- Welcome everyone to Wednesday Nite at The Lab.
I'm Tom Zinnen.
I work here at the UW-Madison Biotechnology Center.
I also work for UW-Extension and Cooperative Extension.
On behalf of those folks and our other co-organizers,
Wisconsin Public Television,
the Wisconsin Alumni Association,
and the UW-Madison Science Alliance.
Thanks again for coming to Wednesday Nite at the Lab.
We do this every Wednesday night, 50 times a year.
Tonight, it's my pleasure to welcome back
to Wednesday Nite at the Lab David Gamm.
He's a professor of ophthalmology and visual sciences.
He's also with the McPherson Eye Institute
and with the Waisman Institute,
and with the Stem Cell and Regenerative Medicine Institute.
He was born in Colorado Springs, Colorado,
went to high school in Grand Rapids, Michigan,
and got his undergraduate degree at the University of Michigan
in molecular biology and cell biology.
Got a PhD at the University of Michigan,
and then got a MD at the University of Michigan,
and then he came over to the light side.
(audience laughs)
And came to UW-Madison to do his ophthalmological residency,
and there are two Ls on ophthalmology, is that correct?
- [David] Ophthalmology, correct?
- That's I always went down on in the spelling bee.
And he also did a fellowship with pediatric eye surgery.
That's why I became a plant pathologist.
And now he's going to talk to us tonight
about making sense of stem cells,
progress toward the treating of blinding disorders.
Please welcome me in joining David Gamm
back to Wednesday Nite at The Lab.
(audience applauds)
- Thanks Tom.
Well, thank you very much.
I really enjoy the opportunity to come and talk to you.
I talk to lay audiences quite a bit,
and this is a very sophisticated lay audience,
so I'm trying to bridge my talks between
the different levels that I try to hit.
And I have a great deal of titles there.
I debated whether or not I wanted to
put all of them up there, but I think it's important that I do,
because they all play a big role
in what I can do here at the university,
and why I am at this university.
I came here for the a residency, as Tom mentioned,
and stayed here because there were just way too many
opportunities in Madison for me to leave.
Then I've stayed here ever since,
for reasons that I think would become obvious to you
as my talk goes along.
So, I'm director of the McPherson Eye Research Institute,
so we're at one of the premier
vision research institutes in the world.
I'm also a part of the Department of Ophthalmology
and Visual Sciences,
which is one of the top clinical and research entities
in vision science in the nation.
And the Waisman Center is a wonderful place
that looks at developmental disabilities.
And so, my interest in blinding disorders
fits in well with them.
And then finally,
the Stem Cell and Regenerative Medicine Center
has been mentioned by many as being
the mecca of stem cell research in the world.
I'm privileged to be in a unique place on the planet
to study what I'm going to talk to you about today.
So, what does my lab do?
So, my lab has a very clear mission,
and I try to bridge what I do and see in the clinic
with what I want to ultimately make changes in
in terms of therapies for the future.
Ultimately, what I'm interested in
is using stem cell technology
to try to build new treatment for blinding disorders
that otherwise fall between the cracks,
diseases that for which we don't have any
traditional therapies that can help patients.
And so, stem cells in general
evoke a lot of questions in people's minds,
and they're all very valid questions
that deserve a lot of attention.
And those include fields of ethics, politics,
as well as medicine and science.
In the interest of time, I'm going to be concentrating
on the medical and scientific aspects
of stem cell research,
but that's not at all to belittle the other ones.
I think they are all very important sources of discussion
that need to be addressed in public forums,
as well as in scientific conferences.
And so, I'm happy to discuss those later on
if there are specific questions.
Speaking of ethics, I need to disclose a couple of things
right off the bat, so that you can decide whether or not
what I'm telling you is the up and up,
or whether I have some bias.
I do have a patent.
We patented the ability to create
three dimensional human retinal structures in a dish.
And that has led to the establishment of a company,
Opsis Therapeutics here in Madison that
collaborates with another company,
established by Jamie Thomson,
and that's Cellular Dynamics International.
I do want you to be aware of that upfront.
