Insulin (featuring Dr. Katrine Whiteson)

Daniel and Kelly chat with Dr. Katrine Whiteson about diabetes, the history of insulin production, and Dr. Lydia Villa-Komaroff. 

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Episode Transcript

Speaker 1 (00:05):
We as humans were scared that we were going to
unleash some kind of monster. What were the consequences of
us genetically engineering things? I mean, more recently, we've had
similar debates about crispers, And maybe you've heard that there
was even a case where a Chinese scientist used crisper
to genetically engineer a baby, a human that has really

(00:27):
really big ethical questions, And this was happening only in bacteria,
but it was the first time it had happened, and
we were rightfully, really thinking carefully about what the consequences
could be. For example, imagine you cloned a bacteria that
contained genes that could break down petroleum, and then you
unleashed that in an oil mining operation. You could really

(00:50):
cause a lot of destruction. And what if that was
just impossible to control and then you destroyed huge natural
resources unintentionally intentionally for that matter. So those were the
kinds of questions people were worried about.

Speaker 2 (01:03):
Or what if it helped the bactery organize and it
crawled out of the vat and like extracted vengeance for
all the brethren that we've tortured in order to extract
incident from them.

Speaker 1 (01:13):
That's a great question, but I'm pretty sure about it.

Speaker 2 (01:16):
That's a very polite answer to a totally bonkers questionin
you all should have seen her face.

Speaker 1 (01:23):
That didn't make it to the top ten list for
discussion out of so lamar.

Speaker 3 (01:40):
Hi.

Speaker 2 (01:41):
I'm Daniel. I'm a particle physicist and a member of
the White Senn Research Institute in Irvine, and today I'm
going to be an extra big fan of biology.

Speaker 3 (01:49):
Hello, I'm Kelly Wiener Smith. Can I be like an
adjunct at the White sin Research Institute?

Speaker 1 (01:54):
Like?

Speaker 3 (01:55):
Is that what friends are called?

Speaker 2 (01:57):
Come be a visiting professor? No problem? Yes, all right?

Speaker 3 (02:01):
Does that come with dinner?

Speaker 2 (02:05):
Dinner is a bonus? Yes? Plus you can add this
as an extra affiliation on all of your papers to
make you sound really.

Speaker 3 (02:11):
Smart, fantastic. I'm go to you. I'm gonna put it
right on my CV. Have you ever done a show
with your wife before?

Speaker 2 (02:17):
I have never done a podcast episode with Katrina, though
I've had lots and lots of science conversations over the
dinner table, so we definitely talked a lot about science
and board our teenagers to death. But no, I don't
think it's ever been recorded. So this is great for posterity.

Speaker 3 (02:33):
Well, and I'm excited because we have talked on the
show often about how, you know, since she studies microbiome stuff,
sometimes you find bags of poop in your freezer and
stuff like that, and I feel like it's really important
for people to like put a voice to those stories.
And today that's gonna happen.

Speaker 2 (02:48):
You just want another poop in the freezer ally on
the show to outvote me. That's what's going on here, really,
I do.

Speaker 3 (02:53):
I want the gross votes to outnumber the people who
are squeamish. And also I like, you know, pushing the
envelope in the direction of gross so that I don't
seem as gross, you know, Like, mostly I want Zach
to realize how lucky he is. Yeah, that there's not
bags of poop in the freezer like the dead bird.
Not a big deal.

Speaker 2 (03:11):
All right, Well, welcome to the podcast where we pretend
to be talking about science, but really we're doing marital therapy.

Speaker 3 (03:19):
Well, and on today's show, we're very lucky to have
Katrina come on to talk to us about diabetes and
the history of insulin production and the future of insulin production.
And she was amazing. She had a lot of incredible insights.

Speaker 2 (03:32):
Yeah, I think a lot of people think they understand
diabetes generally, but there's a lot of really fascinating biochemistry
and a lot of nuance there, and a lot to
understand about the daily life of somebody with diabetes. And
it's kind of amazing that until about one hundred years ago,
diabetes was a death sentence. You got diabetes and you
were dead a couple years later. And now because of
amazing biologists, we can save the lives of all those kids,

(03:54):
and people like my wife can grow up and be
like a professor and had kids and live a full life.
It's really kind of an amazing testament to what science
can do.

Speaker 3 (04:03):
And I'm not going to release any spoilers here, but
there were at least two things she talked about where
I was like, I thought I knew and I was
totally wrong. And so I think we're gonna have a
good episode of sort of dispelling rumors or myths about diabetes.

Speaker 2 (04:17):
All right, Well, then, without further ado, let's welcome my
favorite scientist at the whites And Research Institute. So then
today it's my great pleasure to welcome to the podcast.
Co president of the White Sun Research Institute and winner
of the whites In Research Prize as Professor Katrina whites

(04:38):
In at uc Irvine Katriina, Welcome to the podcast.

Speaker 1 (04:41):
Thank you.

Speaker 3 (04:42):
I'm so excited you're here.

Speaker 1 (04:45):
I didn't even know about those awards, but I will.

Speaker 2 (04:48):
I guess I'll go update your CV right now.

Speaker 3 (04:54):
Update your tenure packet, all the things.

Speaker 2 (04:57):
Yeah, but we did just invite Chain onto the podcast
to joke around with her. We invited her on because
she's a deep expert in today's topic.

Speaker 3 (05:06):
So today we're talking about bioengineering bacteria, we're talking about diabetes,
we're talking about lydia villa comarov and it's going to
be an amazing conversation and we're super excited to have
you here.

Speaker 1 (05:18):
Thank you.

Speaker 3 (05:19):
So by the end of the episode, we're going to
get to bacteria producing pharmaceutical components. But let's start by
talking about diabetes. What are the mechanisms underlying diabetes.

Speaker 1 (05:30):
Well, that's a really good question, and actually even just
using the word diabetes already doesn't give you quite enough
information to be able to answer that question, because there's
two really different forms of diabetes. I guess we could
go back to ancient times when the word first arose,
and in that time we understood that sugar was involved

(05:50):
and that not being able to process sugar was involved.
We've actually known that for hundreds of years, so you
could think of glucose as maybe the first biomarker. There
were really interesting ways that people would detect that someone
had diabetes. It's actually diabetes melitis, and the words mean
that you're losing water due to sugar. And people would
take urine and put it out to see if the

(06:12):
ants were attracted to it. They would taste the urine
to see if it was sweet, and that would give
them a clue that you had this wasting disease where
your body couldn't process sugar. And like, probably the first
thing that pops into mind when you think of diabetes
in modern times is it's associated with obesity, But actually
diabetes is a wasting disease. It means that you can't

(06:33):
get energy from sugar and you actually starve to death
while drowning with lots of sugar in your blood. So
I think that's just actually really amazing and usually counterintuitive.
When I'm teaching, I sometimes show images of the children
who would die from diabetes before the insulin was discovered,
and they are emaciated because they're unable to get any
energy from the sugar that they're eating. So to back up,

(06:54):
I mean, there's two main kinds of diabetes. The first one,
type one diabetes for a while even called juvenile diabetes,
is when your immune system kills the cells in your
pancreas that make insulin, so you're no longer able to
access sugar. So you eat sugar. It gets into your blood,
but the key that allows the sugar to be used
by your cells is just totally missing.

Speaker 2 (07:15):
And so you're saying, insulin is that key. Insulin is
a thing that takes sugar from your blood and into
your cells exactly.

Speaker 1 (07:21):
Insulin is a protein like ham, but it's acting like
a little it's a little robot. It's a little key
that actually summons the transporters that help glucose get into
your cell up to the surface and then the gates
open and the sugar can get into the cells. Without that,
the sugar just sits in your blood and the cells starve.

