteen
• 16:17
  Speaker 1: and he was wasting away because he didn't have any insulin,
• 16:20
  Speaker 1: and he went from being very very ill with very
• 16:23
  Speaker 1: high blood sugar to doing much better, like within hours,
• 16:27
  Speaker 1: and then really soon after that. There's an image that
• 16:31
  Speaker 1: I think is super iconic to anybody who knows about
• 16:33
  Speaker 1: the discovery of insulin, and it's an image of a
• 16:36
  Speaker 1: nurse with a cart and maybe a doctor next to them,
• 16:39
  Speaker 1: and the story goes that they went into this ward
• 16:42
  Speaker 1: of the hospital that had thirty comatose children with type
• 16:45
  Speaker 1: one diabetes, and the parents were there, and then they
• 16:48
  Speaker 1: injected this very experimental cocktail they had made in the
• 16:51
  Speaker 1: lab into those thirty kids and they all woke up,
• 16:55
  Speaker 1: and you know, that was a really big moment in
• 16:58
  Speaker 1: science and must have been amazing for the parents who
• 17:00
  Speaker 1: really had no reason to hope their kids had any
• 17:03
  Speaker 1: chance of getting better.
• 17:05
  Speaker 2: I mean, if your kid is wasting away and the
• 17:06
  Speaker 2: doctor says, hey, we're going to inject this experimental dog
• 17:09
  Speaker 2: organ juice into your kid, you might just be like, yes,
• 17:12
  Speaker 2: do anything please?
• 17:13
  Speaker 1: Right? Yeah, exactly.
• 17:15
  Speaker 2: But how did we know that dog pancreas would produce
• 17:19
  Speaker 2: dog insulin which humans could use. Isn't it possibility that
• 17:22
  Speaker 2: like dog insulin could be different from human insulin.
• 17:25
  Speaker 1: Yeah, that's a really good point. I mean, I guess
• 17:27
  Speaker 1: we tried it and learned in the moment that first
• 17:29
  Speaker 1: fourteen year old was injected with insulin, we figured that out.
• 17:33
  Speaker 1: And we now know that the insulins across animals have
• 17:38
  Speaker 1: really shared features. So you know, animals that have guts
• 17:43
  Speaker 1: also have insulin basically, so insulin is very conserved. This system,
• 17:48
  Speaker 1: which might seem quite delicate, is being used across the
• 17:51
  Speaker 1: animal kingdom, and in general, the insulins are pretty exchangeable, so.
• 17:55
  Speaker 2: You could like extract insulin from a hummingbird and use
• 17:58
  Speaker 2: it on a person.
• 18:00
  Speaker 1: Well, hummingbird. Wow, you'd need a lot of hummingbirds. That's
• 18:02
  Speaker 1: a good question, but yeah, I think so. There was
• 18:07
  Speaker 1: actually a Czech couple, Eva and Victor Saxel, who fled
• 18:11
  Speaker 1: Nazi occupied Czechoslovakia in nineteen forty. She was teaching English
• 18:15
  Speaker 1: in Shanghai when her symptoms of diabetes developed when she
• 18:18
  Speaker 1: was around nineteen or twenty years old. By then, highly
• 18:20
  Speaker 1: purified insulin from cows was available in the pharmacies of Shanghai,
• 18:24
  Speaker 1: and people were living pretty healthy lives in the nineteen
• 18:27
  Speaker 1: forties when they had access to insulin. But then when
• 18:30
  Speaker 1: the Japanese occupied, those pharmacies shut down and Eva was
• 18:34
  Speaker 1: in a really tough spot. How was she going to
• 18:36
  Speaker 1: survive without access to insulin from pharmacies. And so this
• 18:40
  Speaker 1: is really an amazing tale of survival because Eva and
• 18:44
  Speaker 1: Victor they actually figured out they got their hands on
• 18:46
  Speaker 1: a book showing the method that Banting and Best had
• 18:49
  Speaker 1: developed for purifying insulin out of the pancreas. They didn't
• 18:52
  Speaker 1: have dogs or cows, but they figured out that they could.
• 18:55
  Speaker 1: They were knitting socks and selling them to get money
• 18:58
  Speaker 1: to buy water buffalo pancreases, and first they figured out
• 19:01
  Speaker 1: how to get the water buffalo insulin for Eva, but
• 19:04
  Speaker 1: they actually made enough to sustain hundreds of people with
• 19:07
  Speaker 1: diabetes in the ghetto of Shanghai. So hundreds of people
• 19:11
  Speaker 1: survived for the years of World War two depending on
• 19:14
  Speaker 1: the insulin that Eva and her husband were purifying out
• 19:16
  Speaker 1: of the water buffalo pancreas. It's really amazing.
• 19:19
  Speaker 3: Oh that's interesting.
• 19:20
  Speaker 1: There's another story like that in Chile of a husband
• 19:24
  Speaker 1: who learned how to extract insulin from any kind of animal,
• 19:28
  Speaker 1: and he was helping his wife survive. And I think
• 19:30
  Speaker 1: the issue actually was that she would develop immunity to
• 19:33
  Speaker 1: one kind of insulin, and not because of the insulin itself,
• 19:36
  Speaker 1: but the extract is never pure, so she basically would
• 19:38
  Speaker 1: develop allergies to the extract. So then he would move
• 19:41
  Speaker 1: on to another kind of animal. And I think she
• 19:43
  Speaker 1: didn't have access to pharmaceutical grade insulin, so he was
• 19:46
  Speaker 1: helping her survive that way.
• 19:48
  Speaker 2: Because insulin doesn't cure diabetes, right, it just helps get
• 19:51
  Speaker 2: the sugar across the cells. Right now, you need a
• 19:54
  Speaker 2: constant supply of insulin, right, Like, how long will the
• 19:56
  Speaker 2: type one diabetic live if insulin supply just gets shut off.
• 20:00
  Speaker 1: Yeah, just a couple days, And so you hear those
• 20:02
  Speaker 1: stories about the kids wasting away over the course of
• 20:05
  Speaker 1: a year or two. And that's at the beginning of
• 20:07
  Speaker 1: the disease when they still make some insulin. But somebody
• 20:10
  Speaker 1: who has developed long term type one diabetes and has
• 20:13
  Speaker 1: been dependent on insulin for a long time, they literally
• 20:16
  Speaker 1: have no insulin. And then it's not actually a matter
• 20:19
  Speaker 1: of starvation, like you wouldn't live long enough to starve
• 20:22
  Speaker 1: with type one diabetis and no insulin, because your blood
• 20:25
  Speaker 1: sugar would go very high. And then you go into
• 20:28
  Speaker 1: a state that's called ketosis, where your body starts producing
• 20:31
  Speaker 1: key tones, basically wasting away your muscles to get energy,
• 20:36
  Speaker 1: and that process produces a lot of acid, and you
• 20:39
  Speaker 1: basically die from the acid in your blood. It's like
• 20:41
  Speaker 1: when you hit the wall in a marathon and you
• 20:43
  Speaker 1: don't have any more glucose from your liver and muscles.
• 20:46
  Speaker 1: Your liver and muscles have glycogen stores, and so then
• 20:48
  Speaker 1: your body turns to breaking down the protein of your
• 20:51
  Speaker 1: muscles to get energy, and that process produces keytnes, which
• 20:54
  Speaker 1: are acidic, and then you die from the acid in
• 20:56
  Speaker 1: your blood.
• 20:57
  Speaker 2: So we can survive if we extract insulin from these
• 21:00
  Speaker 2: poor animals. But that's a destructive process, right You can't
• 21:02
  Speaker 2: extract insulin from a dog without killing the dog, or
• 21:05
  Speaker 2: can you?
• 21:06
  Speaker 1: The way it's done, as far as I know, has
• 21:08
  Speaker 1: always been destructive. And so I mean, this could lead
• 21:10
  Speaker 1: us to another interesting conversation about like, well, okay, we
• 21:13
  Speaker 1: made this discovery, so then how did we actually produce
• 21:16
  Speaker 1: enough insulin to keep the diabetics of the world alive
• 21:18
  Speaker 1: who need it every couple hours, you know, not just days.
• 21:23
  Speaker 3: And that seems like a great topic to ponder, And
• 21:26
  Speaker 3: we'll return to it after the break and we're back.
• 21:44
  Speaker 3: And so we had just finished discussing how it had
• 21:47
  Speaker 3: been figured out how you can extract the insulin protein
• 21:49
  Speaker 3: from deceased animals, and now we're talking about starting to
• 21:52
  Speaker 3: scale up so that we can provide this in an
• 21:55
  Speaker 3: industrial sort of way.
• 21:56
  Speaker 2: I have another question before we talk about industrial production
• 21:59
  Speaker 2: of insulin, which is a naive question, like if it's
• 22:02
  Speaker 2: about the pancreas producing insulin and your pancreas is not
• 22:04
  Speaker 2: making one, why can't you do a pancreas transplant, like
• 22:07
  Speaker 2: we can do a heart transplant or a kidney transplant
• 22:10
  Speaker 2: or other kinds of transplants. And why can't I just
• 22:12
  Speaker 2: get the pancreas from a human corpse and put it
• 22:14
  Speaker 2: into a diabetic and cure their diabetes.