So, what I'd like to go through today
is basically two sections.
The first is a lot of introduction.
So I'd like to give you some background on
cell biology in general,
just enough so that I can then talk to you
about the eye and the retina,
what are its parts, what does it do,
and then move into degenerative diseases of the retina,
the specific types of diseases that I'm interested in,
and then lead into a discussion of
what is stem cell biology.
And then that'll form the basis for which we can go into
a longer discussion about how we're trying to use
stem cell technology to combat some of these diseases.
And then lastly, I debated whether I wanted to put this upfront,
because I get the privilege of talking to you
about a lot of his work,
but there are tremendous number of people in my laboratory,
collaborators here on campus and in other institutions,
that play a tremendous role in advancing this technology.
And so, while I appear to get the credit
by talking about it,
I want to make sure I have plenty of time to acknowledge
the folks that are doing a lot of the hard work.
So, to begin with, some cell basics.
So, I apologize for folks in the audience
for which this is going to be really, really basic.
But if we take a very stylized cell,
which has a nucleus and a membrane,
and all kinds of organelles within it
that allows it to do its particular job.
Some of those organelles are very basic,
and almost every cell in the body has them,
and some of the specialty functions are
specific to certain types of cellS,
and of course light-recepting cells in the retina
would be one of those very specialized cells.
We'll talk about it at length.
Cells combine together to make tissues,
and multiple different types of cells
are usually involved in production of tissues.
Those come together to make organs,
and then organs are pieces together
to make whole systems and, ultimately, organisms.
So, a healthy call, if we're all lucky,
we'll have healthy cells throughout our life.
But all too often, we experience various types of diseases,
whether it be an infection,
whether it be a genetic disorder,
whether it be an injury.
And in a lot of cases, if we're lucky,
there's a therapeutic of some type,
a drug, or a nutraceutical,
or perhaps even something more advance like a gene therapy
that can turn that diseased cell around
and make it healthy again.
The problem or the dilemma for degenerative diseases
is that it's kind of a point of no return.
In these diseases, they become dysfunctional,
but they're still kind of alive and doing their thing.
And this on the slope, the downward slope
towards degeneration.
But ultimately, these cells break up, they die.
They're no long around,
and there's no way to put Humpty Dumpty back together again.
And so, at that point, you're kind of--
Where are you at?
There's no cell left for a drug to work on.
There's no cell left to stick a new gene in,
or to work on from a nutritional standpoint.
So, in some tissues in the body,
there's an innate ability to regenerate cells.
So, some cells naturally die.
They go through a life cycle,
and they need to be replenished periodically
during your life time.
So they gotten to go to what we call natural cell death,
not through the course of disease.
And in those tissues, there are resident stem cells
that then can produce intermediate cells
that then mature into and replace the healthy cells
that have undergone natural cell death.
And tissues that do that
are ones you're probably familiar with, including blood.
So, red and white blood cells are produced
throughout the course of your life through bone marrow.
So there are bone marrow stem cells
that you might here about, that people get transplanted with
when they have, say, leukemia.
And then the superficial portions of your skin
are sloughing off,
and then you make new skin cells over time.
So those tissues have resident stem cells within them
that know when to kick in into cell division
and to create more of the cell type
that's being continuously lost.
But many tissues in your body just don't do that,
so they have lost the ability to regenerate cells
in some types of tissues in our bodies.
And a primary one that we all think about
is the central nervous system,
so brain, spinal cord, and even retina,
because the retina is part of the brain.
It develops as part of the front part of the brain,
and it's made up of neurons like the brain.
So, it's a very specialized part of the brain,
and it's of course forward facing,
and it's a sensory organ, but it's still brain.
And like other parts of the central nervous system,
it does not have a capacity
to replace its cells once they been lost,
either through disease or injury.
other tissues such as heart muscle,
insulin-secreting cells of the pancreas, as in diabetes,
and cartilage also can't replace themselves,
but the level of need in terms of
developing cell replacement therapies is different
with these tissues.
Cartilage, there's pretty good engineering devices
that can be used to bypass the need for cartilage.