Speaker 3 (07:42):
Is there a toxic effect of the sugar building up
as well? Or is it just that you're starving? Is
the main problem the long term?

Speaker 1 (07:49):
The sugar in your blood is super toxic. But those
are kind of like decade long problems. So if you're
dealing with starving in the course of weeks or months,
then the decade long problem of too much sugar in
your blood is just not something to worry about. But yes, hope,
too much sugar in your blood is definitely toxic. And
I think that's the part that's more famous about diabetes
right now, because most diabetes in our time, ninety percent

(08:12):
of diabetes is what we called type two diabetes, and
it can be lifestyle associated, but amazingly, it's actually more genetic.
It's more inherited to get type two diabetes. So about
ninety percent of the diabetes in the world right now
emerges usually later in life, and it's not because you
don't have insulin. You could actually have plenty of insulin,
it's just not working very well, so your body is

(08:35):
resistant to the use of the insulin. That's associated with
metabolic syndrome, but actually can be quite genetic. You can
be a very healthy, thin looking person and still get
type two diabetes. So that's also a bit of a
misnomertis always assume it's associated with lifestyle, but in the
case of type two diabetes, if it is arising because
of obesity, you can reverse it if you eat less carbs,

(08:57):
exercise more, and in general it don't overload the system
that depends on insulin. You can resensitize your body to
the insulin that it can make, and you can also
take medicines that make the insulin more effective.

Speaker 2 (09:09):
All right, so let me recap for the non biologists.
You eat a ham sandwich, your body turns some of
that into sugar, puts it into your blood, but then
your cells and your body, like your muscles, can't access
it from your blood without insulin, this thing that takes
it from the blood into the cells. And type one
diabetes is when your body kills the cells to produce insulin,

(09:30):
so you just don't have it. Type two is when
you still have insulin, but because of some metabolic things,
it's not working as well, or it's just not.

Speaker 1 (09:38):
As effective, or you just don't have enough. Yeah, that's
about right. There's a lot of nuances you will not
be surprised to hear. For example, your brain, which uses
about twenty percent of the glucus in your body, doesn't
really depend on insulin in the same way. So I
find that kind of amazing that your brain is just
like this constant machine that's using a lot of the
sugar in your blood. It's like the main reason it's

(09:58):
so important that our blod glucose levels are maintained at
a certain level, otherwise your brain doesn't function. So that's
kind of independent of the insulin. And then there's other
really cool exceptions, like your muscles, especially during exercise, they're
extra sensitive to being able to get glucose in. So
there are extreme examples, Like there's a story about a
guy one hundred years ago before there was really insulin,

(10:21):
who kept himself alive with like a really crazy exercise
regiment and he had like amazing muscle mass and he
kind of like extended his capacity to metabolize his diet
even though he didn't have much insulin. So it's kind
of interesting we didn't do more of that, but on average, yeah,
without insulin, your blood will be full of sugar and
your cells will be starving. And if you look at
a picture of a kid who died from type one

(10:43):
diabetes before nineteen twenty one, when insulin was discovered, they
look emaciated, which is just terrible so.

Speaker 2 (10:49):
You're starving, but your blood is filled with sugar and
your pea is filled with sugar. You just don't have
access to it. So it's like being hungry at a buffet.
It's crazy.

Speaker 1 (10:58):
Yeah, exactly.

Speaker 3 (10:59):
Do you know this story of how we discovered insulin.

Speaker 1 (11:02):
Yeah, I mean, there's actually a lot of really good
stories around that. It was a slow process like science
often is, because we got a lot of important clues
even maybe half a century before the discovery of insulin,
Like we knew for a long time, hundreds of years
that it was related to glucose. So then by the
eighteen eighties in Germany, there were scientists who figured out

(11:23):
that if you removed the pancreas from a dog, it
would cause essentially the symptoms of diabetes.

Speaker 2 (11:29):
What were they doing. Were they just like taking random
organs out of dogs one at a time to see
what happens, Like, let's see what happens that dogs don't
have a heart. Oh that didn't work very well.

Speaker 1 (11:37):
Yeah, I guess that's not diabetes related. Good question. I mean,
you know it could be that like some unlucky dog
got kicked by a cow or hit by There weren't
cars in those days, but hit by a horse.

Speaker 3 (11:47):
I guess we did do some pretty awful things to
animals in the past. It wouldn't surprise me if there
were a series of experiments we were like, how do
they do without this? How about without that?

Speaker 2 (11:56):
In the past, biologists are still doing horrible things to animals,
and the name of science.

Speaker 3 (12:00):
We have to go through complicated protocols and institutions and
prove that those animals are needed for scientific discovery these days.
But that could be a whole different episode.

Speaker 2 (12:09):
Unless you want to do experiments on your own children,
in which case you don't have to ask an IRB,
but you should ask your husband.

Speaker 1 (12:17):
But if you're the parent, you could also ask yourself,
especially if it's like something very low risk. This is
a case where I could try to look up the
eighteen eighty nine story that I have in my brain
about the pancreas. But anyway, somehow they realized that there
was a connection between pancreas being missing and diabetes. So

(12:38):
then that sounds like the kind of thing where it
shouldn't have taken more than a couple of months to
go from knowing it was the pancreas to extracting insulin
from the pancreas so that you could save all these
kids who were dying from diabetes. But it wasn't until
nineteen twenty one, twenty two that we finally extracted insulin
from the pancreas. A lot of that time went to

(13:01):
figuring out how to purify the insulin protein away from
all the other digestive enzymes and proteins that are also
produced by the pancreas. So you know, your pancreas is
this organ that's there to help you digest stuff. One
of its main jobs is to produce proteins that break
down our food, and those are also made of protein.

(13:22):
So basically the pancreas is full of stuff that destroys insulin,
since insulin is also a protein, so like separating those
things away from each other. It took forty years or
thirty years. That's a really hard thing to do. Now,
that's the kind of thing we're really good at, but
in those days we had to invent a bunch of
techniques to get good at that.

Speaker 2 (13:39):
It's amazing to me how recently we have like any
idea what big organs in our body do. Like before that,
we're just like we don't know this is just a
blob of meat like stuff that seems to be important.

Speaker 1 (13:50):
What I think is amazing is that when we don't
know what something does, we assume it's irrelevant. So like
we're always saying that the spleen and the appendix, for example,
serve no purpose. You know, you listen to them telling
you in the hospital when you're getting your appendix out, like, hey,
you don't need this, It'll be no big deal. I
find that really funny that when we don't understand something,
we just say it's irrelevant. Like that is definitely not true.

(14:11):
In the case of the appendix, having your appendix there
as a reservoir for gut bacteria is like the difference
between life and death. To be able to recede your
gut microbiome and be protected from infection in the future.
That was like clearly important enough that we developed an
organ and hung onto it, you know, and.

Speaker 3 (14:27):
The evidence for that is really good now, right, that
that is the appendix's role to hold onto those bacteria.

Speaker 1 (14:33):
I mean, it's a hypothesis that's hard to prove, right
because it's very context dependent. But if you think about
the context of human history, that seems like a very
relevant context.

Speaker 2 (14:42):
It's biology. So the answer is it depends.

Speaker 3 (14:46):
It's true. It's true. So they opened up the pancreas,
they've been able to divide out the different proteins that
are in there. How do you get from art I've
divided out the proteins to actually treating the disease. Was
that a pretty easy step?

