- I'm Mary Parker,

and welcome to this episode
of Eureka's Sounds of Science.

(soft upbeat music)

My two guests today are
coming at the same issue

from very different angles.

Laura Gee, a colleague
here at Charles River,

lives with type one diabetes.

She's coming at this chronic
condition from a patient angle,

daily monitoring and control.

Jeffrey Millman, associate
professor of medicine

and biomedical engineering

at Washington University School
of Medicine in St. Louis,

is coming from a research angle.

The Millman Lab is striving

to use cellular replacement therapy,

I therapy to potentially
cure type one diabetes.

They're here to bring these
two perspectives together,

and I'm glad they're
both joining me today.

Welcome Jeffrey, and Laura.

- [Jeffrey] Great.

- [Laura] Thanks for having me.

- [Jeffrey] Same here, thank you.

- [Mary] Only two flubs in my intro,

I'm very proud of myself today.

So let's start with you, Laura.

Can you tell us about your daily routine

living with diabetes?

- [Laura] Sure, Mary.

My daily routine living
with type one diabetes

is anything but easy, but
it is part of my life,

and it has been since I
was just seven years old.

I wake up in the morning,

I think about my day ahead,
and I start planning.

From the minute I wake up,

I think about what am I
gonna eat for breakfast?

What time will I work out?

And all of these things sound very small,

but when you live diabetes,

it is something that really
affects everything I do.

For example, when I come to thinking about

what I'm gonna have for breakfast,

I have to think about
how much insulin I need,

what my current blood sugar is,

and really just what I'm going to be doing

after I have breakfast.

So there are many different aspects

of a daily routine living with diabetes

that must be considered
no matter what I'm doing.

- [Mary] I can see how the stress of that

might add up over time.

Like, even The Rock has a cheat day,

and you can't really do that

living with type one diabetes, right?

- [Laura] Well, there
are days, for example,

let's take a great example,

we have Christmas coming
and there is no way

that I'm gonna go through Christmas

without having some homemade goodness.

Of course to me,

that's a little bit more of a cheat

because it's not something
I would normally do.

I usually don't eat lot of sweets,

but around the holidays, they exist.

So for me, having a cheat day

just means having an
extra big bolus of insulin

to help control my blood sugars.

- [Mary] Yeah, it still takes planning.

It's not just something that
can be overtly spontaneous.

- [Laura] That's right.

It all comes down to planning.

- [Mary] Jeffrey, what is your experience

with speaking with patients?

Are there any questions
that you have for Laura?

- [Jeffrey] Yeah. One of the things

that I didn't really realize

about what it's like to
live with diabetes is,

the day to day and
having to think about it.

In this concept of you can't take a break

from type one diabetes might be the plan,

like what was just discussed here,

but you can't just
completely forget about it

on any given day.

I'd be really interested
hearing from Laura,

what it would feel like,

what it would mean for you,

if there was a true cure, or
a functional cure for diabetes

where you wouldn't need
to think about the disease

on a day to day basis anymore.

- [Laura] Honestly, it
would be a dream come true.

It's such a big dream and something

that I can't even imagine it.

I can't imagine not having a day

where I don't have to think about

all those little things
that I do right now.

So to me, it would be a feeling

I would not even be able to describe.

I don't know if that makes sense,

but that's how it would feel.

- [Mary] I think we can ...

Probably Jeff and I can imagine it,

but we can't really appreciate

what that feeling would be like.

- [Laura] Right.
- [Mary] Yeah.

- [Jeffrey] I think that's maybe

one of the key takeaways here
for members of the audience

who don't have to live with this disease,

is just from my, again,

my experience speaking with patients.

It takes over your life.

At least not take your real life,

but at lets say major component
of your day to day life,

you can't stop thinking about it.

Also, especially if you're a parent

with a child with type one diabetes,

its that kind of angst
and fear can be amplified

much more because it's your own child

that is living with it.

Which is really what
motivates the work that I do

and other scientists in the field

to be working in this space,

because we all realize
how impactful it would be

for patients if we were to come up

with an actual functional
cure of diabetes.

- [Mary] And just so that people in case

they don't know the difference,

the type one diabetes is the
kind that you were born with

as opposed to type two, or gestational,

which might be more environmental.