Insulin-secreting cells, we have insulin,
we have other drugs that can be used
to maximize your own body's ability
to use the insulin that it produces.
Heart muscle, if there's just a little bit
of heart muscle that dies, there are drugs that can be used
to make the rest of the heart muscle work better,
try to overcome those diseases.
In the central nervous system,
there's almost no treatments like that,
except perhaps Parkinson's with L-dopa.
But outside of that, when you're thinking about Alzheimer's,
you're thinking about degenerative diseases of the retina,
or ALS, or Lou Gehrig's disease,
there's really no place to turn.
So, prior to getting more into stem cell biology,
I'd like to switch gears a little bit
and concentrate on the retina.
So, the rest of the talk now, I wanted to give you
kind of a foundation where retina fits
in terms of the landscape of tissues
and application of stem cell technology.
But from here on out, I'm going to concentrate on the retina.
So, I'm going to give you an introduction now
to basic retinal biology.
So, as an ophthalmologist,
we like to dilate pupils, we like to look inside of eyes,
and when we do that, this is what we see.
So, this is a normal retinal.
The whitish, yellowish circle towards the left
is the optic nerve.
this is where all of the
nerve impulses that are collected in the retina
from looking at objects
gets collected and sent back to the brain.
The red lines that you're seeing
are the retinal blood vessels that feed
the inner portions of the retina.
And then the rest of it that looks kind of orange,
the retina itself is really transparent like cellophane.
The reason why it looks orange
is that there's a very vascular layer right behind it.
And so, that red blood
shining through the rest of the tissues
makes it look orangish.
So that's a healthy retina.
And just like everyone tells you,
you only use 10% of your brain.
For the most part, when us as humans,
we use the central portion of our retina called the macula.
And that's just to the right of optic nerve
in that kind of area where it looks like there are no blood vessels.
So that's the very important part of our retina
that we use to recognize faces, to read.
It gives us our highest acuity vision and our color vision.
The rest, everything else around that
is for peripheral vision.
And there are some cones and some color sensation too,
but that's more for night vision and peripheral vision,
but it affords us very poor acuity.
So, the high acuity vision that we rely on so much
is right there in the center.
And so, this would be then a normal visual field
that someone might have with a healthy retina.
So, now let's delve into this a little bit more.
If we take that same eye and we cut it in half,
and we look at it from the side,
we get this sort of schematic here.
So, on the left side, that's a cross section of your cornea.
It's clear.
It's part of the refractive portion of the eye
that bends light.
The oval to the right of that is the lens,
light passes through that,
and then that gets refracted even more,
and that's actually a dynamic structure
so it can refract light.
Well, I'm starting to lose that ability,
but when you're young, you can refract light,
and then adjust the focus of objects onto your retina.
And then on the very back,
everything that looks orange is a chamber
filled with what's called vitreous fluid,
so that's kind of a jelly that's in there.
And then along the back of the eye, like a wallpaper,
is where the retina lies.
It's like film in the camera.
And so, if you take a little piece of that retina
and blow it up, and look at it on the side,
so now we're looking at that piece of cellophane
on its edge, and we've blown it up under a microscope,
and we see that it's really not just a boring piece of cellophane,
but it's actually a very elegant layer cake
with multiple different cell layers,
each of which does a very particular job.
And it's easiest to think about the retina
as a simple brain.
That has essentially three neurons or three cells
arranged in a circuit.
Deepest in the retina, and this is why it's transparent,
but deepest in the retina, closest to the blood supply
that makes the retina look orange,
because it's such a highly metabolic cell type,
is our photoreceptor cells.
These are the rods, which detect gray vision,
white and black, and then cones,
which are your blue, your red, and your green cones.
They're deepest within the retina
in a layer called the outer nuclear layer.
And they exist right up next to
but another layer of cells called
the retinal pigment epithelium.
And these are kind of like the Batman and Robin of vision.
So, photo receptors get all the credit
because they're the rods and the cones that detect light.
But the retinal pigment epithelium are their handmaidens.