Speaker 1 (14:59):
That's a real cool question. And this all happened at
a university. It was at the University of Toronto, and
there was a medical student there that summer, Best, and
he was working with a lab supervisor, Banting. So Banting
and Best are the famous team who discovered insulin that
summer in Toronto. The second they had it purified out,

(15:19):
they started treating a dog who had had their pancreas
taken out, and they were able to keep a dog
alive for a couple of months using the dog insulin extract,
which was pretty crude. In the meantime, they also worked
on better purifying insulin from cows and that's when they
started considering using it to treat a child. And they
actually moved to this really quickly.

Speaker 3 (15:41):
Interesting.

Speaker 1 (15:42):
I would say that would still happen today because it
would definitely be a life or death circumstance. We still
have these compassionate use exemptions from the FDA, the Food
and Drug Administration. In fact, I use those for our
phage therapy trials, where if somebody has no other options,
we'll allow you to do with something more experimental. But
that means that this like lab guy, a med student

(16:04):
who was certainly not a professional at making medicines, was
just taking this extract they made in the lab. And
the first boy they treated was a Canadian boy at
the hospital at the University of Toronto. He was fourteen
and he was wasting away because he didn't have any insulin,
and he went from being very very ill with very
high blood sugar to doing much better, like within hours,

(16:27):
and then really soon after that. There's an image that
I think is super iconic to anybody who knows about
the discovery of insulin, and it's an image of a
nurse with a cart and maybe a doctor next to them,
and the story goes that they went into this ward
of the hospital that had thirty comatose children with type
one diabetes, and the parents were there, and then they

(16:48):
injected this very experimental cocktail they had made in the
lab into those thirty kids and they all woke up,
and you know, that was a really big moment in
science and must have been amazing for the parents who
really had no reason to hope their kids had any
chance of getting better.

Speaker 2 (17:05):
I mean, if your kid is wasting away and the
doctor says, hey, we're going to inject this experimental dog
organ juice into your kid, you might just be like, yes,
do anything please?

Speaker 1 (17:13):
Right? Yeah, exactly.

Speaker 2 (17:15):
But how did we know that dog pancreas would produce
dog insulin which humans could use. Isn't it possibility that
like dog insulin could be different from human insulin.

Speaker 1 (17:25):
Yeah, that's a really good point. I mean, I guess
we tried it and learned in the moment that first
fourteen year old was injected with insulin, we figured that out.
And we now know that the insulins across animals have
really shared features. So you know, animals that have guts
also have insulin basically, so insulin is very conserved. This system,

(17:48):
which might seem quite delicate, is being used across the
animal kingdom, and in general, the insulins are pretty exchangeable, so.

Speaker 2 (17:55):
You could like extract insulin from a hummingbird and use
it on a person.

Speaker 1 (18:00):
Well, hummingbird. Wow, you'd need a lot of hummingbirds. That's
a good question, but yeah, I think so. There was
actually a Czech couple, Eva and Victor Saxel, who fled
Nazi occupied Czechoslovakia in nineteen forty. She was teaching English
in Shanghai when her symptoms of diabetes developed when she
was around nineteen or twenty years old. By then, highly

(18:20):
purified insulin from cows was available in the pharmacies of Shanghai,
and people were living pretty healthy lives in the nineteen
forties when they had access to insulin. But then when
the Japanese occupied, those pharmacies shut down and Eva was
in a really tough spot. How was she going to
survive without access to insulin from pharmacies. And so this
is really an amazing tale of survival because Eva and

(18:44):
Victor they actually figured out they got their hands on
a book showing the method that Banting and Best had
developed for purifying insulin out of the pancreas. They didn't
have dogs or cows, but they figured out that they could.
They were knitting socks and selling them to get money
to buy water buffalo pancreases, and first they figured out
how to get the water buffalo insulin for Eva, but

(19:04):
they actually made enough to sustain hundreds of people with
diabetes in the ghetto of Shanghai. So hundreds of people
survived for the years of World War two depending on
the insulin that Eva and her husband were purifying out
of the water buffalo pancreas. It's really amazing.

Speaker 3 (19:19):
Oh that's interesting.

Speaker 1 (19:20):
There's another story like that in Chile of a husband
who learned how to extract insulin from any kind of animal,
and he was helping his wife survive. And I think
the issue actually was that she would develop immunity to
one kind of insulin, and not because of the insulin itself,
but the extract is never pure, so she basically would
develop allergies to the extract. So then he would move

(19:41):
on to another kind of animal. And I think she
didn't have access to pharmaceutical grade insulin, so he was
helping her survive that way.

Speaker 2 (19:48):
Because insulin doesn't cure diabetes, right, it just helps get
the sugar across the cells. Right now, you need a
constant supply of insulin, right, Like, how long will the
type one diabetic live if insulin supply just gets shut off.

Speaker 1 (20:00):
Yeah, just a couple days, And so you hear those
stories about the kids wasting away over the course of
a year or two. And that's at the beginning of
the disease when they still make some insulin. But somebody
who has developed long term type one diabetes and has
been dependent on insulin for a long time, they literally
have no insulin. And then it's not actually a matter
of starvation, like you wouldn't live long enough to starve

(20:22):
with type one diabetis and no insulin, because your blood
sugar would go very high. And then you go into
a state that's called ketosis, where your body starts producing
key tones, basically wasting away your muscles to get energy,
and that process produces a lot of acid, and you
basically die from the acid in your blood. It's like
when you hit the wall in a marathon and you

(20:43):
don't have any more glucose from your liver and muscles.
Your liver and muscles have glycogen stores, and so then
your body turns to breaking down the protein of your
muscles to get energy, and that process produces keytnes, which
are acidic, and then you die from the acid in
your blood.

Speaker 2 (20:57):
So we can survive if we extract insulin from these
poor animals. But that's a destructive process, right You can't
extract insulin from a dog without killing the dog, or
can you?

Speaker 1 (21:06):
The way it's done, as far as I know, has
always been destructive. And so I mean, this could lead
us to another interesting conversation about like, well, okay, we
made this discovery, so then how did we actually produce
enough insulin to keep the diabetics of the world alive
who need it every couple hours, you know, not just days.

Speaker 3 (21:23):
And that seems like a great topic to ponder, And
we'll return to it after the break and we're back.

(21:44):
And so we had just finished discussing how it had
been figured out how you can extract the insulin protein
from deceased animals, and now we're talking about starting to
scale up so that we can provide this in an
industrial sort of way.

Speaker 2 (21:56):
I have another question before we talk about industrial production
of insulin, which is a naive question, like if it's
about the pancreas producing insulin and your pancreas is not
making one, why can't you do a pancreas transplant, like
we can do a heart transplant or a kidney transplant
or other kinds of transplants. And why can't I just
get the pancreas from a human corpse and put it
into a diabetic and cure their diabetes.

Speaker 1 (22:18):
You can do that actually, and you know, Canada has
been so important in all these diabetes developments and the
Edmonton Protocol was developed also in Canada. Point is, yes,
you can transplant a pancreas into a person, but then
you have to give them immunosuppressants. In order to survive
after an organ transplant, you have to take immunosuppressive drugs,

(22:38):
which mean that your risk of cancer and infectious disease
become very high. So to do that to a young
person who otherwise has a healthy life expectancy is dooming
them to a less healthy and shorter life.

Speaker 3 (22:50):
I assume who would you do that for.

Speaker 1 (22:51):
Then there's one context where it happens a lot, which
is really cool, which is if you have kidney failure,
which is also more common in people with diabetes, and
doing a kidney transplant, you can do a tandem transplant
of kidney and pancreas, and you have to take the
immunister presence anyway for the kidney transplant, so then you
get a bonus of no longer being diabetic, which is
great because it also protects the kidney. So that's a

(23:13):
really cool procedure, which is pretty common that people get
a kidney and a pancreas transplant together.