• 22:18
  Speaker 1: You can do that actually, and you know, Canada has
• 22:20
  Speaker 1: been so important in all these diabetes developments and the
• 22:23
  Speaker 1: Edmonton Protocol was developed also in Canada. Point is, yes,
• 22:27
  Speaker 1: you can transplant a pancreas into a person, but then
• 22:30
  Speaker 1: you have to give them immunosuppressants. In order to survive
• 22:34
  Speaker 1: after an organ transplant, you have to take immunosuppressive drugs,
• 22:38
  Speaker 1: which mean that your risk of cancer and infectious disease
• 22:41
  Speaker 1: become very high. So to do that to a young
• 22:43
  Speaker 1: person who otherwise has a healthy life expectancy is dooming
• 22:47
  Speaker 1: them to a less healthy and shorter life.
• 22:50
  Speaker 3: I assume who would you do that for.
• 22:51
  Speaker 1: Then there's one context where it happens a lot, which
• 22:54
  Speaker 1: is really cool, which is if you have kidney failure,
• 22:57
  Speaker 1: which is also more common in people with diabetes, and
• 23:00
  Speaker 1: doing a kidney transplant, you can do a tandem transplant
• 23:03
  Speaker 1: of kidney and pancreas, and you have to take the
• 23:05
  Speaker 1: immunister presence anyway for the kidney transplant, so then you
• 23:08
  Speaker 1: get a bonus of no longer being diabetic, which is
• 23:11
  Speaker 1: great because it also protects the kidney. So that's a
• 23:13
  Speaker 1: really cool procedure, which is pretty common that people get
• 23:17
  Speaker 1: a kidney and a pancreas transplant together.
• 23:19
  Speaker 2: All right, So if you don't get a pancreas transplant,
• 23:21
  Speaker 2: you need your steady supply of insulin. And we were saying,
• 23:24
  Speaker 2: we don't want to just keep killing dogs in order
• 23:26
  Speaker 2: to in order to extract the insulin from their pancreas,
• 23:29
  Speaker 2: or rats of China or whatever, So then tell us
• 23:32
  Speaker 2: about how we produce insulin without killing all of our
• 23:35
  Speaker 2: furry friends.
• 23:36
  Speaker 1: Well, for many years between around nineteen twenty something and
• 23:40
  Speaker 1: the nineteen eighties, we relied on animals that we produce
• 23:44
  Speaker 1: for food, so cows and pigs were our main source
• 23:47
  Speaker 1: of insulin for all those years, and so that scaled up.
• 23:51
  Speaker 1: In the nineteen twenties. There were two main companies that emerged,
• 23:54
  Speaker 1: and there's lots of stories about how the patents all
• 23:56
  Speaker 1: worked out, but basically Eli Lilly in Indiana became the
• 24:00
  Speaker 1: US leader in producing insulin, and Novo Nordisk in Denmark
• 24:04
  Speaker 1: became the European leader and making insulin. Currently there's a
• 24:07
  Speaker 1: third producer, so Nofi, they're French. Ninety percent of the
• 24:11
  Speaker 1: insulin in the world is still produced by those three companies.
• 24:13
  Speaker 1: And initially all their insulin was coming from animals, and
• 24:16
  Speaker 1: so you would get pig pancreas or cow pancreas from butchers.
• 24:22
  Speaker 1: It became a very refined process, and I think it
• 24:25
  Speaker 1: took you know, a crazy amount of pig pancreas. I mean,
• 24:30
  Speaker 1: you know, it was like a thousand pounds of pancreas
• 24:33
  Speaker 1: would would lead to one pound of insulin being produced.
• 24:36
  Speaker 1: It took a lot of purification and so and we
• 24:39
  Speaker 1: kept that going, and this supply was quite widespread and
• 24:42
  Speaker 1: a lot of people's lives were sustained with that insulin.
• 24:45
  Speaker 1: I don't think we could have kept scaling up. So
• 24:48
  Speaker 1: it's very good we had an early and amazing advance
• 24:51
  Speaker 1: and changing how we produced insulin around the eighties. But yeah,
• 24:55
  Speaker 1: for all those years we were collecting pigs and cow
• 24:59
  Speaker 1: pancreas from butcher an extracting insulin from there. And actually
• 25:04
  Speaker 1: we know a few people like Daniel, our friend Mones.
• 25:07
  Speaker 1: His mom she worked at Nova NOORDESK and she was
• 25:10
  Speaker 1: one of the people who developed those procedures, or at
• 25:13
  Speaker 1: least she was involved, I know in extracting insulin from pigs.
• 25:17
  Speaker 1: A lot of people were involved in making that happen.
• 25:19
  Speaker 2: I wonder if that was complicated for some folks, like
• 25:21
  Speaker 2: people who were vegetarians but diabet and then they had
• 25:24
  Speaker 2: to essentially use this animal product. Or what if you
• 25:27
  Speaker 2: were like Hindu and didn't want to use cow insulin,
• 25:30
  Speaker 2: or your Muslim and you didn't want to use pig insulin. Yeah,
• 25:33
  Speaker 2: could people like choose which animal it came from.
• 25:35
  Speaker 1: Yeah? I never had to use animal insulin myself, so
• 25:38
  Speaker 1: I don't know, but yes, I think you could choose
• 25:41
  Speaker 1: which animal source it came from. That was part of
• 25:44
  Speaker 1: the what you knew about the product. That's one very
• 25:47
  Speaker 1: big issue. Another big issue is that people would typically
• 25:50
  Speaker 1: develop sensitivities or allergies to it over time, and then
• 25:54
  Speaker 1: it would be less effective. It was a solution in
• 25:56
  Speaker 1: many ways, and there are people who lived for decades
• 25:59
  Speaker 1: taking and cow insulin, but it wasn't as easy to
• 26:02
  Speaker 1: keep that going your whole life because a lot of
• 26:04
  Speaker 1: people developed sensitivities like allergies, you mean.
• 26:07
  Speaker 2: Like your immune system is responding because it's like, hey,
• 26:09
  Speaker 2: this is a cow product, not something from inside the body.
• 26:12
  Speaker 1: Yeah, I don't even think it was the insulin itself.
• 26:15
  Speaker 1: And despite all the purification I just talked about, I
• 26:17
  Speaker 1: think it was hard to remove everything allergenic about it,
• 26:21
  Speaker 1: so then you would develop immunity.
• 26:23
  Speaker 3: Were there any concerns about diseases passing from pigs and
• 26:27
  Speaker 3: cows to people or the purification process or to cleared
• 26:30
  Speaker 3: that out.
• 26:31
  Speaker 1: That's a really cool question, and there were actually concerns.
• 26:34
  Speaker 1: I don't think we even knew about it at the time,
• 26:36
  Speaker 1: but now there's a lot of concern about preon diseases,
• 26:39
  Speaker 1: and so actually diabetics are sometimes excluded from blood donation
• 26:44
  Speaker 1: and other kind of organ transplant because of concern for
• 26:47
  Speaker 1: preon diseases, especially coming from cows. So yeah, people who
• 26:52
  Speaker 1: have been having a lot of animal products like that,
• 26:55
  Speaker 1: in theory could have been exposed to preon diseases, which
• 26:59
  Speaker 1: I think were less and at that time, also because
• 27:01
  Speaker 1: of agricultural practices, like I think preon diseases became more
• 27:04
  Speaker 1: common towards the end of the twentieth century because we
• 27:08
  Speaker 1: were doing all this like feed animal waste, like chopped
• 27:13
  Speaker 1: up animal bits to the animals themselves, and that would
• 27:17
  Speaker 1: kind of concentrate the chances of preon diseases developing. And
• 27:21
  Speaker 1: that's better now. We know not to do that now.
• 27:24
  Speaker 3: And so you indicated in the nineteen eighties something changed.
• 27:28
  Speaker 3: What was the thing that changed.
• 27:29
  Speaker 1: Well, it's so amazing to me that this happened as
• 27:32
  Speaker 1: early as it did in the eighties. But we actually
• 27:34
  Speaker 1: figured out how to produce human insulin by fermenting it
• 27:38
  Speaker 1: in bacteria and sometimes yeast by the early eighties, and
• 27:43
  Speaker 1: so this was connected to the first genetically engineered organisms.
• 27:47
  Speaker 1: In the fifties and sixties, we made the discovery of DNA.
• 27:50
  Speaker 1: We understood the central dogma that DNA was the storage
• 27:54
  Speaker 1: material of biology and that it was a blueprint for
• 27:58
  Speaker 1: producing RNA and then protein insulin is a protein. You know,
• 28:02
  Speaker 1: it was only a decade or maybe twenty years after
• 28:05
  Speaker 1: we understood that that we were really making use of
• 28:08
  Speaker 1: that information, which I think is really cool. So by
• 28:11
  Speaker 1: the seventies, the hotbed of a lot of this activity
• 28:14
  Speaker 1: was California and also Boston. People were starting to clone
• 28:19
  Speaker 1: and like they were starting to be able to, like,
• 28:21
  Speaker 1: you know, use little molecular scissors to chop out a
• 28:24
  Speaker 1: piece of DNA from a bacteria and replace it with
• 28:28
  Speaker 1: another piece of DNA that encoded something you were interested in.