They do a lot of the work.
They're there to provide all the nutrients
so the photoreceptors can stay healthy and active.
And they also take away all the waste products
that photoreceptors produce in large abundance,
and pull them away and deposit them
into that blood supply behind it
just so they can get carried away.
So then you have photoreceptors and RPE.
And the important thing to remember is that
the RPE, because they're so important for
taking care of photoreceptors, if that layer dies,
the photoreceptors aren't long for the world.
They'll also go to, because they're very needy.
Now, photo receptors are then hooked up
to another cell type the called type called a bipolar cell,
which in turn connect to another cell type
called a ganglion cell,
and you can see they exist in these different layers.
And then ganglion cells
have their output processes or axons.
Those are what coalesced to form the optic nerve
to go back to the brain,
which actually does the scene, right?
Takes all that information, and then gives us a formed image.
So you have a photoreceptor, a bipolar cell,
and a ganglion cell.
And light passes all the way through this,
so that's why, again, it's transparent,
strikes a specialized structure
at the very distal end of the photoreceptor cell,
almost like a light-catching antenna
called an outer segment.
That induces a series of chemical changes
that ultimately lead to an electrical impulse
that carries back through the optic nerve into the brain.
Now, there's processing that goes on in the retina,
and there's also processing that goes on in the brain
that ultimately brings it all together and gives you your image,
so it's much more complex than this,
but we'll keep it simple.
My laboratory is interested in that
photoreceptor RPE cohort of cells.
So, while there are degenerative diseases
that also affect ganglion cells,
so optic nerve disorders, glaucoma,
my laboratory, while interested in that, doesn't focus on that.
So, I could certainly take questions later on
about degenerative diseases affecting the optic nerve,
but for the purposes of this talk,
I'll be concentrating on diseases that affect
the photoreceptors or the RPE,
which collectively are referred to as the outer retina.
This is what actual retinal pigment epithelium looks like.
So if you were to peel back the retina,
and just look at those handmaiden cells en face,
so you're looking at them straight down on them,
they are actually pigmented, so they're brownish black.
And that helps absorb stray light,
so you have less dazzling.
So, everything about these cells, there's a purpose for it.
And they look like little stop signs,
and each one of those little stop signs,
those little geometric figures that you see there,
subserves multiple different photoreceptors,
so they envelop them and they provide the nutrients,
pull away waste products.
So the photoreceptors sit on top of them,
so they'd be going into the screen.
Photoreceptors look a little prettier.
So, the reason it looks green or red
is that we're using special stains and antibodies
that pick up on proteins that are specific
for certain types of cells,
in this case, the green color is due to
a particular type of protein
that's only expressed in photoreceptors,
and the red is only expressed in areas
where there are synapsis occurring.
And this picture, I got to give credit to Nico Cuenca,
a friend of mine from Spain
who is an outstanding histologist
and makes just the most beautiful pictures
from animal retinas.
And this is actually a non-human primate retina.
And so, the lower part there, those little appendages,
those little antennas that stick down,
those are the outer segments.
So, they're stacked just elegantly
so that you have multiple different--
are called disks
that are filled with proteins that detect light.
So there's essentially a perfect light catcher,
and they're arranged in such that
if a photon of light comes through,
there's a good probability that one of these cells will catch it,
and that will create the cascade of events
that leads to an impulse going to the brain
so that's a very important part of these cells.
And it's showed here more stylized
by those little lines you see going across.
Those are the stack disks. Okay.
And then below it is the RPE cells,
and you could see that they actually have
appendages themselves, like little squid tentacles
that go up and wrap around them.
So they really envelop and serve those photoreceptors.
And I'm not asking.
There's no quiz at the end of this, there's no reason--
I put this up here actually for you to read,
but the purpose is to show that
this is a very complex cell.
The business of detecting light is not easy at all.
So these cells have to have thousands of proteins
in the right place at the right time acting in concert.
And so, when you start to think about
trying to build these in a dish
or trying to coerce cells to create them,
it's a pretty tall order.