Speaker 2 (23:19):
All right, So if you don't get a pancreas transplant,
you need your steady supply of insulin. And we were saying,
we don't want to just keep killing dogs in order
to in order to extract the insulin from their pancreas,
or rats of China or whatever, So then tell us
about how we produce insulin without killing all of our
furry friends.

Speaker 1 (23:36):
Well, for many years between around nineteen twenty something and
the nineteen eighties, we relied on animals that we produce
for food, so cows and pigs were our main source
of insulin for all those years, and so that scaled up.
In the nineteen twenties. There were two main companies that emerged,
and there's lots of stories about how the patents all

(23:56):
worked out, but basically Eli Lilly in Indiana became the
US leader in producing insulin, and Novo Nordisk in Denmark
became the European leader and making insulin. Currently there's a
third producer, so Nofi, they're French. Ninety percent of the
insulin in the world is still produced by those three companies.
And initially all their insulin was coming from animals, and
so you would get pig pancreas or cow pancreas from butchers.

(24:22):
It became a very refined process, and I think it
took you know, a crazy amount of pig pancreas. I mean,
you know, it was like a thousand pounds of pancreas
would would lead to one pound of insulin being produced.
It took a lot of purification and so and we
kept that going, and this supply was quite widespread and
a lot of people's lives were sustained with that insulin.

(24:45):
I don't think we could have kept scaling up. So
it's very good we had an early and amazing advance
and changing how we produced insulin around the eighties. But yeah,
for all those years we were collecting pigs and cow
pancreas from butcher an extracting insulin from there. And actually
we know a few people like Daniel, our friend Mones.

(25:07):
His mom she worked at Nova NOORDESK and she was
one of the people who developed those procedures, or at
least she was involved, I know in extracting insulin from pigs.
A lot of people were involved in making that happen.

Speaker 2 (25:19):
I wonder if that was complicated for some folks, like
people who were vegetarians but diabet and then they had
to essentially use this animal product. Or what if you
were like Hindu and didn't want to use cow insulin,
or your Muslim and you didn't want to use pig insulin. Yeah,
could people like choose which animal it came from.

Speaker 1 (25:35):
Yeah? I never had to use animal insulin myself, so
I don't know, but yes, I think you could choose
which animal source it came from. That was part of
the what you knew about the product. That's one very
big issue. Another big issue is that people would typically
develop sensitivities or allergies to it over time, and then
it would be less effective. It was a solution in

(25:56):
many ways, and there are people who lived for decades
taking and cow insulin, but it wasn't as easy to
keep that going your whole life because a lot of
people developed sensitivities like allergies, you mean.

Speaker 2 (26:07):
Like your immune system is responding because it's like, hey,
this is a cow product, not something from inside the body.

Speaker 1 (26:12):
Yeah, I don't even think it was the insulin itself.
And despite all the purification I just talked about, I
think it was hard to remove everything allergenic about it,
so then you would develop immunity.

Speaker 3 (26:23):
Were there any concerns about diseases passing from pigs and
cows to people or the purification process or to cleared
that out.

Speaker 1 (26:31):
That's a really cool question, and there were actually concerns.
I don't think we even knew about it at the time,
but now there's a lot of concern about preon diseases,
and so actually diabetics are sometimes excluded from blood donation
and other kind of organ transplant because of concern for
preon diseases, especially coming from cows. So yeah, people who

(26:52):
have been having a lot of animal products like that,
in theory could have been exposed to preon diseases, which
I think were less and at that time, also because
of agricultural practices, like I think preon diseases became more
common towards the end of the twentieth century because we
were doing all this like feed animal waste, like chopped

(27:13):
up animal bits to the animals themselves, and that would
kind of concentrate the chances of preon diseases developing. And
that's better now. We know not to do that now.

Speaker 3 (27:24):
And so you indicated in the nineteen eighties something changed.
What was the thing that changed.

Speaker 1 (27:29):
Well, it's so amazing to me that this happened as
early as it did in the eighties. But we actually
figured out how to produce human insulin by fermenting it
in bacteria and sometimes yeast by the early eighties, and
so this was connected to the first genetically engineered organisms.
In the fifties and sixties, we made the discovery of DNA.

(27:50):
We understood the central dogma that DNA was the storage
material of biology and that it was a blueprint for
producing RNA and then protein insulin is a protein. You know,
it was only a decade or maybe twenty years after
we understood that that we were really making use of
that information, which I think is really cool. So by

(28:11):
the seventies, the hotbed of a lot of this activity
was California and also Boston. People were starting to clone
and like they were starting to be able to, like,
you know, use little molecular scissors to chop out a
piece of DNA from a bacteria and replace it with
another piece of DNA that encoded something you were interested in.

(28:32):
And so it's kind of interesting to me to think
about how these molecular biologists who were more like theoreticians
about the biology almost these weren't like doctors who were
thinking about solutions so much. But they're like, Hey, I
wonder what a good important protein to try to clone
would be. And they're like, hey, insulin. A lot of
people need that. Let's try that. And so one of
the first things that was involved in these early cloning

(28:53):
projects just to demonstrate, like, hey, can we clone stuff
in bacteria was insulin and so in the seven we
started to do that kind of cloning. And then around
the mid seventies there was this moment where everyone realized, like,
oh my god, what are we doing. If I, like
complete these experiments, have I just created something that could
go on and replicate and cause a lot of destruction.

(29:15):
And so there was actually a meeting in a Sillamart, California.
I think it was around nineteen seventy seven. We all
know this meeting, the Silamar meeting about the safety of
genetic engineering basically, and maybe one hundred and fifty people
were there, mostly scientists, but politicians too, and they had
a real look in the mirror, like what are we

(29:37):
doing and is this safe? And everybody halted their work
until the meeting so that we could decide what to do.
And during that meeting there were a lot of discussion
about whether it was okay, and in the end there
were rules around what you were allowed to do, but
it was decided that you could indeed proceed with cloning,
especially under controlled circumstances. So the project for cloning insulin

(30:02):
was one of the ones that halted until after that meeting,
and then once the decision was made that it was
okay to proceed, then the scientists continued with their cloning projects.
And so I think it was about around nineteen seventy eight,
which is also the year I was born, that the
first insulin cloning project was completed.

Speaker 3 (30:21):
So when I hear the word clone, I think of
like copying and pasting and organism.

Speaker 1 (30:25):
Mm hmm.

Speaker 3 (30:26):
Is it you're essentially copying and pasting bacteria that now
have the human insulin gene. Is that the right way
to think about it?

Speaker 1 (30:33):
Yeah, exactly, So the human insulin gene was copied and
pasted into a bacteria, and then they asked the bacterial
cell to grow and produce the insulin. Now, I just
made it sound really simple like there was just only
one thing that had to be copied in But to
be honest, a lot of genetic engineering had to happen
so that the insulin could be produced. They had to

(30:53):
make sure that all the ingredients were there, that it
was in a spot that the bacterial sell again its
own needs, was producing this protein. You know, it's not
like the bacteria needed the insulin, So they had to
kind of rewire some of the metabolic pathways to force
that to happen. So, to be honest, it was a
combination of real savvy and luck that insulin could be

(31:15):
produced that way. A lot of bacteria don't have the
right tools for making other kinds of modifications to proteins
that are common in eukaryotic cells, and so the fact
that they could do that a little bit was luck.
And when we look back at which bacteria were initially
chosen for some of these cloning projects, they were just random,

(31:36):
Like the most common Ecoli, the kind of bacteria this
was done and is called ecoli assure Shia coli. And
there's this really famous strain of E. Coli ecol I
K twelve that was the one that was used in
this project. And E. Coli K twelve was isolated from
a Stanford patient who had some kind of infectious disease.
I think diphtheria just randomly taken from this person's gut,

(32:00):
and then it happened to have properties that were good
for cloning. Like I have equal IK twelve in my lab.
All biologists no equal IK twelve, but it's just like
a random Standford patient from the nineteen twenties ecoli.