- [Jeffrey] It could be a little
bit more nuanced than that.

Type one, some people aren't
necessarily born with it,

but a lot of people
develop it in childhood.

But that isn't true for everybody.

There is a significant portion of people

with type one diabetes

that actually don't have it in adulthood,

but then what cause the type one diabetes

is a autoimmune attack
where the immune system

has failed to recognize
the in secreting cells

that are found in the pancreas as self

and mistakenly attack
and destroy those cells.

Meaning that the body is no
longer able to produce insulin.

This is in contrast
with type two diabetes,

which is, there's a lot of nuances here,

but typically it's associated with obesity

and insulin resistance where
essentially the beta cells

end up having to work too hard

in order to meet the metabolic
needs of the patient,

and just can't keep up
with how much insulin

the patient needs.

But so in the case of type two diabetes,

oftentimes this can be
managed with things like diet,

or taking drugs to increase
the body's sensitivity

to insulin.

For type one diabetes that doesn't work,

because there just isn't any
significant amounts of insulin

being produced here,

no amount of dieting is
going to manage diabetes.

The only real way of
managing type one diabetes

is insulin injections.

- [Mary] And you have to
monitor your blood pressure,

to make sure that you're
not taking too much insulin

as well as not having enough.

- [Jeffrey] Correct. That's
very much difficulty here,

it is a balance.

It's not just maintaining
a high level of a drug

so it's effective,

which is maybe how you would think

about treating other diseases.

It is a balancing act here
where your blood sugar

being too high, or too low is
both very dangerous to you.

- [Mary] Before we get
into your research Jeff,

Laura, I understand, and from
browsing your online presence,

that you like to share
about life with diabetes,

and healthy recipes, and
fitness tips, things like that.

Why is it important for you

to get that information out there?

- [Laura] I do really love to share about

living with diabetes, and
recipes and things like that,

because it's so reassuring
for me as a person

to be able to see how other people

that live with diabetes are living.

For example, as a diabetic,
quite often, we feel insecure.

We are worried if we're
doing the right thing,

we're wondering just how
we fit in, and are we okay?

Little things like that

because we just really
want to do a good job.

Most of us do anyway.

By sharing little glimpses of my life

and maybe some recipes I've tried that

I've enjoyed that had a
nice low glycemic index

that didn't skyrocket my
blood sugars, for example,

I feel like I'm contributing a little bit.

I'm also allowing people

that might be a little bit more quiet,

or unsure to be able to see
into my life a little bit

and just understand, and
know that they're okay too,

that we're all in it together.

- [Mary] That's wonderful.

Jeffrey, let's get it into it.

How did your research come about?

Where did it start?

- [Jeffrey] I actually
got into this research

through a little bit of a different path

than many people who are motivated

to do research in diabetes.

I was actually doing my
PhD in out of all things,

chemical engineering.

So I wasn't really focused on biology,

let alone regenerative
medicine for diabetes.

Towards the end of my PhD,

I was fortunate to have the lab I was in

get a research grant from JDRF

which is the largest private funder

of type one diabetes
research in the world.

Through that, they had patients

and the scientists who
are working the space

that I gotta meet through it.

It really showed me a
whole new area of research

that I wasn't really aware of

being from a engineering background.

And by speaking with them
and learning about the field,

I started to see how my
different perspective of science

could approach the problems
that were faced in the field

in a new and creative way.

And so once I got done with my PhD,

I decided to completely change
the structory of my career

and training to be dedicated

to coming up with a
functional care for diabetes.

And since then, I have been working

in the space now for over a decade

and have been really focused
on the use of stem cells

for the study and treatment of diabetes.

Particularly, as a source
of replacement cells

that could potentially be
transplanted into patients

to mean that they wouldn't
have to inject themselves

with insulin anymore.

- [Mary] That's really funny

that you come from a chemical
engineering background

because Laura, essentially,

you're running chemical
tests on yourself every day.

- [Laura] Every day is a
new experiment, really.

- [Mary] Absolutely.

You're a chemist as well.

- [Laura] You can eat the
same thing five days in a row.

You can do the same activities.

You can have every single day
exactly the same on paper,

but the way the body
reacts every single day,

it could be a little bit different.