And so, even with the advent of stem cell technology
back in the late '90s,
I can remember everybody saying, "Well, this is fine and good.
"We might be able to make a few little cells here and there,
"but we're never going to be able to make something
"as complex as a photoreceptor cell."
And I hope to show you a little bit later on that I was...
this is a recurring theme... wrong.
So, this is my attempt to make things kind of 3D.
I had a little fun with this.
So, here we're kind of looking at the same--
Just to try and give you another perspective on that,
so here's the RPE layer,
and you are kind of seeing it on tangent,
and then on top of that then are the photoreceptor cells
with their outer segments, their lighting catching antenna
interacting with those RPE cells.
And so, if we kind of stack them up,
we ultimately get to this idea
where there's tens of millions of these photoreceptors
subserved by all these photoreceptors,
and they're all working in concert.
So, diseases of the outer retina.
So what happens in the diseases
that I'm interested in my clinic and in my lab?
So the two broad categories of diseases that we look at are,
one is retinitis pigmentosa.
I'm a pediatric ophthalmologist,
so this one is particularly near and dear to my heart,
because it affects children.
It affect children and adolescence,
and then that's when they first get it,
and then it carries on into adulthood.
It's actually a group of disorders.
So there's over a hundred genes
that can cause retinitis pigmentosa,
but ultimately they kind of all do the same thing,
and that is lead to the death of particular
types of cells in the outer retina.
It's relatively rare.
As a total group, it has about two million people worldwide
that are affected,
but it's the significant cause of blindness
in that younger population,
and it's really devastating both to the patients,
as well as to the families.
You can imagine someone coming in,
because their child just failed a vision test,
and maybe they're having a little trouble
maneuvering around in the dark.
And then you take a look inside their eye,
you do a couple tests,
and you realize they're going to go blind in a few years,
and you have to be the one to tell that to the parents.
I don't like that.
I am number two in the room
in terms of not wanting to hear or say that,
and so that's really what's driven me in my laboratory,
is to be able to say something a little bit more than
"Here's what you got,
"and I hope things workout well for you."
And again, almost no treatments are available.
There are couple gene therapy trials out there right now
that show some promise in terms of
trying to gain a little bit of vision back.
But for the most part,
we don't have anything that's really
very significant to offer these patients.
Then the other group is on the other end of the spectrum,
and that's age-related macular degeneration.
This is very common, so it's a little bit different,
in that instead of being relatively rare,
it's very common and growing,
because our population is aging.
There's over 10 million people alone in the US
that are affected, that will grow,
that'll probably double over the course
of the next couple of decades.
And it robs you of the central portion of your vision.
I'll give you an example of that a little bit later on.
And unfortunately, although there are some therapies,
there's vitamins you can take to try to slow it down,
if you got particular types of AMD,
and there are injections you can get
if you've got blood vessels
that are contributing to your vision loss.
But ultimately, there's a death of cells,
and once those cells are gone,
there isn't a drug or an injection
that can bring them back, right now at least.
So, just to graphically kind of show you this.
In retinitis pigmentosa, these are genetic disorders
so these patients are born with a gene
that ultimately fails them, and leads to death of the cells.
Most of the time, that gene defect
is expressed in the photoreceptors themselves,
such that they cause primary loss
of those photoreceptors over time,
and that's your slow inexorable loss of vision.
In some cases though, the gene is expressed
in the helper cells, the RPE.
And as I mentioned, if those die,
the photoreceptors then go,
and then you get your vision loss.
And this is kind what it looks like.
So you could see it looks dramatically different
than a normal retina.
The optic nerve is there, it looks pale.
The blood vessels are much thinner.
You see all these kind of pigmentary change
in the peripheral retina,
which is a harbinger of loss of photoreceptors,
and abnormal migration of the retinal pigment epithelium
into the retina proper.
And it affects generally, usually,
the outer portions first,
and then the central portions last,
such that kids do to pretty well,
because they maintain their central vision,
but they lose their peripheral vision
and their night vision first.
But ultimately, what happens in a lot of cases, unfortunately,
is they eventually lose that central vision too,
and it could be devastating and lead to total blindness.