Speaker 2 (32:12):
I have some basic questions about how this works, like
why are we using bacteria? Is it just like the
simplest unit that we think we could still genetically engineer.
Why can't we genetically engineer dogs to make human insulin?

Speaker 1 (32:24):
I mean, I think we were using bacteria thinking that
that would be a really great way to scale up
and not have a combination of ethics and safety and
just production. How great is it if the same way
you brew beer you can brew insulin. You know, that
was the thinking. We're good at producing things with bacteria.
Yogurt beer beer is mostly yeast, but still bread. We

(32:48):
have microbial fermentation for food production really down, So the
idea was to pivot that towards making medicines.

Speaker 2 (32:57):
I see, so bacteria can't make cute puppy eyes, care
about growing them up and slaughtering them all for our.

Speaker 1 (33:03):
Insulin, sure, I mean that's one way of looking at it.
But also just from a purely energy climate and finance perspective,
bacteria are very efficient, so you know it's going to
be quick and.

Speaker 3 (33:17):
Much more short generation times.

Speaker 1 (33:20):
Yes, exactly, E Coli double in twenty minutes. I still
think that a batch of insulin is not an overnight process,
like I think even in modern insulin production factories it
probably takes like a month or two to go from
the overnight culture of the bacteria producing the insulin to
like all of the different processing steps. Insulin is a

(33:42):
really complicated protein because it's so you know, powerful, which
you know, with great power comes great responsibility. Too much
insulin can very quickly kill you in our own bodies.
Our insulin is produced in an inactive form, and it
has to be cleaved to become active. And so the
insulin that's produced in the bacteria initially also is in

(34:04):
that inactive form, and then all that processing that would
normally happen in someone's body has to happen in the
factory so that the form that you inject is already active.
So there's a lot of complex steps there. And if
you were to try to take it out of puppies,
I think that would be way less effective. I mean,
the number of cows we needed to produce enough insulin
to support humanity was becoming untenable. Like there weren't enough

(34:27):
cows to make all the insulin, even though we have
a crazy appetite for meat and beef, but we still
couldn't probably sustain all the diabetics who needed insulin.

Speaker 2 (34:36):
And why do we need to build this in a
life form anyway? Like we know how to do chemistry,
I mean I don't, but some people do. Why can't
you just like stick the atoms together and build this
thing out of little lego pieces, you know, synthesize the
thing in the lab.

Speaker 1 (34:49):
Yeah, I like that idea. And there is a thing
called cell free extract production that people sometimes use these days.
I think it just is convenient and handy that these
bacteria in a way are great little factories. They already
know how to make copies of themselves. So I think
from an efficiency perspective, I mean, how great is it

(35:10):
that the bacteria you just give them a little glucose
and they go figure all that stuff out for themselves.
Otherwise you'd have to manufacture thousands and thousands of different
components that the bacteria otherwise just build for themselves, and.

Speaker 2 (35:23):
They're self replicating, which is much more than our grad
students can do.

Speaker 1 (35:27):
I mean, to be honest, to the way we produce
a lot of the things you might consider putting into
a sell free artificial manufacturing process, we'd probably get them
from microbial production to a lot of the things that
we produce that way we do with the help of microps.

Speaker 2 (35:42):
Like cheese. I don't think I want to eat lab
synthesized cheese either. We actually have a friend who was
working on plant free food and he give us a
taste from like chemically synthesized butter, and it wasn't good. No,
I didn't like it. No mascrecy, but it wasn't better.

(36:02):
But what I have one more question, simple, which is
you talk about inserting these genes into the bacteria to
make it do its thing, which makes it feel like
the bacteria is some sort of computer and you're just
like changing the program and you're like, hey, can you
make this instead of that? Is it as simple as that?
Can you go a little bit into the detail of
like how do we know how to write this code?
And then how do we take the code and actually

(36:24):
put it into the genome? Right, it's not as simple
as like logging into the bacteria and editing the files.
You need to actually like put it into the DNA.
How do we know how to do any of that?

Speaker 1 (36:33):
Yeah? What a good question. I'm not sure I know
all the answers, but I can tell you that one
of the first proteins that we ever even figured out
what the sequence of it was was insulin. And so
that's at the protein level, like the sequence of amino
acids that you need to make insulin, that's what makes
insulin insulin. From there, the protein sequence could have lots

(36:55):
of different DNA sequences that lead to the same protein
sequence because we have redund and see in the genetic code.
So usually you have three nucleotide bases encoding an amino
acid for a protein sequence, and there's many combinations of
DNA that would lead to the right sequence for the protein.
I actually don't know how they chose what DNA sequence

(37:18):
to initially clone into the E. Coli. In theory, it
could be that they just this is not how they
did it because they didn't have the right tools to
do this. But in theory, it could be that they
were just like, oh, well, we know what protein sequence
we want, so therefore any of these bajillion different DNA
sequences will work, So we'll just artificially synthesize one of
those and do it from there. We could do that today.
That's actually pretty easy thing to do. I've often thought

(37:41):
about that, Like, if you knew something you wanted to produce,
you could synthesize the piece of DNA and send it
to a yogurt manufacturer anywhere in the world, and they
could make vast quantities of a protein that you were
interested in if you could get the cells to cooperate.
I mean, there's a few things that would be hard
about it, but yeah, I think they must have known
this sequence for human DNA and then physically got in

(38:04):
their hands on that and chopped it out and then
like physically we use the word ligation, it just means
like pasting it into the bacteria, and it wasn't just that,
And a lot of this happened also with the company Genentech.
I'm sure that many people know more about this history
than I do. But some of it is proprietary, right
because it was happening at a company, some of it anyway.

(38:28):
And so they cloned the human DNA sequence, copied it
into the bacterial cell, and just fired the bacteria up
to produce it.

Speaker 3 (38:37):
So now you've got the bacteria with the code, and
you figured out how to get them to be running
that code all the time, so they're making more insulin. Yeah,
is that insulin accumulating inside the bacteria or do they
excrete it? How do we get it after that?

Speaker 1 (38:51):
That's a really good question, and I think there's actually
several ways you could do that, and I would not
be surprised if both of those options are happening in
various factories in the world right now. One way it
can happen often when a bacterial cell is confronted with
like a crazy amount of something it doesn't quite know
what to do with, it pumps it into a little
compartment called a vacuole, and it just like makes little

(39:13):
pouches of it. That's my understanding for the main thing
that happens is that you get these little pouches of
the vacuoles from the cells, and then the next step
is to pop the cells, pull out all those vacuoles,
and then get the insulin from there. So I'm pretty
sure that's the main way that it's done these days
from E. Coli. Not all insulin is made in bacteria

(39:34):
and ecoli. There's I think maybe twenty or thirty percent
of the insulin that's manufactured in the world is in
yeast and sachromics service. And then it's going to be
yet another process. And so yeah, theory, you could make
the cell excrete the insulin into the liquid, which might
make your process easier, but since insulin's a protein and
it can get broken down by enzymes that eat proteins,

(39:56):
in a way, you might be better off having it
be in a protected pouch that you could just pull
those aside and get the insulin out.

Speaker 3 (40:04):
I don't think I've thought before about the complicated process
of acquiring this stuff after the bacteria has made it.
Like I guess i'd imagine, like you know, you skim
the top and there's the insulin and you stick it
into needles. But yeah, I mean extracting all of those vacules, Yeah,
and popping them doesn't sound like easy work.