So it is, every day is another experiment.

- [Jeffrey] It actually how
the cells can behave as well.

I think this is where the
chemical engineering mentality

really intersects and synergizes well

with the stem cell
biology that goes on here.

Essentially, the way that
I have been approaching

the problem of how to make
these instigating cells

at the end of our
manufacturing process is,

I treat it like a chemical reaction,

like in chemical engineering,

the way we're usually talked about things,

is that you have a starting chemical,

as a chemical A, you may go

and create one, two, three, four,

maybe more types of cell compounds

before you finally get
to the final chemical

that you're wanting to derive here.

And think about each of
these as separate stages.

They get stage one, you go
from chemical A to chemical B,

stage two, go from
chemical B to chemical C.

And you do them in a serialized fashion

to have the final chemical
that you want there.

Basically, what I've been trying
to do for the last 10 year,

is apply that mentality.

But instead of having
it just be chemicals,

having the chemicals in the
final product to be cells,

that we have stem cells

that if we stick them
into somebody's body,

they're not really going to do anything

and figure out what are the
correct intermediate cell types

we have to make before we actually get

to the final product here,

which is the pancreatic
and secreting beta cell.

- [Mary] Okay well.

So how does the treatment actually work?

The cellular replacement therapy,

which is a mouthful by the way.

- [Jeffrey] There's a
lot of other terminology

that we could use for
that might be the easiest

one to deal with.
- [Mary] Its fine.

I can deal with it.

- [Jeffrey] In terms of the problem

of controlling blood sugar levels

in patients with type one diabetes,

ultimately, this is an issue
of there just not being

enough healthy, and secreting beta cells

in the patient's body anymore.

I mentioned earlier that
these cells are mostly lost

due to a autoimmune attack.

And so the basic procedure here is,

can we manufacture
these cells artificially

in a lab

at a large enough scale,

so that we would have
enough replacement cells

that could be transplanted
back into the patient?

These exogenous artificial
manufactured cells

can basically replace the function

that has been lost in the
patients endogenous beta cells.

And we refer to this collectively

as cell replacement therapy.

And so the very first step of the process

is what we refer to as
germ layer specification.

That's basically what kind
of broad category of cell

is the stem cell going to be called.

The type of cell that we want
to make, in this instance,

to be able to make the
un-secreting beta cells,

they're called endodermal cells,

definitive endoderm in particular.

And so we have a particular cues,

and it's mostly nodal signaling

and wind signaling for people
who care about those things,

that instruct the stem cells

to go from a cell to go from a cell

that could become any cell
type found in the body,

to only becoming cell types

that come from definitive endoderm.

I mentioned that the
pancreas comes from there,

but also the intestines,
the liver, the lungs

come from that germ layer as well.

But once the cells decides
to become a endoderm cell,

they could no longer become
brain, or nerve, or skin,

or heart, or blood, or muscle,

or any of the other cell types

that come from the other germ layers.

Basically, we went from any
cell type being possible

to now basically only one
third of the cell types

in the body being possible.

And we basically repeat that exercise

through six distinct stages

where we go from any
cell type being possible

to be produced from the stem cells,

all the way to just having beta cells

and a few other pancreatic
cell types as well,

being present at the end of
the manufacturing process.

Again, this is all done with soluble cues

like proteins in chemicals there.

It can be done at fairly large scale,

we're able to manufacture a
few billion of these cells

at a time.

And really the hope here

is that with these manufactured cells,

we would take probably
about maybe half a billion,

or 1 billion of these cells,

and to transplant them into patients.

And as long as those cells survive

and have access to the blood,

they should be able to
perform their function

of sensing sugar levels in the blood,

and secreting a sufficient
amount of insulin

in order to keep the blood sugar levels

at a normal set points even after a meal

is consumed by the recipient.

- [Mary] And the cells can
come from donors, right?

They don't necessarily have
to be the patient's own cells?

- [Jeffrey] Right. We
look at both options here.

That we have them work

where we have taken either blood cells,

or skin cells from patients
with type one diabetes,

or some other forms of diabetes
we study as well in the lab.

And then we could reprogram these cells

into the stem cells that we
need to sort off the process.