Not always, in fact, it's kind of rare for you
to be totally blind from RP, but it certainly does happen.
Let's contrast that to age-related macular degeneration,
which isn't caused by any single gene,
although there are risk factors for it.
But it primarily attacks the RPE.
So the RPE is lost,
and as I mentioned, because the RPE is gone,
the photoreceptors are gone too.
And that's if there's no bleeding or abnormal blood vessels,
then it's called the dry type.
In the case of wet AMD,
you have the RPE that gets lost,
and then those blood vessels that grow behind it,
that are so important for serving the photoreceptors,
abnormally grow up next to the photoreceptors
where they can break and bleed.
And when that happens, it can lead
to very rapid loss of vision, and loss of photoreceptors.
And so, the dry type is shown there on the left.
It looks just sort of like somebody took a blow torch
and took out a lot of the retina.
That's an area, like a cookie cutter,
where all the photoreceptors are gone,
and the RPE is gone as well.
On the right side, this is a patient that has something similar to the left,
but also super imposed upon that has experienced a bleed,
And this is what patient with advanced AMD would see.
They wouldn't go blind entirely,
because their peripheral vision is unaffected,
but they lose that central portion,
and so you're left with essentially
very little ability to, essentially,
to drive, to recognize faces, or to read,
all these things that you really look forward to doing
once you retire.
So, that brings us to some--
There we are.
If we have loss of cells, what are our choices?
Just theoretically thinking about this.
If you've lost cells in the retina
that are critical for detecting light,
you essentially have two options at that point.
You can either bypass the whole system.
So you say, "Okay, well, the photoreceptors are gone,
so we have no natural ability to detect light,
which means we're going to not have vision
in the area where the photoreceptors are lost.
So can we take some of the downstream cells,
like the bipolar cells and ganglion cells,
and get them to detect light?
That's something called optogenetics.
Or can we directly stimulate the ganglion cells
with a chip?
And that's also available these days.
Second Sight has a chip that will directly stimulate.
And that has helped patients who are totally blind
get flashes of light,
detect movement,
provide them some sort of vision.
And that's, while crude,
something that has not been available decade or more ago.
And I bring this up to mention that
there are other places you can turn, besides stem cells.
What I think stem cells bring to the table
is because it's a natural replacement,
the ceiling is a lot higher.
And if we can get it right, we're more likely
to restore a more natural type of vision,
as opposed to an artificial light on, light off.
Okay?
So, my laboratory is interested in the idea of replacement.
And so, that brings up the next question,
which is, okay, where are the spare parts going to come from?
So, if you're going to replace photoreceptors
or RPE cells that are lost in disease,
you have to find some place that you can get them.
Living donors, so you can say, "What about a kidney?
"Can't you take something from my other eye
"and put it into this eye?"
Just like in the brain,
when you mess with the eye, you're going to blind somebody.
So, you don't have the ability to reach in
and take your twin's retina
and try to replace something that's been lost.
What about a deceased donor or a cadaver.
Again, that's been tried,
and it just doesn't hook up very well.
If you take a mature retina
that's already been fully formed
and try to pull it a part,
they're so fragile at that point
that they tend to die,
and they don't hook back up again.
What about non-human? We used pig valves.
And saw other animal parts sometimes
we use for other tissues.
That has not been directly tested in the eye,
but the same thought would generally apply.
But if you take something that's fully formed,
a fully formed part of the retina,
just like a part of the brain, that those brain transplants,
these transplants are fully formed neurons
just don't do a good job in these patients.
So, what about then lab manufactured?
So, can we actually--
Can we make these cells in a dish,
usher them to an appropriate stage
where we think they might conducive to
installing them and getting them to hook back up
into a deceased retina, so that we can restore vision.
And that was a great thought,
and many people worked towards that,
but there really was no source material for that.
Until in the late '90s,
this person Jamie Thomson, collaborator of mine,
and somebody that helped get me into the field,
discovered a way to take
a part of a five-day-old blastocyst,
called the inner cell mass, and grow that in a dish.