Speaker 1 (40:20):
No, that's a sophisticated process. And then the protein sequence
still contains extra bits that make it inactive on purpose,
so that it's not in our bodies. We don't want
it to be active exactly when it's produced. It's like
unleashed and activated very intentionally, So to get it to
be in that active form takes yet more steps.

Speaker 3 (40:40):
All right, awesome, So we're going to take a break now,
and when we get back from the break, we're going
to hear about lydia Villa Komorov's contribution to this field.

(41:04):
All right, and we're back. So it's Women's History month.
We're trying to feature some amazing women that most people
have perhaps not heard of. And you agreed to come
on the show and talk to us about lydia Villa Comarov.
What was her contribution to this field.

Speaker 1 (41:19):
Well, lydia Villa Comorov was a grad student in the
nineteen seventies during this era where we were just figuring
out that we could clone bacteria. So not only did
we understand the central dogma, the way that molecular biology
is encoded. We were now starting to be able to
manipulate it.

Speaker 3 (41:36):
Interesting, So a few.

Speaker 1 (41:37):
People had done anything in this area. Right around the
time that doctor Villa Komarova finished her PhD from MIT
in nineteen seventy five and she embarked on a really
bold post doc at Harvard. It was to clone the
human insulin gene into bacteria. It was so bold that
Harvard actually asked them to stop. They paused the project
for fear of ethical consideration for what the consequences of

(42:02):
humans cloning things could be. So she actually continued her
project at Cold Spring Harbor. There were lots of failures.
I think that was a really tough post doc, but
ultimately she succeeded. I think that was around nineteen seventy eight,
and by the early eighties there was commercially available human
insulin that had been synthesized in bacteria, and her project

(42:23):
was to clone the gene for insulin into E. Coli,
the bacteria. So she has a paper in PNAS, the
Proceedings of the National Academy of Science, and in that
paper she demonstrates that you can pull the insulin gene
from humans, clone it into bacteria and get the bacterial

(42:44):
cells to replicate. So it was a big step, not
just that this was an idea, but that it could
actually be done, and everyone had their eyes on this happening.
It was considered risky and important enough that her project
was halted as these considerations about the ethics were being
discussed at the ASILAMAR meeting, and after the ASILAMAR meeting

(43:07):
she was allowed to proceed. And it all happened very
fast because her paper was already published in nineteen seventy eight,
and I think the Assillamar meeting was only in nineteen
seventy seven, So I bet that was intense. I bet
she was working hard with.

Speaker 2 (43:20):
What ethics concerns do we have? Because, as we said earlier,
bacteria can't make peppy eyes, so what are the ethical issues.

Speaker 1 (43:26):
It was a very new idea that humans could clone things,
that we could decide what the DNA that a creature
encoded was. And in some ways, I don't think it's
different than agriculture, not just farming of crops, but I
mean dog breeding or horse breeding or anything where you
select for traits that you care about and then intentionally

(43:47):
push a population towards having specific traits that we had
always only done that in the context of selection, where
all of the reproducing was happening by itself, or you know,
what you might consider a natural way, in the sense
that you were just like picking out the peas that
had the color you were excited about and crossing those,
and then you get more, and after hundreds of years

(44:09):
you can't even recognize the organism compared to where it started.

Speaker 2 (44:12):
From the way we transformed corn from like a tiny
little grain to this like hugely productive.

Speaker 1 (44:18):
Food, for example, exactly, or like watermelons, or you know
something where watermelons weren't these like amazing, gicy, genormous fruits
when we first found them, right, We cultivated that, and
the consequences of the cultivation are obviously encoded in the
genome and in some ways not really different than cloning

(44:39):
something on purpose. In fact, we're not that good at cloning.
Like cloning requires us as humans to decide what pieces
of DNA belong in an organism, and we typically are
kind of bad at that. It's interesting. I went to
grad school in an era where rational design of proteins
was really popular and a lot of people's projects were

(45:00):
like looking at protein sequences and being like, oh, I
think we should put an alanine there, and that's going
to make this work better. That kind of thing, and
typically it didn't actually work better. So in some ways,
I think we've come to respect that evolution and allowing
natural selection to happen is if in some ways, a
more powerful way to pull off things you want to do.

(45:21):
But you would never get insulin production through evolution. I mean,
bacteria would never produce insulin. So it's actually a really
great case for genetic engineering. It was a very cool
problem that lydia Villa comorov took on because it was
so effective and it really would never have happened without cloning.
So your question was how did it come to be

(45:42):
that this was an ethical problem? And the real issue
was just that we as humans were scared that we
were going to unleash some kind of monster. What were
the consequences of us genetically engineering things? I mean, more recently,
we've had similar debates about crispers, and you've heard that
there is even a case where a Chinese scientist used

(46:04):
Crisper to genetically engineer a baby, a human that has really,
really big ethical questions, And this was happening only in bacteria,
but it was the first time it had happened, and
we were rightfully, really thinking carefully about what the consequences
could be. For example, imagine you cloned a bacteria that
contained genes that could break down petroleum, and then you

(46:27):
unleashed that in an oil mining operation. You could really
cause a lot of destruction. And what if that was
just impossible to control and then you destroyed huge natural
resources unintentionally or intentionally for that matter. So those were
the kinds of questions people were worried about.

Speaker 2 (46:45):
Or what if it helped the bacteria organize and it
crawled out of the vat and like extracted vengeance for
all the brethren that we've tortured in order to extract
insulin from them.

Speaker 1 (46:54):
That's a great question, but I'm pretty sure they didn't
talk about it.

Speaker 2 (46:57):
That's a very polite answer to a totally bunkers question.
You all should have seen her face.

Speaker 1 (47:04):
That didn't make it to the top ten list for
discussion out of Solomar.

Speaker 2 (47:08):
I bet there were some science fiction writers there. They
would have come up with that scenario. It didn't take
me very long to think about it.

Speaker 3 (47:15):
I think there was a recent ant Solomar meeting that
was sort of inspired by then prior meeting. So you
mentioned the ethical issues associated with Crisper. Yeah, but I
think they like literally had another Ansilomar meeting with like
similar goals to figure out what direction.

Speaker 1 (47:30):
I think it's next month, Oh is it? Yeah? I
think it's next week. I think you guys could have
this episode coincide or we could look into that. That'd
be cool. Yeah, because my friend Jen Martini was invited,
but she couldn't go because she's teaching, and I know
she doesn't start teaching until.

Speaker 3 (47:41):
Next week's I mean maybe we should have a whole
episode on the ethical implications of Crisper too. That yeah,
important and timely.

Speaker 2 (47:49):
So how ballsy was it for her to take on
this project because if it didn't work, she could ended
up with basically nothing, no result. I mean, this was
like really swinging for a home run, wasn't it.

Speaker 1 (47:59):
Yeah, that's a really good question. It'd be fun to
talk to the people who are around at that time.
I don't think I would give this to a student
as their only project. It does seem really risky. But yeah,
if you look at the people involved, like who her
bosses were and who their collaborators were. You know, they
were used to taking on really big projects and hitting
for home runs. So that's what you do in Boston, Yeah, exactly.

Speaker 3 (48:25):
So what came for her after this? So she did
this amazing breakthrough, was the first person to do this
amazing thing. What did she do after that?