• 28:32
  Speaker 1: And so it's kind of interesting to me to think
• 28:34
  Speaker 1: about how these molecular biologists who were more like theoreticians
• 28:37
  Speaker 1: about the biology almost these weren't like doctors who were
• 28:39
  Speaker 1: thinking about solutions so much. But they're like, Hey, I
• 28:42
  Speaker 1: wonder what a good important protein to try to clone
• 28:45
  Speaker 1: would be. And they're like, hey, insulin. A lot of
• 28:47
  Speaker 1: people need that. Let's try that. And so one of
• 28:50
  Speaker 1: the first things that was involved in these early cloning
• 28:53
  Speaker 1: projects just to demonstrate, like, hey, can we clone stuff
• 28:56
  Speaker 1: in bacteria was insulin and so in the seven we
• 29:00
  Speaker 1: started to do that kind of cloning. And then around
• 29:03
  Speaker 1: the mid seventies there was this moment where everyone realized, like,
• 29:07
  Speaker 1: oh my god, what are we doing. If I, like
• 29:09
  Speaker 1: complete these experiments, have I just created something that could
• 29:13
  Speaker 1: go on and replicate and cause a lot of destruction.
• 29:15
  Speaker 1: And so there was actually a meeting in a Sillamart, California.
• 29:19
  Speaker 1: I think it was around nineteen seventy seven. We all
• 29:22
  Speaker 1: know this meeting, the Silamar meeting about the safety of
• 29:26
  Speaker 1: genetic engineering basically, and maybe one hundred and fifty people
• 29:30
  Speaker 1: were there, mostly scientists, but politicians too, and they had
• 29:34
  Speaker 1: a real look in the mirror, like what are we
• 29:37
  Speaker 1: doing and is this safe? And everybody halted their work
• 29:40
  Speaker 1: until the meeting so that we could decide what to do.
• 29:44
  Speaker 1: And during that meeting there were a lot of discussion
• 29:47
  Speaker 1: about whether it was okay, and in the end there
• 29:49
  Speaker 1: were rules around what you were allowed to do, but
• 29:52
  Speaker 1: it was decided that you could indeed proceed with cloning,
• 29:56
  Speaker 1: especially under controlled circumstances. So the project for cloning insulin
• 30:02
  Speaker 1: was one of the ones that halted until after that meeting,
• 30:05
  Speaker 1: and then once the decision was made that it was
• 30:08
  Speaker 1: okay to proceed, then the scientists continued with their cloning projects.
• 30:13
  Speaker 1: And so I think it was about around nineteen seventy eight,
• 30:15
  Speaker 1: which is also the year I was born, that the
• 30:18
  Speaker 1: first insulin cloning project was completed.
• 30:21
  Speaker 3: So when I hear the word clone, I think of
• 30:23
  Speaker 3: like copying and pasting and organism.
• 30:25
  Speaker 1: Mm hmm.
• 30:26
  Speaker 3: Is it you're essentially copying and pasting bacteria that now
• 30:30
  Speaker 3: have the human insulin gene. Is that the right way
• 30:32
  Speaker 3: to think about it?
• 30:33
  Speaker 1: Yeah, exactly, So the human insulin gene was copied and
• 30:37
  Speaker 1: pasted into a bacteria, and then they asked the bacterial
• 30:41
  Speaker 1: cell to grow and produce the insulin. Now, I just
• 30:44
  Speaker 1: made it sound really simple like there was just only
• 30:46
  Speaker 1: one thing that had to be copied in But to
• 30:48
  Speaker 1: be honest, a lot of genetic engineering had to happen
• 30:51
  Speaker 1: so that the insulin could be produced. They had to
• 30:53
  Speaker 1: make sure that all the ingredients were there, that it
• 30:56
  Speaker 1: was in a spot that the bacterial sell again its
• 31:00
  Speaker 1: own needs, was producing this protein. You know, it's not
• 31:03
  Speaker 1: like the bacteria needed the insulin, So they had to
• 31:06
  Speaker 1: kind of rewire some of the metabolic pathways to force
• 31:08
  Speaker 1: that to happen. So, to be honest, it was a
• 31:11
  Speaker 1: combination of real savvy and luck that insulin could be
• 31:15
  Speaker 1: produced that way. A lot of bacteria don't have the
• 31:18
  Speaker 1: right tools for making other kinds of modifications to proteins
• 31:23
  Speaker 1: that are common in eukaryotic cells, and so the fact
• 31:26
  Speaker 1: that they could do that a little bit was luck.
• 31:28
  Speaker 1: And when we look back at which bacteria were initially
• 31:32
  Speaker 1: chosen for some of these cloning projects, they were just random,
• 31:36
  Speaker 1: Like the most common Ecoli, the kind of bacteria this
• 31:39
  Speaker 1: was done and is called ecoli assure Shia coli. And
• 31:42
  Speaker 1: there's this really famous strain of E. Coli ecol I
• 31:44
  Speaker 1: K twelve that was the one that was used in
• 31:46
  Speaker 1: this project. And E. Coli K twelve was isolated from
• 31:51
  Speaker 1: a Stanford patient who had some kind of infectious disease.
• 31:54
  Speaker 1: I think diphtheria just randomly taken from this person's gut,
• 32:00
  Speaker 1: and then it happened to have properties that were good
• 32:02
  Speaker 1: for cloning. Like I have equal IK twelve in my lab.
• 32:05
  Speaker 1: All biologists no equal IK twelve, but it's just like
• 32:08
  Speaker 1: a random Standford patient from the nineteen twenties ecoli.
• 32:12
  Speaker 2: I have some basic questions about how this works, like
• 32:14
  Speaker 2: why are we using bacteria? Is it just like the
• 32:17
  Speaker 2: simplest unit that we think we could still genetically engineer.
• 32:21
  Speaker 2: Why can't we genetically engineer dogs to make human insulin?
• 32:24
  Speaker 1: I mean, I think we were using bacteria thinking that
• 32:27
  Speaker 1: that would be a really great way to scale up
• 32:30
  Speaker 1: and not have a combination of ethics and safety and
• 32:34
  Speaker 1: just production. How great is it if the same way
• 32:37
  Speaker 1: you brew beer you can brew insulin. You know, that
• 32:40
  Speaker 1: was the thinking. We're good at producing things with bacteria.
• 32:44
  Speaker 1: Yogurt beer beer is mostly yeast, but still bread. We
• 32:48
  Speaker 1: have microbial fermentation for food production really down, So the
• 32:53
  Speaker 1: idea was to pivot that towards making medicines.
• 32:57
  Speaker 2: I see, so bacteria can't make cute puppy eyes, care
• 33:00
  Speaker 2: about growing them up and slaughtering them all for our.
• 33:03
  Speaker 1: Insulin, sure, I mean that's one way of looking at it.
• 33:05
  Speaker 1: But also just from a purely energy climate and finance perspective,
• 33:12
  Speaker 1: bacteria are very efficient, so you know it's going to
• 33:15
  Speaker 1: be quick and.
• 33:17
  Speaker 3: Much more short generation times.
• 33:20
  Speaker 1: Yes, exactly, E Coli double in twenty minutes. I still
• 33:24
  Speaker 1: think that a batch of insulin is not an overnight process,
• 33:28
  Speaker 1: like I think even in modern insulin production factories it
• 33:33
  Speaker 1: probably takes like a month or two to go from
• 33:35
  Speaker 1: the overnight culture of the bacteria producing the insulin to
• 33:40
  Speaker 1: like all of the different processing steps. Insulin is a
• 33:42
  Speaker 1: really complicated protein because it's so you know, powerful, which
• 33:47
  Speaker 1: you know, with great power comes great responsibility. Too much
• 33:50
  Speaker 1: insulin can very quickly kill you in our own bodies.
• 33:53
  Speaker 1: Our insulin is produced in an inactive form, and it
• 33:57
  Speaker 1: has to be cleaved to become active. And so the
• 34:01
  Speaker 1: insulin that's produced in the bacteria initially also is in
• 34:04
  Speaker 1: that inactive form, and then all that processing that would
• 34:07
  Speaker 1: normally happen in someone's body has to happen in the
• 34:09
  Speaker 1: factory so that the form that you inject is already active.
• 34:12
  Speaker 1: So there's a lot of complex steps there. And if
• 34:15
  Speaker 1: you were to try to take it out of puppies,
• 34:17
  Speaker 1: I think that would be way less effective. I mean,
• 34:19
  Speaker 1: the number of cows we needed to produce enough insulin
• 34:23
  Speaker 1: to support humanity was becoming untenable. Like there weren't enough
• 34:27
  Speaker 1: cows to make all the insulin, even though we have
• 34:29
  Speaker 1: a crazy appetite for meat and beef, but we still
• 34:33
  Speaker 1: couldn't probably sustain all the diabetics who needed insulin.
• 34:36
  Speaker 2: And why do we need to build this in a
• 34:38
  Speaker 2: life form anyway? Like we know how to do chemistry,
• 34:40
  Speaker 2: I mean I don't, but some people do. Why can't
• 34:43
  Speaker 2: you just like stick the atoms together and build this
• 34:45
  Speaker 2: thing out of little lego pieces, you know, synthesize the
• 34:48
  Speaker 2: thing in the lab.