These were embryonic stem cells.
Everyone knew that they existed,
because ultimately all of the tissues in our body
emanate from this mass of cells.
But the ability to grow it in a dish in a laboratory
had never been shown prior to Dr. Thomson's work.
And embryonic stem cells are just one type of cells
of stem cells, and I want to take a brief detour
just to mention that not all stem cells are created equal.
So, people throw term stem cells around all the time,
and there are different types of stem cells.
So, there are what are called tissue-restricted stem cells.
And those are like the bone marrow stem cells
I mentioned earlier.
These are resident stem cells in tissues that regenerate.
They only have the capacity to make cells
from the tissue from which they come from.
So in other words, a bone marrow stem cells,
you'll says, "Well, I'll get those bone marrows,
"stick them in my eye.
"They're stem cells, right?"
Well, they can make blood, but they can't make retina.
Similar with skin stem cells
and stem cells that line your gut.
They can make cells
that are normally found in those tissues,
but they can't make other cell types.
And so, that's a point of confusion that sometimes
people who are trying to fool their customers try to use
in order to get them to open up their billfolds,
and go towards a treatment that isn't ready yet.
This is as opposed to pluripotent stem cells.
Pluripotent stem cells are
an entirely different type of stem cell
that is more primitive.
And it has two main properties.
The first is that it has the ability to divide
and make more of itself indefinitely.
And that's important because it, theoretically at least,
gives us an unlimited supply of cells with which we can
perhaps make a lot of different types of tissues
or cell types.
And then secondly, it has, if you treat it just right
and push it down the right pathway,
you might be able to get it to form
multiple different cell types,
so not just the cells of one particular tissue,
but multiple tissues.
And theoretically, perhaps even every cell type in the body.
And that's a very powerful thing,
but it also makes it very difficult to work with.
Because if you have essentially a clay-like cell
that has the capacity to make
almost any cell type in your body,
that's great, but the trouble is,
you got to harness that someway,
because you don't want to just let it go willy-nilly,
and make a hundred different cell types
if you want, for instance, a photoreceptor.
You have to find some way to get that to work in your favor,
push it down a pathway, whereby at the end of the day
you get the cells that you want
and not a lot of contaminating cells
that will just mess up your plans.
So, sources, as I mentioned before,
there's embryonic stem cells
that are derived from blastocyst,
generally from in vitro fertilization...
and eggs that are going to be discarded, and they're shown here.
So each one of those circles there in the center in the square
are thousands of individual embryonic stem cells.
The other cells that are rounded are feeder cells.
We generally don't have to use those very much anymore,
but those very bland-looking colonies of cells
are what all the fuss is about.
And they do indeed have the, at least, theoretical capacity
to produce all the different cell types in a human,
but it can't make a human,
but it can make all the different cell types.
And then along around 2006, 2007,
there came about another type of pluripotent stem cell
called an induced pluripotent stem cell.
And Dr. Thomson here at UW-Madison
as well as Shinya Yamanaka in Japan,
both almost concurrently figured out a way
to take somatic cells,
so cells from an adult human,
and to genetically reprogram them back to a state
where they're very similar to, if not identical to,
embryonic stem cells.
So, because these are cells that were
induced to become pluripotent,
instead of being that way to begin with,
they are called induced pluripotent stem cells.
And this was a wonderful advancement,
because it allowed us to make, essentially, stem cells,
pluripotent stem cells from any human being
on the face of the planet.
And here's what they look like.
So they're grown in the exact same way.
They grow in these colonies that are relatively bland looking.
And ultimately, they can, at least theoretically,
produce all the cell types of a human body.
But because they're produced from adults,
we can take, for instance,
a patient that has a particular disease
and through a skin or blood sample, reprogram those cells.
So, these days, you can take a blood sample.
Note, not much dissimilar from a sample you might send
for a cholesterol check,
and isolate certain cell types,
genetically reprogram them
back to this IPS cell or stem cell state.
And at that point, you have that particular patient's
genetic material encapsulated in their own stem cells.