Speaker 1 (48:32):
She stayed in science. Actually, she made a really good
use of her science education, and she went on to
work on not just insulin, but other hormones that are
related to insulin. Some of them are called insulin like
growth factors. It's a really complex field that I honestly
couldn't tell you too much about what all the implications are,
but I do know that she ran a lab and

(48:55):
spent many years studying hormones that are related to insulin.
And so she stayed in that field. And she also
really put a lot of energy into being a role
model and a leader for other people who wanted to
become scientists. She'd encountered definitely roadblocks herself, considering that most
institutions wouldn't even accept women as applicants to graduate school

(49:18):
when she was applying, and so she became a co
founding member of the Society for the Advancement of Chicanos
and Hispanics and Native Americans and Science or SACNAS, And
that was back in the nineteen seventies, and I actually
didn't know that. I personally have had a lot of
students who have been supported by SAKNAS to go to conferences.
They have meetings every year. I work at UC Irvine,

(49:40):
which is a Hispanic serving institution, and a lot of
our students have gone to those meetings and had a
really good time. So I think that's really cool she
founded that.

Speaker 2 (49:50):
And why isn't she a zillionaire? I mean, I know
that this technology is the foundation of like billions of
dollars of annual profit for Nova Noordis and Eli Lilly.
Why isn't she elon Musk?

Speaker 1 (50:02):
What a good question. I don't know the details of
what kind of IP they tried to get for the
technique that they developed. I also know that genen Tech
was really involved, and so actually an important thing to
say is that, you know, so her paper came out
in nineteen seventy eight, she didn't keep up with this
specific feel. I know that genen Tech was the company

(50:22):
that really developed the possibility of producing insulin in bacteria.
My sense is that what she did was proof of concept,
I see, which was critical because it made people ready
for the idea. But my guess is that genen Tech
went on and developed the technology in its own specific
way that could then have ip that stayed within the company.

Speaker 2 (50:44):
Isn't there like fast acting and long acting with insulin stuff.

Speaker 1 (50:48):
Her paper came out in nineteen seventy eight, and I
know that by nineteen eighty two the Food and Drug
Administration had approved human insulin to be given to people.
I was diagnosed with type one diabetes in nineteen eighty
four and I never took animal insulin. I only got
the human insulin at that time. It was just the
straight up human insulin sequence. It hadn't been modified to
have new properties. But that's pretty amazing that we scaled

(51:11):
that up for humanity that quickly. And so the insulins
that I took with like regular insulin, is still produced
today and I used it for twelve years, like multiple
injections daily, And now if you go to Walmart, you
can actually buy that kind of insulin for twenty five dollars.
This is probably the most important thing I'm saying like

(51:33):
ever anytime I have an audience, I say this because
it could really save lives that you can buy regular
human insulin at Walmart. It's intended for cats and dogs
who have diabetes. But it's exactly the insulin that I
used for many years, and it cost twenty five dollars
and you don't need a prescription. It's just over the counter.
You can just go to Walmart and buy this insulin

(51:54):
and it's exactly the same bottle as the one that
I used in the nineteen eighties. So, starting in the
nineteen eight e we scaled up fermentation of human insulin
to be available for all people. I wouldn't say access
is perfect, but it's pretty good. Like there's definitely parts
of the world where you can buy insulin at a
pretty reasonable cost. I'm sure you've heard a lot about

(52:16):
the cost of insulin, Like if you cross the border
into Mexico, you can buy this insulin at a very
reasonable cost too. It wasn't until the nineties that engineered
insulins that have different kinetics, like they can be faster
and slower. Those came out in the nineties. The slower
insulins were available earlier, like the insulin you can buy
at Walmart. There's a slower one too, that's called NPH,

(52:37):
and that didn't require crazy bioengineering or I don't know,
they've somehow figured that out way earlier.

Speaker 3 (52:42):
Why would you want faster and slower insulin, Well.

Speaker 1 (52:45):
The regular insulin it takes a few hours to become active.
So the insulin exists in little trimers around zinc molecules
in a dimer. So there's two zinc molecules that each
have three insulin molecules attached to them, So there's six
insulin molecules all hanging out together. You have to wait
for them to dissociate because the insulin is only active

(53:08):
as a monomer by itself, So when you inject regular insulin,
you have to wait one hour for it to even
start working at all, and it doesn't peak until three hours. Now,
when you eat your food, it doesn't come in immediately either,
But regular insulin is too slow for an average meal,
so most people would have to either inject their insulin early,

(53:29):
but that's kind of dangerous. Imagine you inject your insulin,
but you're like your food is late, or you're on
a walk and you forget to eat or you know,
something like that. If your blood seger goes too low,
you die from low blood sugar immediately. It's like the
most common cause of death in people with type one diabetes.
So that's really really something you have to be careful with.
So having your insulin kinetics not really matching when you

(53:52):
need the insulin is both for convenience and basic survival,
really really important. There was a big arms race between
Eli Lilly and Novonordisk in the nineties to rationally design
insulins that had different properties, and they both succeeded in
slightly different ways. And now you can buy insulin that

(54:14):
falls apart more easily. Those dimers on the trimers of
the zinc are not as stable, so they fall apart
more quickly. And now when you inject the insulin, it
starts to become active within minutes and peaks within an hour,
which matches how people eat much better. So it's safer
and a little bit easier to keep your blood sugar

(54:36):
within range. But matching the kinetics of your food with
the kinetics of your insulin is just a major challenge.

Speaker 3 (54:41):
So is it still the case that today people with
diabetes need to be really careful about, like what kinds
of insulin that they're injecting. Has it gotten easier over time?
I feel like I heard once that there are these
things that can attach to your body that sort of
do all the measuring for you. What is it like today.

Speaker 1 (54:56):
Well, so there's been big changes both in how we
deliver insulin and how we monitor blood sugar. So we
haven't talked about blood sugar monitoring at all in any
of this, but I'll bring up that, you know, we've
known for centuries how to detect glucose and urine, but
that's very old information. By the time the sugar hits
your urine, that's like happened hours ago, and you can't

(55:18):
really take that sample and demand quite in the same
way as you can take a blood sample. So we
started poking our fingers to get blood sugar measurements. Those
devices started being available at home in the nineteen eighties
and then for about ten or fifteen years. We now
have these sensors that you can put a little sensor
on your arm and you get blood sugar information every
five minutes. So those sensors help you see what your

(55:41):
blood sugar is. We also have both injections for insulin
and also insulin pumps. So the pump will deliver insulin
at rates that you tell it to give you the insulin.
But none of this is happening without a lot of thought.
There's not like a machine that just takes care of
it for you. A lot of people when they see
an insulin pump imagine like, oh, that must be so

(56:03):
nice that like, oh, the AI is taking care of
your bl chicker for you, And that's not the case
at all. Insulin pumps just do what you tell them
to do.

Speaker 3 (56:10):
That is what I imagined. Thanks for clarifying that.

Speaker 1 (56:13):
Even my doctors, like if I go to the eye doctor,
they're like, oh, it must be some nice having your
pump doing that for you. But I mean, no, the
pump is not operating independently.

Speaker 2 (56:22):
And talk per a minute about why that's a hard problem.
I mean, people might be thinking, well, you have a
sense of that tells you how much glucose you have,
and you have insulin which brings the glucose down. Why
can't you just you know, fit a straight line to
that and descide how much insulin I have? Why do
you need a human brain in the loop there or
why is it a hard problem.