• 34:49
  Speaker 1: Yeah, I like that idea. And there is a thing
• 34:51
  Speaker 1: called cell free extract production that people sometimes use these days.
• 34:56
  Speaker 1: I think it just is convenient and handy that these
• 34:59
  Speaker 1: bacteria in a way are great little factories. They already
• 35:03
  Speaker 1: know how to make copies of themselves. So I think
• 35:07
  Speaker 1: from an efficiency perspective, I mean, how great is it
• 35:10
  Speaker 1: that the bacteria you just give them a little glucose
• 35:12
  Speaker 1: and they go figure all that stuff out for themselves.
• 35:15
  Speaker 1: Otherwise you'd have to manufacture thousands and thousands of different
• 35:19
  Speaker 1: components that the bacteria otherwise just build for themselves, and.
• 35:23
  Speaker 2: They're self replicating, which is much more than our grad
• 35:25
  Speaker 2: students can do.
• 35:27
  Speaker 1: I mean, to be honest, to the way we produce
• 35:29
  Speaker 1: a lot of the things you might consider putting into
• 35:32
  Speaker 1: a sell free artificial manufacturing process, we'd probably get them
• 35:36
  Speaker 1: from microbial production to a lot of the things that
• 35:39
  Speaker 1: we produce that way we do with the help of microps.
• 35:42
  Speaker 2: Like cheese. I don't think I want to eat lab
• 35:44
  Speaker 2: synthesized cheese either. We actually have a friend who was
• 35:51
  Speaker 2: working on plant free food and he give us a
• 35:54
  Speaker 2: taste from like chemically synthesized butter, and it wasn't good. No,
• 35:59
  Speaker 2: I didn't like it. No mascrecy, but it wasn't better.
• 36:02
  Speaker 2: But what I have one more question, simple, which is
• 36:05
  Speaker 2: you talk about inserting these genes into the bacteria to
• 36:08
  Speaker 2: make it do its thing, which makes it feel like
• 36:10
  Speaker 2: the bacteria is some sort of computer and you're just
• 36:13
  Speaker 2: like changing the program and you're like, hey, can you
• 36:15
  Speaker 2: make this instead of that? Is it as simple as that?
• 36:17
  Speaker 2: Can you go a little bit into the detail of
• 36:19
  Speaker 2: like how do we know how to write this code?
• 36:22
  Speaker 2: And then how do we take the code and actually
• 36:24
  Speaker 2: put it into the genome? Right, it's not as simple
• 36:26
  Speaker 2: as like logging into the bacteria and editing the files.
• 36:29
  Speaker 2: You need to actually like put it into the DNA.
• 36:31
  Speaker 2: How do we know how to do any of that?
• 36:33
  Speaker 1: Yeah? What a good question. I'm not sure I know
• 36:36
  Speaker 1: all the answers, but I can tell you that one
• 36:38
  Speaker 1: of the first proteins that we ever even figured out
• 36:41
  Speaker 1: what the sequence of it was was insulin. And so
• 36:44
  Speaker 1: that's at the protein level, like the sequence of amino
• 36:47
  Speaker 1: acids that you need to make insulin, that's what makes
• 36:50
  Speaker 1: insulin insulin. From there, the protein sequence could have lots
• 36:55
  Speaker 1: of different DNA sequences that lead to the same protein
• 36:58
  Speaker 1: sequence because we have redund and see in the genetic code.
• 37:01
  Speaker 1: So usually you have three nucleotide bases encoding an amino
• 37:06
  Speaker 1: acid for a protein sequence, and there's many combinations of
• 37:10
  Speaker 1: DNA that would lead to the right sequence for the protein.
• 37:14
  Speaker 1: I actually don't know how they chose what DNA sequence
• 37:18
  Speaker 1: to initially clone into the E. Coli. In theory, it
• 37:21
  Speaker 1: could be that they just this is not how they
• 37:24
  Speaker 1: did it because they didn't have the right tools to
• 37:25
  Speaker 1: do this. But in theory, it could be that they
• 37:27
  Speaker 1: were just like, oh, well, we know what protein sequence
• 37:28
  Speaker 1: we want, so therefore any of these bajillion different DNA
• 37:32
  Speaker 1: sequences will work, So we'll just artificially synthesize one of
• 37:35
  Speaker 1: those and do it from there. We could do that today.
• 37:38
  Speaker 1: That's actually pretty easy thing to do. I've often thought
• 37:41
  Speaker 1: about that, Like, if you knew something you wanted to produce,
• 37:45
  Speaker 1: you could synthesize the piece of DNA and send it
• 37:49
  Speaker 1: to a yogurt manufacturer anywhere in the world, and they
• 37:51
  Speaker 1: could make vast quantities of a protein that you were
• 37:54
  Speaker 1: interested in if you could get the cells to cooperate.
• 37:56
  Speaker 1: I mean, there's a few things that would be hard
• 37:58
  Speaker 1: about it, but yeah, I think they must have known
• 38:00
  Speaker 1: this sequence for human DNA and then physically got in
• 38:04
  Speaker 1: their hands on that and chopped it out and then
• 38:08
  Speaker 1: like physically we use the word ligation, it just means
• 38:11
  Speaker 1: like pasting it into the bacteria, and it wasn't just that,
• 38:15
  Speaker 1: And a lot of this happened also with the company Genentech.
• 38:18
  Speaker 1: I'm sure that many people know more about this history
• 38:21
  Speaker 1: than I do. But some of it is proprietary, right
• 38:24
  Speaker 1: because it was happening at a company, some of it anyway.
• 38:28
  Speaker 1: And so they cloned the human DNA sequence, copied it
• 38:32
  Speaker 1: into the bacterial cell, and just fired the bacteria up
• 38:36
  Speaker 1: to produce it.
• 38:37
  Speaker 3: So now you've got the bacteria with the code, and
• 38:39
  Speaker 3: you figured out how to get them to be running
• 38:41
  Speaker 3: that code all the time, so they're making more insulin. Yeah,
• 38:44
  Speaker 3: is that insulin accumulating inside the bacteria or do they
• 38:48
  Speaker 3: excrete it? How do we get it after that?
• 38:51
  Speaker 1: That's a really good question, and I think there's actually
• 38:54
  Speaker 1: several ways you could do that, and I would not
• 38:56
  Speaker 1: be surprised if both of those options are happening in
• 39:00
  Speaker 1: various factories in the world right now. One way it
• 39:03
  Speaker 1: can happen often when a bacterial cell is confronted with
• 39:06
  Speaker 1: like a crazy amount of something it doesn't quite know
• 39:08
  Speaker 1: what to do with, it pumps it into a little
• 39:10
  Speaker 1: compartment called a vacuole, and it just like makes little
• 39:13
  Speaker 1: pouches of it. That's my understanding for the main thing
• 39:16
  Speaker 1: that happens is that you get these little pouches of
• 39:19
  Speaker 1: the vacuoles from the cells, and then the next step
• 39:22
  Speaker 1: is to pop the cells, pull out all those vacuoles,
• 39:25
  Speaker 1: and then get the insulin from there. So I'm pretty
• 39:28
  Speaker 1: sure that's the main way that it's done these days
• 39:30
  Speaker 1: from E. Coli. Not all insulin is made in bacteria
• 39:34
  Speaker 1: and ecoli. There's I think maybe twenty or thirty percent
• 39:37
  Speaker 1: of the insulin that's manufactured in the world is in
• 39:39
  Speaker 1: yeast and sachromics service. And then it's going to be
• 39:42
  Speaker 1: yet another process. And so yeah, theory, you could make
• 39:45
  Speaker 1: the cell excrete the insulin into the liquid, which might
• 39:49
  Speaker 1: make your process easier, but since insulin's a protein and
• 39:52
  Speaker 1: it can get broken down by enzymes that eat proteins,
• 39:56
  Speaker 1: in a way, you might be better off having it
• 39:58
  Speaker 1: be in a protected pouch that you could just pull
• 40:02
  Speaker 1: those aside and get the insulin out.
• 40:04
  Speaker 3: I don't think I've thought before about the complicated process
• 40:07
  Speaker 3: of acquiring this stuff after the bacteria has made it.
• 40:10
  Speaker 3: Like I guess i'd imagine, like you know, you skim
• 40:12
  Speaker 3: the top and there's the insulin and you stick it
• 40:14
  Speaker 3: into needles. But yeah, I mean extracting all of those vacules, Yeah,
• 40:17
  Speaker 3: and popping them doesn't sound like easy work.
• 40:20
  Speaker 1: No, that's a sophisticated process. And then the protein sequence
• 40:24
  Speaker 1: still contains extra bits that make it inactive on purpose,
• 40:28
  Speaker 1: so that it's not in our bodies. We don't want
• 40:30
  Speaker 1: it to be active exactly when it's produced. It's like
• 40:33
  Speaker 1: unleashed and activated very intentionally, So to get it to
• 40:37
  Speaker 1: be in that active form takes yet more steps.
• 40:40
  Speaker 3: All right, awesome, So we're going to take a break now,
• 40:42
  Speaker 3: and when we get back from the break, we're going
• 40:43
  Speaker 3: to hear about lydia Villa Komorov's contribution to this field.
• 41:04
  Speaker 3: All right, and we're back. So it's Women's History month.