These are a special type of stem cell

that are called IPS cells,

or induced pluripotent stem cells.

So these cells, again,

have the ability to become any
cell type found in the body.

And then we can give
them our six stage recipe

for converting them over into
the un-secreting beta cells.

Alternatively, you can use cells

that are derived from a donor,

or make beta cells and transplant those

into patients as well.

That has the advantage from
a manufacturing perspective.

It's a lot easier and cheaper
to take one donor cell line,

and make all the replacement cells

that you'd want to
generate and use from it

for the hundred thousands,
millions of patients

that you'd want to transplant that into,

as opposed to having to drive

individual IPS lines

from each potential patient,

make the beta cells from them,

and put them back in into there.

But we're pretty open to both concepts

as being a way to go forward with this.

- [Mary] I understand you
have successfully done this

in mice, I saw some news
headlines recently about your lab.

How has that gone so far?

- [Jeffrey] Yeah we've had,

so for many years now,

we've published our protocol
for making these cells

and a lot of various refinements

to the process that have
all worked very well

in mouse models and
the current generation,

like the current 2021
versions of the protocol,

as you could imagine,

work a lot better than the prior reports

that we had published.

In terms of being able to
rapidly reverse diabetes

and the mice,

and being able to maintain
control of blood sugar

in these mice for essentially
the entire remaining life span

of the mice.

But one thing as well that,

I don't think we had a
chance to talk about this

when we were chatting before
the recording started,

but the original technology
that I helped to develop

for this has actually
gone into patients now.

This is back when I was a
postdoc at Harvard University,

starting off working with this.

I was one of the first
authors and inventors

of the publication

that came out of Harvard in 2014,

showing the first significant report

of being able to make these cells at all,

and again, showed it to work well in mice.

Since then, that technology
has been licensed

and Vertex Pharmaceuticals

is conducting a phase one
clinical trial with these cells,

and they actually have
released their results

for the first recipient of these cells

maybe about a month ago, showing that.

So the first recipient
who received a half dose

of these cells is almost
completely off of insulin.

His insulin requirements
has been reduced by 91%,

and he overall is doing quite well

and has avoided any severe
negative complications

with this yet.

And it's also maybe most
importantly for him,

because he had a lot of problems

with this before the transplant

has avoided complications
due to hypoglycemia.

- [Mary] That's amazing.

My next question was, what
are some of the next steps

to bring this research to the next level,

but now it's in the hands of
the pharmaceutical company,

and also it just has to go through

the regular scheduled drug
approval process at this point.

- [Jeffrey] For that
version of the technology,

that's definitely correct,

but there's definitely a lot more work

that needs to be done in order for this

to be a true functional cure

that can be deployed widespread

in order to help the over 1 million people

living with type one diabetes in the US

and beyond of course.

The biggest one that I am thinking about,

that other people have
thought in the field as well,

is the issue of the immune system.

And so what the Vertex
clinical trials are doing

in order to prevent their
expanse from being rejected,

is that they are giving the patients

immunosuppressant drugs,

which are something that
nobody ever wants to take.

They come with their own
risk of complications

that for many people who are
living with type one diabetes

probably would not be worth

getting off of insulin therapy for.

There are a certain category of people

with type one diabetes,

for which that can make
a lot of sense for.

And like I said, this first recipient

had a lot of problems
controlling his diabetes

and had been hospitalized quite a bit

due to complications
before receiving the cells

in the Vertex clinical trial.

But I and everybody else who are working

in this space really want this

to be a much more
widespread therapy available

to basically anybody.

And the big elephant into the room

that we have to address with
this, is the immune system.

So how can we deliver
these cells into recipients

in a way that the cells
will not be destroyed

by the immune system,

but the patient also doesn't need

to take immunosuppressant drugs.

That's proven to be a very
hard challenge to overcome.

A lot of groups of have focused

on trying to coat the
manufactured in-secreting cells

with various types of materials

that will basically physically shield them

from the immune system.

There has been some success in that,

and I've actually
published on that myself.

But it seems to have problems scaling

to work effectively in a full
grown adult with diabetes.

In other words, it works well with mice,

but it doesn't seem to
really a scale to humans.

And so-
- [Mary] Gotcha.