Speaker 1 (56:39):
There's a lot of reasons it's a hard problem. A
big one is that the way that we're giving the
insulin just subcutaneously means that it's slow. So you know,
when you eat, your pancreas is exactly in the right
place at the right time, sensing the glucose as it's
getting released from your digestion. So then not only do

(56:59):
you get real time information, but you also have the
insulin being delivered exactly where you need it. So when
you take insulin subcutaneously, it takes like a good half
an hour to dissolve and become active. I guess. Another
really important thing to say is that the insulin's activity
is affected by your own activity. So if you're exercising,

(57:20):
the insulin that you're taking will do a lot more work.
And your own pancrease has more than one hormone. It
has insulin and also glucagon, so it's a two component system.
Insulin drives your blood sugar down, Glucagon drives your blood
sugar up. So what glucagon does is it releases the
glycogen stores in your liver and muscle to raise your

(57:41):
blood sugar. So if this dangerous thing starts to happen
that your insulin drives your blood sugar too low. Then
the glucagon can pick it up from the floor and
save your life so you don't die from low blood sugar.
Our insulin pumps don't have glucagon in them. Glucagon is
a really delicate hormone. There's about one hundred companies there
engineering more stable glukug on. Maybe we'll have that soon,

(58:03):
but right now the pumps just have insulin. There is
a company that's trying to make a two component pump
that also has glucagon, but anyway, that doesn't happen yet.
So there's a number of reasons, like you could, in theory,
use the glucose information, the old information you're getting from
the sensor in your arm, and have that direct the
dosing of the insulin from your pump. However, your pump

(58:26):
doesn't know if you're about to go running, or if
you are sick, or you know. The amount of insulin
you need is affected by easily forty two factors that
most of them can't be measured, and so you need
your brain to synthesize all those factors and think through
the decision of how much insulin you need, and.

Speaker 2 (58:43):
You don't trust chat GPT to make those decisions for
you yet.

Speaker 1 (58:46):
I mean, I wouldn't mind like chatting with chat GPT
about it and getting ideas, but I would definitely want
to be the one who's the buck stops with me
when it comes to that decision.

Speaker 2 (58:55):
All right, So then our last question is what do
you see happening in the future, like in ten year
and fifty years, in one hundred years, what's going to
change about our treatment of diabetes or understanding of the
biochemical processes.

Speaker 1 (59:08):
Well, there's biological and engineering fronts to talk about, and
actually I should make a really big shout out to
the group of people who are engineering devices. There's even
groups of people who have built algorithms that do take
the information from the glucose sensors and use it to
dose the insulin. Sometimes they're called loopers. They're closing the loop.

(59:29):
Many of those algorithms are open source, and people are
having good results with better blood sugar control using those algorithms.
It takes a really tech savvy person and somebody who
you know. In my case, I go running every day
and I don't think those algorithms take exercise into account
in a way that works for me. So that's why

(59:50):
I personally am not using the looping algorithms, although I'm interested.
So if there's someone out there who's into looping, like,
my mind is open. So there are people making really
big progress on the algorithms, I think those are going
to be a really big frontier that our algorithms are
going to get better and better. Some of the major
insulin pump companies have soft versions of those algorithms with

(01:00:11):
a lot of safety on them, where they keep the
average blood sugar values a little higher to give you
a safety buffer. So that's starting to happen already. In fact,
the pump I use has a soft algorithm like that that,
especially for sleeping at night when there's not as many
different changes going on, it can do a really good
job of helping you keep your blood sugar in control.

(01:00:32):
So that's already getting better. I'd say the engineering front
will include better sensors, better algorithms. If we had glucagon,
then that will also close the loop and help to
make the measurements better overall, though, I mean, humans are
really complex. Like one of my favorite results recently showed
how people eating exactly the same meal one week apart

(01:00:53):
and wearing a continuous glucose monitor had different blood sugar
responses to the same meal, which I think highlights that
challenge of why it has to be pretty thoughtful how
you are dosing insulin even for the same meal and
the same person. You can't assume it's going to work
the same way each time. But then on the biology front,
there's also really big progress. So we have been learning

(01:01:16):
how to direct the program of stem cells and differentiating
them into different kinds of cells that we can use
for different kinds of medicine. There's a whole arm of
research towards building pancreatic beta cells, the ones that secrete insulin,
so that they could be transplanted. The first versions of

(01:01:37):
these have required people to take immunosuppressants, just like for
a pancreased transplant, so it didn't feel as exciting to me,
but that's actually starting to get better, and there are
efforts towards making hypoimmune, so like not giving an immune
response cells, so that people could get transplants with these

(01:01:59):
kind of cells and not have to take imminosuppressants and
potentially have them work to control their blood sugar. I
don't know, it's interesting to me to imagine trusting a
little renegade group of cells to do that. But you know,
that will get tested and we'll know a lot more
those are. On the treatment front, there's another whole aspect
to talk about, which is, you know, the way that

(01:02:20):
type one diabetes develops, at least your immune system starts
to attack your pancreas. This process can take a couple
of years. A lot of people when they're diagnosed, imagine that.
You know, oh, I got a cold and then I
got diabetes, or I took finals and I was all
stressed out and that caused my diabetes. But really it
was just the straw that broke the camel's back. And
this was a process that was going on for a

(01:02:41):
couple of years, and then a stressful circumstance made you
need more insulin, so then the system couldn't support you anymore.
But now there's actually a treatment for people who are
just starting to build the antibodies that are killing their
pancreatic cells, and that treatment will basically target and slow

(01:03:01):
down the immune process. It's called tea yield. And we
actually have a friend whose son was caught early because
he had a really savvy mom who understood what was
going on, and she helped him get that treatment, and
it's supposed to delay the onset of his type one
diabetes for several years. So he's probably still on that path,
but I could imagine us getting even better at that.

(01:03:22):
And to be honest, the reason I became a microbiome
scientist is that we know that the diagnosis of autoimmune
diseases is becoming more and more frequent. EXAMA allergies, type
one diabetes, a lot of autoimmune diseases are becoming more common,
and we don't exactly know why. It's clearly a change
in our immune development and the exposures we have in

(01:03:45):
early life. And for example, most babies born in human
history were breastfed and their guts became dominated by a
biffidobacteria that's good at helping break down the breast milk fibers,
and that's now missing from most people in the industrialized world.
So there are big studies right now to try to

(01:04:06):
reintroduce that biffodobacteria and see if it helps us reduce
our incidence of autoimmune diseases. So the easiest disease to
study is ezema in some ways because it emerges within
the first year or so of life, and they're now
are big studies using biffidobacteria to see if we can
reduce those diseases. But there's also right now there's a
big study in Europe across five countries with more than

(01:04:29):
a thousand people who are from families who are a
little bit more at risk for developing type one diabetes,
and they're introducing that biffodobacteria. So it's going to take
like probably ten years until we have the beginnings of
the answer, because type one diabetes can happen in childhood
or even adulthood. But we're gonna know if these changes
in microbiome exposure that put us on a better immune

(01:04:52):
development course could help to reduce the incidence of type
one diabetes. So it might be akin to vaccination in
the future that we intentionally develop our microbial exposures to
direct the way our immune systems develop so we don't
end up with all these autoimmune diseases.

Speaker 2 (01:05:11):
All right, Well, it sounds like a lot of potential
progress and lots of different directions. I hope that young
scientists out there are excited about working in all of
these angles and taking big risks like Lydia did.

Speaker 3 (01:05:22):
Yeah, thanks for being on the show, kut Ri enough,
that was awesome.

Speaker 1 (01:05:25):
Thank you.

Speaker 2 (01:05:26):
I'm going to nominate you for next year's White Sin
Research Award as well, even that you've twenty five years ago.

Speaker 1 (01:05:30):
Now I'm going to nominate you. You. I mean, I
think it's amazing that our society has produced all this
insulin to keep so many people with diabetes alive. And
we could do better with the access. But I mean,
considering that it's like water for so many people to
depend on the insulin, it's kind of amazing that we've

(01:05:52):
kept these systems going.

Speaker 2 (01:05:54):
All right. Well, thanks very much, China, and thanks everybody
for listening.

Speaker 3 (01:06:04):
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