• 41:07
  Speaker 3: We're trying to feature some amazing women that most people
• 41:10
  Speaker 3: have perhaps not heard of. And you agreed to come
• 41:14
  Speaker 3: on the show and talk to us about lydia Villa Comarov.
• 41:17
  Speaker 3: What was her contribution to this field.
• 41:19
  Speaker 1: Well, lydia Villa Comorov was a grad student in the
• 41:22
  Speaker 1: nineteen seventies during this era where we were just figuring
• 41:26
  Speaker 1: out that we could clone bacteria. So not only did
• 41:29
  Speaker 1: we understand the central dogma, the way that molecular biology
• 41:32
  Speaker 1: is encoded. We were now starting to be able to
• 41:34
  Speaker 1: manipulate it.
• 41:36
  Speaker 3: Interesting, So a few.
• 41:37
  Speaker 1: People had done anything in this area. Right around the
• 41:40
  Speaker 1: time that doctor Villa Komarova finished her PhD from MIT
• 41:44
  Speaker 1: in nineteen seventy five and she embarked on a really
• 41:47
  Speaker 1: bold post doc at Harvard. It was to clone the
• 41:51
  Speaker 1: human insulin gene into bacteria. It was so bold that
• 41:54
  Speaker 1: Harvard actually asked them to stop. They paused the project
• 41:57
  Speaker 1: for fear of ethical consideration for what the consequences of
• 42:02
  Speaker 1: humans cloning things could be. So she actually continued her
• 42:05
  Speaker 1: project at Cold Spring Harbor. There were lots of failures.
• 42:08
  Speaker 1: I think that was a really tough post doc, but
• 42:11
  Speaker 1: ultimately she succeeded. I think that was around nineteen seventy eight,
• 42:14
  Speaker 1: and by the early eighties there was commercially available human
• 42:18
  Speaker 1: insulin that had been synthesized in bacteria, and her project
• 42:23
  Speaker 1: was to clone the gene for insulin into E. Coli,
• 42:28
  Speaker 1: the bacteria. So she has a paper in PNAS, the
• 42:32
  Speaker 1: Proceedings of the National Academy of Science, and in that
• 42:35
  Speaker 1: paper she demonstrates that you can pull the insulin gene
• 42:40
  Speaker 1: from humans, clone it into bacteria and get the bacterial
• 42:44
  Speaker 1: cells to replicate. So it was a big step, not
• 42:48
  Speaker 1: just that this was an idea, but that it could
• 42:51
  Speaker 1: actually be done, and everyone had their eyes on this happening.
• 42:55
  Speaker 1: It was considered risky and important enough that her project
• 42:59
  Speaker 1: was halted as these considerations about the ethics were being
• 43:02
  Speaker 1: discussed at the ASILAMAR meeting, and after the ASILAMAR meeting
• 43:07
  Speaker 1: she was allowed to proceed. And it all happened very
• 43:10
  Speaker 1: fast because her paper was already published in nineteen seventy eight,
• 43:13
  Speaker 1: and I think the Assillamar meeting was only in nineteen
• 43:15
  Speaker 1: seventy seven, So I bet that was intense. I bet
• 43:18
  Speaker 1: she was working hard with.
• 43:20
  Speaker 2: What ethics concerns do we have? Because, as we said earlier,
• 43:22
  Speaker 2: bacteria can't make peppy eyes, so what are the ethical issues.
• 43:26
  Speaker 1: It was a very new idea that humans could clone things,
• 43:29
  Speaker 1: that we could decide what the DNA that a creature
• 43:33
  Speaker 1: encoded was. And in some ways, I don't think it's
• 43:37
  Speaker 1: different than agriculture, not just farming of crops, but I
• 43:41
  Speaker 1: mean dog breeding or horse breeding or anything where you
• 43:43
  Speaker 1: select for traits that you care about and then intentionally
• 43:47
  Speaker 1: push a population towards having specific traits that we had
• 43:52
  Speaker 1: always only done that in the context of selection, where
• 43:56
  Speaker 1: all of the reproducing was happening by itself, or you know,
• 44:00
  Speaker 1: what you might consider a natural way, in the sense
• 44:02
  Speaker 1: that you were just like picking out the peas that
• 44:04
  Speaker 1: had the color you were excited about and crossing those,
• 44:07
  Speaker 1: and then you get more, and after hundreds of years
• 44:09
  Speaker 1: you can't even recognize the organism compared to where it started.
• 44:12
  Speaker 2: From the way we transformed corn from like a tiny
• 44:16
  Speaker 2: little grain to this like hugely productive.
• 44:18
  Speaker 1: Food, for example, exactly, or like watermelons, or you know
• 44:21
  Speaker 1: something where watermelons weren't these like amazing, gicy, genormous fruits
• 44:27
  Speaker 1: when we first found them, right, We cultivated that, and
• 44:31
  Speaker 1: the consequences of the cultivation are obviously encoded in the
• 44:35
  Speaker 1: genome and in some ways not really different than cloning
• 44:39
  Speaker 1: something on purpose. In fact, we're not that good at cloning.
• 44:43
  Speaker 1: Like cloning requires us as humans to decide what pieces
• 44:47
  Speaker 1: of DNA belong in an organism, and we typically are
• 44:51
  Speaker 1: kind of bad at that. It's interesting. I went to
• 44:54
  Speaker 1: grad school in an era where rational design of proteins
• 44:57
  Speaker 1: was really popular and a lot of people's projects were
• 45:00
  Speaker 1: like looking at protein sequences and being like, oh, I
• 45:03
  Speaker 1: think we should put an alanine there, and that's going
• 45:06
  Speaker 1: to make this work better. That kind of thing, and
• 45:08
  Speaker 1: typically it didn't actually work better. So in some ways,
• 45:11
  Speaker 1: I think we've come to respect that evolution and allowing
• 45:15
  Speaker 1: natural selection to happen is if in some ways, a
• 45:17
  Speaker 1: more powerful way to pull off things you want to do.
• 45:21
  Speaker 1: But you would never get insulin production through evolution. I mean,
• 45:25
  Speaker 1: bacteria would never produce insulin. So it's actually a really
• 45:28
  Speaker 1: great case for genetic engineering. It was a very cool
• 45:31
  Speaker 1: problem that lydia Villa comorov took on because it was
• 45:35
  Speaker 1: so effective and it really would never have happened without cloning.
• 45:39
  Speaker 1: So your question was how did it come to be
• 45:42
  Speaker 1: that this was an ethical problem? And the real issue
• 45:45
  Speaker 1: was just that we as humans were scared that we
• 45:49
  Speaker 1: were going to unleash some kind of monster. What were
• 45:52
  Speaker 1: the consequences of us genetically engineering things? I mean, more recently,
• 45:57
  Speaker 1: we've had similar debates about crispers, and you've heard that
• 46:00
  Speaker 1: there is even a case where a Chinese scientist used
• 46:04
  Speaker 1: Crisper to genetically engineer a baby, a human that has really,
• 46:08
  Speaker 1: really big ethical questions, And this was happening only in bacteria,
• 46:13
  Speaker 1: but it was the first time it had happened, and
• 46:15
  Speaker 1: we were rightfully, really thinking carefully about what the consequences
• 46:19
  Speaker 1: could be. For example, imagine you cloned a bacteria that
• 46:23
  Speaker 1: contained genes that could break down petroleum, and then you
• 46:27
  Speaker 1: unleashed that in an oil mining operation. You could really
• 46:31
  Speaker 1: cause a lot of destruction. And what if that was
• 46:33
  Speaker 1: just impossible to control and then you destroyed huge natural
• 46:39
  Speaker 1: resources unintentionally or intentionally for that matter. So those were
• 46:43
  Speaker 1: the kinds of questions people were worried about.
• 46:45
  Speaker 2: Or what if it helped the bacteria organize and it
• 46:47
  Speaker 2: crawled out of the vat and like extracted vengeance for
• 46:50
  Speaker 2: all the brethren that we've tortured in order to extract
• 46:53
  Speaker 2: insulin from them.
• 46:54
  Speaker 1: That's a great question, but I'm pretty sure they didn't
• 46:56
  Speaker 1: talk about it.
• 46:57
  Speaker 2: That's a very polite answer to a totally bunkers question.
• 47:00
  Speaker 2: You all should have seen her face.
• 47:04
  Speaker 1: That didn't make it to the top ten list for
• 47:07
  Speaker 1: discussion out of Solomar.
• 47:08
  Speaker 2: I bet there were some science fiction writers there. They
• 47:10
  Speaker 2: would have come up with that scenario. It didn't take
• 47:12
  Speaker 2: me very long to think about it.
• 47:15
  Speaker 3: I think there was a recent ant Solomar meeting that
• 47:17
  Speaker 3: was sort of inspired by then prior meeting. So you
• 47:20
  Speaker 3: mentioned the ethical issues associated with Crisper. Yeah, but I
• 47:23
  Speaker 3: think they like literally had another Ansilomar meeting with like
• 47:26
  Speaker 3: similar goals to figure out what direction.
• 47:30
  Speaker 1: I think it's next month, Oh is it? Yeah? I
• 47:32
  Speaker 1: think it's next week. I think you guys could have
• 47:33
  Speaker 1: this episode coincide or we could look into that. That'd
• 47:36
  Speaker 1: be cool. Yeah, because my friend Jen Martini was invited,
• 47:38
  Speaker 1: but she couldn't go because she's teaching, and I know
• 47:40
  Speaker 1: she doesn't start teaching until.