- [Jeffrey] The next thing
that people are looking at,

and that I personally have
a lot of enthusiasm for,

is this idea of using CRISPR gene editing

to genetically modify the
cells to be immuno evasive.

So basically for the immune system

to be able to tolerate the cells

and not reject the cells,

either due to the auto immunity,

or due to them being
from a different donor.

- [Mary] This is pure
speculation from a non-scientist,

but COVID has proven really good

at evading the immune system.

Could you maybe use there
it's defense mechanisms

as part of the process?

- [Jeffrey] Well, it's
funny that you say that.

I don't know about COVID itself,

but the approach that people
are taking in the field

is to look at other
systems that are out there,

and seeing how they normally
avoid the immune system.

And then trying to just
basically hijack that

in a cell type that's not
usually applicable for.

Two main examples that can
give for that would be,

how do cancer cells ...
Are they the immune system?

And there's certain surface proteins

that are expressed on
cancer cells like PD-L1

that help it to avoid
destruction by the immune system.

Or another example that I've heard people

are employing right now,

is how are fetuses in utero are tolerated

and not rejected by the
mother's immune system?

There's several layers
of protection there,

but there's certain HOAs

that are expressed by the fetal material

in order to avoid being
rejected by the immune system.

In other words,

the COVID idea is not too far fetched

from how scientists are trying
to approach this problem.

And we've seen success with this concept

of trying to take known biological systems

and understanding how it works in nature,

and then applying it to translating it

into actual biomedical needs.

And this is where CRISPR came from,

for example, CRISPR-Cas9 is
a defense mechanism of cells,

but it's so happens to be
really good at editing DNA,

and now it's a extremely common tool

used in biomedical research,

and is being looked at
for therapy as well.

- [Mary] Laura, do you keep
on top of diabetes research?

What do you think of the lab's work?

- [Laura] I do try,

and I say try because
there's always something new

and it's so exciting.

What Jeff is talking
about sound super cool,

and I look forward to the day.

- [Mary] Imagine just like
an off the shelf product,

but speaking of that,
besides the immune system,

I imagine that the other problem

with that type of future is scalability

and literally manufacturing plants

that can make these cells at a scale

that would be needed by patients.

- [Jeffrey] That's another
really big challenge as well.

We have achieved a decent degree of scale,

but I think new
advancements need to be made

more from a biotechnology angle

in order to really scale
it to produce cells

for even any significant
fraction of the number of people

with type one diabetes.

But even five years ago,

there wasn't really much of a need

to focus on scalability manufacturing,

because it first reports
of the sales had come out

and there hadn't been enough time

for people to try to
reproduce those results.

Now we know that it's real, the technology

is here right now,

and now biotech companies

are starting to take it seriously

and are starting to think about

these very practical questions

such as how are we going
to make a million doses

of this therapy?

- [Mary] Right.

This is a running theme in
some of the other episodes,

is that the science always
precedes the infrastructure.

Just because Nikola Tesla, or Edison,

or whoever invented a way to
power things with electricity,

doesn't mean that the next
day there were power lines

sprung up all over the world.

One has to come before the other,

and infrastructure always comes after.

- [Jeffrey] I think it's
a really good analogy.

And again, I think it
really just shows us how

exciting of a space this is

and how fast things have
progressed over the last few years.

- [Mary] Before we wrap it up,

do you guys have any
questions for each other?

- [Laura] I'm just thinking,

Jeff let's say, you did cure diabetes.

How would that make you feel,

and what do you see the
cure doing for the nation?

Big question.

- [Jeffrey] That might be a
little bit above my pay grade,

that's just the one,

but I'll do the best that I can.

I fully expect to know

how I will feel

because I fully expect
to see in my lifetime,

just because of how fast this is evolved,

and how well it is working.

Maybe I give you my true response

to it once it actually happens,

but I guess I would speculate of course,

that it would be amazingly fulfilling.

I changed my entire career trajectory

to dedicate myself to this problem,

because I saw how important
it would be for many people.

- [Mary] Thank you both so
much for joining me for this.

This has been a really
thrilling conversation for me,

and I really appreciate your time.

- [Laura] Thank you, Mary.

- [Jeffrey] Yeah, thank you.

I really appreciate it.

(soft upbeat music)