• 47:41
  Speaker 3: Next week's I mean maybe we should have a whole
• 47:44
  Speaker 3: episode on the ethical implications of Crisper too. That yeah,
• 47:48
  Speaker 3: important and timely.
• 47:49
  Speaker 2: So how ballsy was it for her to take on
• 47:51
  Speaker 2: this project because if it didn't work, she could ended
• 47:54
  Speaker 2: up with basically nothing, no result. I mean, this was
• 47:56
  Speaker 2: like really swinging for a home run, wasn't it.
• 47:59
  Speaker 1: Yeah, that's a really good question. It'd be fun to
• 48:01
  Speaker 1: talk to the people who are around at that time.
• 48:04
  Speaker 1: I don't think I would give this to a student
• 48:05
  Speaker 1: as their only project. It does seem really risky. But yeah,
• 48:09
  Speaker 1: if you look at the people involved, like who her
• 48:12
  Speaker 1: bosses were and who their collaborators were. You know, they
• 48:15
  Speaker 1: were used to taking on really big projects and hitting
• 48:18
  Speaker 1: for home runs. So that's what you do in Boston, Yeah, exactly.
• 48:25
  Speaker 3: So what came for her after this? So she did
• 48:27
  Speaker 3: this amazing breakthrough, was the first person to do this
• 48:30
  Speaker 3: amazing thing. What did she do after that?
• 48:32
  Speaker 1: She stayed in science. Actually, she made a really good
• 48:35
  Speaker 1: use of her science education, and she went on to
• 48:38
  Speaker 1: work on not just insulin, but other hormones that are
• 48:41
  Speaker 1: related to insulin. Some of them are called insulin like
• 48:44
  Speaker 1: growth factors. It's a really complex field that I honestly
• 48:49
  Speaker 1: couldn't tell you too much about what all the implications are,
• 48:52
  Speaker 1: but I do know that she ran a lab and
• 48:55
  Speaker 1: spent many years studying hormones that are related to insulin.
• 48:59
  Speaker 1: And so she stayed in that field. And she also
• 49:02
  Speaker 1: really put a lot of energy into being a role
• 49:05
  Speaker 1: model and a leader for other people who wanted to
• 49:08
  Speaker 1: become scientists. She'd encountered definitely roadblocks herself, considering that most
• 49:14
  Speaker 1: institutions wouldn't even accept women as applicants to graduate school
• 49:18
  Speaker 1: when she was applying, and so she became a co
• 49:20
  Speaker 1: founding member of the Society for the Advancement of Chicanos
• 49:24
  Speaker 1: and Hispanics and Native Americans and Science or SACNAS, And
• 49:28
  Speaker 1: that was back in the nineteen seventies, and I actually
• 49:30
  Speaker 1: didn't know that. I personally have had a lot of
• 49:33
  Speaker 1: students who have been supported by SAKNAS to go to conferences.
• 49:37
  Speaker 1: They have meetings every year. I work at UC Irvine,
• 49:40
  Speaker 1: which is a Hispanic serving institution, and a lot of
• 49:43
  Speaker 1: our students have gone to those meetings and had a
• 49:46
  Speaker 1: really good time. So I think that's really cool she
• 49:49
  Speaker 1: founded that.
• 49:50
  Speaker 2: And why isn't she a zillionaire? I mean, I know
• 49:52
  Speaker 2: that this technology is the foundation of like billions of
• 49:56
  Speaker 2: dollars of annual profit for Nova Noordis and Eli Lilly.
• 50:00
  Speaker 2: Why isn't she elon Musk?
• 50:02
  Speaker 1: What a good question. I don't know the details of
• 50:04
  Speaker 1: what kind of IP they tried to get for the
• 50:07
  Speaker 1: technique that they developed. I also know that genen Tech
• 50:11
  Speaker 1: was really involved, and so actually an important thing to
• 50:13
  Speaker 1: say is that, you know, so her paper came out
• 50:15
  Speaker 1: in nineteen seventy eight, she didn't keep up with this
• 50:18
  Speaker 1: specific feel. I know that genen Tech was the company
• 50:22
  Speaker 1: that really developed the possibility of producing insulin in bacteria.
• 50:28
  Speaker 1: My sense is that what she did was proof of concept,
• 50:31
  Speaker 1: I see, which was critical because it made people ready
• 50:34
  Speaker 1: for the idea. But my guess is that genen Tech
• 50:37
  Speaker 1: went on and developed the technology in its own specific
• 50:41
  Speaker 1: way that could then have ip that stayed within the company.
• 50:44
  Speaker 2: Isn't there like fast acting and long acting with insulin stuff.
• 50:48
  Speaker 1: Her paper came out in nineteen seventy eight, and I
• 50:50
  Speaker 1: know that by nineteen eighty two the Food and Drug
• 50:52
  Speaker 1: Administration had approved human insulin to be given to people.
• 50:57
  Speaker 1: I was diagnosed with type one diabetes in nineteen eighty
• 50:59
  Speaker 1: four and I never took animal insulin. I only got
• 51:02
  Speaker 1: the human insulin at that time. It was just the
• 51:05
  Speaker 1: straight up human insulin sequence. It hadn't been modified to
• 51:08
  Speaker 1: have new properties. But that's pretty amazing that we scaled
• 51:11
  Speaker 1: that up for humanity that quickly. And so the insulins
• 51:15
  Speaker 1: that I took with like regular insulin, is still produced
• 51:19
  Speaker 1: today and I used it for twelve years, like multiple
• 51:23
  Speaker 1: injections daily, And now if you go to Walmart, you
• 51:27
  Speaker 1: can actually buy that kind of insulin for twenty five dollars.
• 51:30
  Speaker 1: This is probably the most important thing I'm saying like
• 51:33
  Speaker 1: ever anytime I have an audience, I say this because
• 51:35
  Speaker 1: it could really save lives that you can buy regular
• 51:38
  Speaker 1: human insulin at Walmart. It's intended for cats and dogs
• 51:42
  Speaker 1: who have diabetes. But it's exactly the insulin that I
• 51:45
  Speaker 1: used for many years, and it cost twenty five dollars
• 51:49
  Speaker 1: and you don't need a prescription. It's just over the counter.
• 51:51
  Speaker 1: You can just go to Walmart and buy this insulin
• 51:54
  Speaker 1: and it's exactly the same bottle as the one that
• 51:57
  Speaker 1: I used in the nineteen eighties. So, starting in the
• 51:59
  Speaker 1: nineteen eight e we scaled up fermentation of human insulin
• 52:03
  Speaker 1: to be available for all people. I wouldn't say access
• 52:07
  Speaker 1: is perfect, but it's pretty good. Like there's definitely parts
• 52:11
  Speaker 1: of the world where you can buy insulin at a
• 52:13
  Speaker 1: pretty reasonable cost. I'm sure you've heard a lot about
• 52:16
  Speaker 1: the cost of insulin, Like if you cross the border
• 52:18
  Speaker 1: into Mexico, you can buy this insulin at a very
• 52:20
  Speaker 1: reasonable cost too. It wasn't until the nineties that engineered
• 52:25
  Speaker 1: insulins that have different kinetics, like they can be faster
• 52:28
  Speaker 1: and slower. Those came out in the nineties. The slower
• 52:31
  Speaker 1: insulins were available earlier, like the insulin you can buy
• 52:34
  Speaker 1: at Walmart. There's a slower one too, that's called NPH,
• 52:37
  Speaker 1: and that didn't require crazy bioengineering or I don't know,
• 52:40
  Speaker 1: they've somehow figured that out way earlier.
• 52:42
  Speaker 3: Why would you want faster and slower insulin, Well.
• 52:45
  Speaker 1: The regular insulin it takes a few hours to become active.
• 52:49
  Speaker 1: So the insulin exists in little trimers around zinc molecules
• 52:55
  Speaker 1: in a dimer. So there's two zinc molecules that each
• 52:58
  Speaker 1: have three insulin molecules attached to them, So there's six
• 53:01
  Speaker 1: insulin molecules all hanging out together. You have to wait
• 53:05
  Speaker 1: for them to dissociate because the insulin is only active
• 53:08
  Speaker 1: as a monomer by itself, So when you inject regular insulin,
• 53:12
  Speaker 1: you have to wait one hour for it to even
• 53:15
  Speaker 1: start working at all, and it doesn't peak until three hours. Now,
• 53:19
  Speaker 1: when you eat your food, it doesn't come in immediately either,
• 53:22
  Speaker 1: But regular insulin is too slow for an average meal,
• 53:25
  Speaker 1: so most people would have to either inject their insulin early,
• 53:29
  Speaker 1: but that's kind of dangerous. Imagine you inject your insulin,
• 53:32
  Speaker 1: but you're like your food is late, or you're on
• 53:35
  Speaker 1: a walk and you forget to eat or you know,
• 53:37
  Speaker 1: something like that. If your blood seger goes too low,
• 53:39
  Speaker 1: you die from low blood sugar immediately. It's like the
• 53:42
  Speaker 1: most common cause of death in people with type one diabetes.
• 53:46
  Speaker 1: So that's really really something you have to be careful with.
• 53:48
  Speaker 1: So having your insulin kinetics not really matching when you
• 53:52
  Speaker 1: need the insulin is both for convenience and basic survival,
• 53:57
  Speaker 1: really really important. There was a big arms race between
• 54:01
  Speaker 1: Eli Lilly and Novonordisk in the nineties to rationally design
• 54:06
  Speaker 1: insulins that had different properties, and they both succeeded in
• 54:10
  Speaker 1: slightly different ways. And now you can buy insulin that
• 54:14
  Speaker 1: falls apart more easily. Those dimers on the trimers of
• 54:18
  Speaker 1: the zinc are not as stable, so they fall apart
• 54:21
  Speaker 1: more quickly. And now when you inject the insulin, it
• 54:24
  Speaker 1: starts to become active within minutes and peaks within an hour,
• 54:28
  Speaker 1: which matches how people eat much better. So it's safer
• 54:33
  Speaker 1: and a little bit easier to keep your blood sugar
• 54:36
  Speaker 1: within range. But matching the kinetics of your food with
• 54:38
  Speaker 1: the kinetics of your insulin is just a major challenge.
• 54:41
  Speaker 3: So is it still the case that today people with
• 54:44
  Speaker 3: diabetes need to be really careful about, like what kinds
• 54:46
  Speaker 3: of insulin that they're injecting. Has it gotten easier over time?
• 54:50
  Speaker 3: I feel like I heard once that there are these
• 54:52
  Speaker 3: things that can attach to your body that sort of
• 54:54
  Speaker 3: do all the measuring for you. What is it like today.
• 54:56
  Speaker 1: Well, so there's been big changes both in how we
• 55:00
  Speaker 1: deliver insulin and how we monitor blood sugar. So we
• 55:04
  Speaker 1: haven't talked about blood sugar monitoring at all in any
• 55:06
  Speaker 1: of this, but I'll bring up that, you know, we've
• 55:09
  Speaker 1: known for centuries how to detect glucose and urine, but
• 55:13
  Speaker 1: that's very old information. By the time the sugar hits
• 55:15
  Speaker 1: your urine, that's like happened hours ago, and you can't
• 55:18
  Speaker 1: really take that sample and demand quite in the same
• 55:20
  Speaker 1: way as you can take a blood sample. So we
• 55:22
  Speaker 1: started poking our fingers to get blood sugar measurements. Those
• 55:26
  Speaker 1: devices started being available at home in the nineteen eighties
• 55:29
  Speaker 1: and then for about ten or fifteen years. We now
• 55:32
  Speaker 1: have these sensors that you can put a little sensor
• 55:34
  Speaker 1: on your arm and you get blood sugar information every
• 55:37
  Speaker 1: five minutes. So those sensors help you see what your
• 55:41
  Speaker 1: blood sugar is. We also have both injections for insulin
• 55:45
  Speaker 1: and also insulin pumps. So the pump will deliver insulin
• 55:49
  Speaker 1: at rates that you tell it to give you the insulin.
• 55:52
  Speaker 1: But none of this is happening without a lot of thought.
• 55:56
  Speaker 1: There's not like a machine that just takes care of
• 55:58
  Speaker 1: it for you. A lot of people when they see
• 56:00
  Speaker 1: an insulin pump imagine like, oh, that must be so
• 56:03
  Speaker 1: nice that like, oh, the AI is taking care of
• 56:05
  Speaker 1: your bl chicker for you, And that's not the case
• 56:08
  Speaker 1: at all. Insulin pumps just do what you tell them
• 56:10
  Speaker 1: to do.
• 56:10
  Speaker 3: That is what I imagined. Thanks for clarifying that.
• 56:13
  Speaker 1: Even my doctors, like if I go to the eye doctor,
• 56:15
  Speaker 1: they're like, oh, it must be some nice having your
• 56:17
  Speaker 1: pump doing that for you. But I mean, no, the
• 56:19
  Speaker 1: pump is not operating independently.
• 56:22
  Speaker 2: And talk per a minute about why that's a hard problem.
• 56:24
  Speaker 2: I mean, people might be thinking, well, you have a
• 56:26
  Speaker 2: sense of that tells you how much glucose you have,
• 56:28
  Speaker 2: and you have insulin which brings the glucose down. Why
• 56:31
  Speaker 2: can't you just you know, fit a straight line to
• 56:33
  Speaker 2: that and descide how much insulin I have? Why do
• 56:35
  Speaker 2: you need a human brain in the loop there or
• 56:38
  Speaker 2: why is it a hard problem.
• 56:39
  Speaker 1: There's a lot of reasons it's a hard problem. A
• 56:41
  Speaker 1: big one is that the way that we're giving the
• 56:44
  Speaker 1: insulin just subcutaneously means that it's slow. So you know,
• 56:49
  Speaker 1: when you eat, your pancreas is exactly in the right
• 56:52
  Speaker 1: place at the right time, sensing the glucose as it's
• 56:56
  Speaker 1: getting released from your digestion. So then not only do
• 56:59
  Speaker 1: you get real time information, but you also have the
• 57:03
  Speaker 1: insulin being delivered exactly where you need it. So when
• 57:05
  Speaker 1: you take insulin subcutaneously, it takes like a good half
• 57:09
  Speaker 1: an hour to dissolve and become active. I guess. Another
• 57:13
  Speaker 1: really important thing to say is that the insulin's activity
• 57:17
  Speaker 1: is affected by your own activity. So if you're exercising,
• 57:20
  Speaker 1: the insulin that you're taking will do a lot more work.
• 57:23
  Speaker 1: And your own pancrease has more than one hormone. It
• 57:27
  Speaker 1: has insulin and also glucagon, so it's a two component system.
• 57:31
  Speaker 1: Insulin drives your blood sugar down, Glucagon drives your blood
• 57:34
  Speaker 1: sugar up. So what glucagon does is it releases the
• 57:38
  Speaker 1: glycogen stores in your liver and muscle to raise your
• 57:41
  Speaker 1: blood sugar. So if this dangerous thing starts to happen
• 57:45
  Speaker 1: that your insulin drives your blood sugar too low. Then
• 57:48
  Speaker 1: the glucagon can pick it up from the floor and
• 57:50
  Speaker 1: save your life so you don't die from low blood sugar.
• 57:54
  Speaker 1: Our insulin pumps don't have glucagon in them. Glucagon is
• 57:56
  Speaker 1: a really delicate hormone. There's about one hundred companies there
• 58:00
  Speaker 1: engineering more stable glukug on. Maybe we'll have that soon,
• 58:03
  Speaker 1: but right now the pumps just have insulin. There is
• 58:06
  Speaker 1: a company that's trying to make a two component pump
• 58:09
  Speaker 1: that also has glucagon, but anyway, that doesn't happen yet.
• 58:12
  Speaker 1: So there's a number of reasons, like you could, in theory,
• 58:16
  Speaker 1: use the glucose information, the old information you're getting from
• 58:19
  Speaker 1: the sensor in your arm, and have that direct the
• 58:22
  Speaker 1: dosing of the insulin from your pump. However, your pump
• 58:26
  Speaker 1: doesn't know if you're about to go running, or if
• 58:29
  Speaker 1: you are sick, or you know. The amount of insulin
• 58:31
  Speaker 1: you need is affected by easily forty two factors that
• 58:35
  Speaker 1: most of them can't be measured, and so you need
• 58:38
  Speaker 1: your brain to synthesize all those factors and think through
• 58:41
  Speaker 1: the decision of how much insulin you need, and.
• 58:43
  Speaker 2: You don't trust chat GPT to make those decisions for
• 58:46
  Speaker 2: you yet.
• 58:46
  Speaker 1: I mean, I wouldn't mind like chatting with chat GPT
• 58:49
  Speaker 1: about it and getting ideas, but I would definitely want
• 58:52
  Speaker 1: to be the one who's the buck stops with me
• 58:54
  Speaker 1: when it comes to that decision.
• 58:55
  Speaker 2: All right, So then our last question is what do
• 58:57
  Speaker 2: you see happening in the future, like in ten year
• 59:00
  Speaker 2: and fifty years, in one hundred years, what's going to
• 59:03
  Speaker 2: change about our treatment of diabetes or understanding of the
• 59:06
  Speaker 2: biochemical processes.
• 59:08
  Speaker 1: Well, there's biological and engineering fronts to talk about, and
• 59:12
  Speaker 1: actually I should make a really big shout out to
• 59:15
  Speaker 1: the group of people who are engineering devices. There's even
• 59:19
  Speaker 1: groups of people who have built algorithms that do take
• 59:22
  Speaker 1: the information from the glucose sensors and use it to
• 59:25
  Speaker 1: dose the insulin. Sometimes they're called loopers. They're closing the loop.
• 59:29
  Speaker 1: Many of those algorithms are open source, and people are
• 59:33
  Speaker 1: having good results with better blood sugar control using those algorithms.
• 59:37
  Speaker 1: It takes a really tech savvy person and somebody who
• 59:42
  Speaker 1: you know. In my case, I go running every day
• 59:44
  Speaker 1: and I don't think those algorithms take exercise into account
• 59:47
  Speaker 1: in a way that works for me. So that's why
• 59:50
  Speaker 1: I personally am not using the looping algorithms, although I'm interested.
• 59:54
  Speaker 1: So if there's someone out there who's into looping, like,
• 59:56
  Speaker 1: my mind is open. So there are people making really
• 59:59
  Speaker 1: big progress on the algorithms, I think those are going
• 1:00:02
  Speaker 1: to be a really big frontier that our algorithms are
• 1:00:05
  Speaker 1: going to get better and better. Some of the major
• 1:00:07
  Speaker 1: insulin pump companies have soft versions of those algorithms with
• 1:00:11
  Speaker 1: a lot of safety on them, where they keep the
• 1:00:14
  Speaker 1: average blood sugar values a little higher to give you
• 1:00:17
  Speaker 1: a safety buffer. So that's starting to happen already. In fact,
• 1:00:21
  Speaker 1: the pump I use has a soft algorithm like that that,
• 1:00:24
  Speaker 1: especially for sleeping at night when there's not as many
• 1:00:27
  Speaker 1: different changes going on, it can do a really good
• 1:00:29
  Speaker 1: job of helping you keep your blood sugar in control.
• 1:00:32
  Speaker 1: So that's already getting better. I'd say the engineering front
• 1:00:35
  Speaker 1: will include better sensors, better algorithms. If we had glucagon,
• 1:00:39
  Speaker 1: then that will also close the loop and help to
• 1:00:42
  Speaker 1: make the measurements better overall, though, I mean, humans are
• 1:00:46
  Speaker 1: really complex. Like one of my favorite results recently showed
• 1:00:49
  Speaker 1: how people eating exactly the same meal one week apart
• 1:00:53
  Speaker 1: and wearing a continuous glucose monitor had different blood sugar
• 1:00:56
  Speaker 1: responses to the same meal, which I think highlights that
• 1:01:00
  Speaker 1: challenge of why it has to be pretty thoughtful how
• 1:01:03
  Speaker 1: you are dosing insulin even for the same meal and
• 1:01:06
  Speaker 1: the same person. You can't assume it's going to work
• 1:01:08
  Speaker 1: the same way each time. But then on the biology front,
• 1:01:12
  Speaker 1: there's also really big progress. So we have been learning
• 1:01:16
  Speaker 1: how to direct the program of stem cells and differentiating
• 1:01:21
  Speaker 1: them into different kinds of cells that we can use
• 1:01:23
  Speaker 1: for different kinds of medicine. There's a whole arm of
• 1:01:26
  Speaker 1: research towards building pancreatic beta cells, the ones that secrete insulin,
• 1:01:33
  Speaker 1: so that they could be transplanted. The first versions of
• 1:01:37
  Speaker 1: these have required people to take immunosuppressants, just like for
• 1:01:41
  Speaker 1: a pancreased transplant, so it didn't feel as exciting to me,
• 1:01:46
  Speaker 1: but that's actually starting to get better, and there are
• 1:01:50
  Speaker 1: efforts towards making hypoimmune, so like not giving an immune
• 1:01:54
  Speaker 1: response cells, so that people could get transplants with these
• 1:01:59
  Speaker 1: kind of cells and not have to take imminosuppressants and
• 1:02:01
  Speaker 1: potentially have them work to control their blood sugar. I
• 1:02:05
  Speaker 1: don't know, it's interesting to me to imagine trusting a
• 1:02:08
  Speaker 1: little renegade group of cells to do that. But you know,
• 1:02:11
  Speaker 1: that will get tested and we'll know a lot more
• 1:02:14
  Speaker 1: those are. On the treatment front, there's another whole aspect
• 1:02:17
  Speaker 1: to talk about, which is, you know, the way that
• 1:02:20
  Speaker 1: type one diabetes develops, at least your immune system starts
• 1:02:23
  Speaker 1: to attack your pancreas. This process can take a couple
• 1:02:27
  Speaker 1: of years. A lot of people when they're diagnosed, imagine that.
• 1:02:30
  Speaker 1: You know, oh, I got a cold and then I
• 1:02:32
  Speaker 1: got diabetes, or I took finals and I was all
• 1:02:34
  Speaker 1: stressed out and that caused my diabetes. But really it
• 1:02:37
  Speaker 1: was just the straw that broke the camel's back. And
• 1:02:39
  Speaker 1: this was a process that was going on for a
• 1:02:41
  Speaker 1: couple of years, and then a stressful circumstance made you
• 1:02:44
  Speaker 1: need more insulin, so then the system couldn't support you anymore.
• 1:02:48
  Speaker 1: But now there's actually a treatment for people who are
• 1:02:52
  Speaker 1: just starting to build the antibodies that are killing their
• 1:02:55
  Speaker 1: pancreatic cells, and that treatment will basically target and slow
• 1:03:01
  Speaker 1: down the immune process. It's called tea yield. And we
• 1:03:04
  Speaker 1: actually have a friend whose son was caught early because
• 1:03:08
  Speaker 1: he had a really savvy mom who understood what was
• 1:03:10
  Speaker 1: going on, and she helped him get that treatment, and
• 1:03:13
  Speaker 1: it's supposed to delay the onset of his type one
• 1:03:16
  Speaker 1: diabetes for several years. So he's probably still on that path,
• 1:03:20
  Speaker 1: but I could imagine us getting even better at that.
• 1:03:22
  Speaker 1: And to be honest, the reason I became a microbiome
• 1:03:25
  Speaker 1: scientist is that we know that the diagnosis of autoimmune
• 1:03:30
  Speaker 1: diseases is becoming more and more frequent. EXAMA allergies, type
• 1:03:34
  Speaker 1: one diabetes, a lot of autoimmune diseases are becoming more common,
• 1:03:38
  Speaker 1: and we don't exactly know why. It's clearly a change
• 1:03:42
  Speaker 1: in our immune development and the exposures we have in
• 1:03:45
  Speaker 1: early life. And for example, most babies born in human
• 1:03:50
  Speaker 1: history were breastfed and their guts became dominated by a
• 1:03:55
  Speaker 1: biffidobacteria that's good at helping break down the breast milk fibers,
• 1:03:59
  Speaker 1: and that's now missing from most people in the industrialized world.
• 1:04:04
  Speaker 1: So there are big studies right now to try to
• 1:04:06
  Speaker 1: reintroduce that biffodobacteria and see if it helps us reduce
• 1:04:11
  Speaker 1: our incidence of autoimmune diseases. So the easiest disease to
• 1:04:14
  Speaker 1: study is ezema in some ways because it emerges within
• 1:04:17
  Speaker 1: the first year or so of life, and they're now
• 1:04:19
  Speaker 1: are big studies using biffidobacteria to see if we can
• 1:04:22
  Speaker 1: reduce those diseases. But there's also right now there's a
• 1:04:26
  Speaker 1: big study in Europe across five countries with more than
• 1:04:29
  Speaker 1: a thousand people who are from families who are a
• 1:04:32
  Speaker 1: little bit more at risk for developing type one diabetes,
• 1:04:35
  Speaker 1: and they're introducing that biffodobacteria. So it's going to take
• 1:04:38
  Speaker 1: like probably ten years until we have the beginnings of
• 1:04:41
  Speaker 1: the answer, because type one diabetes can happen in childhood
• 1:04:43
  Speaker 1: or even adulthood. But we're gonna know if these changes
• 1:04:48
  Speaker 1: in microbiome exposure that put us on a better immune
• 1:04:52
  Speaker 1: development course could help to reduce the incidence of type
• 1:04:57
  Speaker 1: one diabetes. So it might be akin to vaccination in
• 1:05:00
  Speaker 1: the future that we intentionally develop our microbial exposures to
• 1:05:05
  Speaker 1: direct the way our immune systems develop so we don't
• 1:05:08
  Speaker 1: end up with all these autoimmune diseases.
• 1:05:11
  Speaker 2: All right, Well, it sounds like a lot of potential
• 1:05:13
  Speaker 2: progress and lots of different directions. I hope that young
• 1:05:15
  Speaker 2: scientists out there are excited about working in all of
• 1:05:18
  Speaker 2: these angles and taking big risks like Lydia did.
• 1:05:22
  Speaker 3: Yeah, thanks for being on the show, kut Ri enough,
• 1:05:25
  Speaker 3: that was awesome.
• 1:05:25
  Speaker 1: Thank you.
• 1:05:26
  Speaker 2: I'm going to nominate you for next year's White Sin
• 1:05:28
  Speaker 2: Research Award as well, even that you've twenty five years ago.
• 1:05:30
  Speaker 1: Now I'm going to nominate you. You. I mean, I
• 1:05:37
  Speaker 1: think it's amazing that our society has produced all this
• 1:05:41
  Speaker 1: insulin to keep so many people with diabetes alive. And
• 1:05:44
  Speaker 1: we could do better with the access. But I mean,
• 1:05:46
  Speaker 1: considering that it's like water for so many people to
• 1:05:50
  Speaker 1: depend on the insulin, it's kind of amazing that we've
• 1:05:52
  Speaker 1: kept these systems going.
• 1:05:54
  Speaker 2: All right. Well, thanks very much, China, and thanks everybody
• 1:05:56
  Speaker 2: for listening.
• 1:06:04
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• 1:06:08
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