And if you have the ability then to push those,
forward engineer those to,
in our case, replacement retinal cells,
then perhaps you could put that back into the patient.
But along the way, you're also going to have
to probably correct if there's a genetic defect.
You want to correct that, otherwise you're just going to have
the same disease occurring again.
The other option would be to take
anther source of IPS cells from a different individual
who doesn't have that particular disease,
who perhaps is closely immune matched,
and we'll talk about that at the very end.
Now, something else that you could do with these
IPS cells that's important to point out,
but I won't talk about,
is something called disease modeling.
In this case, you have these IPS cells from the patient.
And if you can create the cell types
that are affected by that disease,
you automatically now have an unlimited supply
of that patient's affected tissue in a dish.
And it has the same genetic disease.
It has all the other genetic makeup that that patient has,
And so, you can study that disease,
that patient's disease in a dish,
and then perhaps test drugs, test gene therapies,
test more traditional approaches to therapy
to see whether or not you can affect
the course of that disease.
And that way, you can use IPS cell technology
to help the patient without having to put that cell
necessarily back into the patient.
So, I'm not going to go into that,
but it's a very powerful application of the technology
that does not require transplantation,
so keep that in mind.
About half of my lab works on this type
of disease modeling project.
But in both cases, like I said before,
the trick is you have to make the cells.
You haave to ultimately get these stem cells
to create the cells that you need to study
or to place back into the patient.
So, how do we do that?
In almost every case,
we use development.
So, developmental biology is our guide.
So, stem cells are, during the course of their lifetime,
normally, have to go down different pathways,
are affected by different cues and factors,
and that's what tells them to go in a certain direction,
become a certain cell or a certain tissue.
And so, we try to recreate that environment
and those steps in a dish
to push them towards the cell type of interest.
In this case, this is a very early,
just a couple week old, developing neural tube,
and the future retina develops as a couple of budding balls
on both sides of the front part of that future brain,
and that's called the optic vesicles.
So these kind of almost like a balloon being
pulled out from the neural tube.
And it actually is a hallow vesicular structure.
And this kind of more in 3D, what it looks like.
You see it kind of folds up on its self,
and forms a hollow jawbreaker.
And the over time, it folds in itself.
It does it in some other rearrangements.
And then ultimately, all those different layers
of the neural retina are formed.
The lens comes in. The cornea comes on over it.
There's a lot of coordinated
activity that occurs to create ultimately the whole eye.
And between the formation of the front part of the brain
to the formation of the optic vesicle,
and ultimately the neural retina,
there's all kinds of forks in the road.
And this is horribly simple, over simplified.
But you can think about
that you have to make decisions along the way.
Am I going to become a part of the brain,
or I'm going to be part of the gut?
What am going to become in a broad sense?
And then you start narrowing yourself down
as you move along in development.
In some cases, there's like natural clock inside the cells
that tells them when it's time to make a decision,
but there are also other cues in the environment,
and they could be diffusible factors or chemicals
that are made by the embryo.
They can be physical interactions
where something pushing on another thing
or touches another thing
that it influences what it's going to become ultimately.
And so, it's a tall order, right?
We're going to try and somehow recapitulate this in a dish.
It turns out we're pretty lucky,
because a lot of it kind of does it on its own.
And so, we do have to nudge it in certain critical times,
but what we found is
with just perhaps a few key cues or manipulations,
then we could really get these cells to respond
in a way that we want to,
whether that be Tim Kamp here trying to make
cardiac myocytes for heart disease
or Shusen Zhang trying to make
dopaminergic neurons for Parkinson's,
or us trying to make photoreceptors for retinal diseases.
So, we're going to go through
just kind of on a high level what we do
to get them to towards retina.
Here's, again, a colony.
We have a couple of colonies of IPS cells.
We pick those up off the plate,
and let them grow in a three-dimensional structure.
As it turns out, anything that wants to be brain
likes to grow on these free-floating structures.
So that's by itself a step
that helps us to get in the right direction,
just a simple picking it up off of a plate
so that it can grow by itself
in a suspended aggregation.
We also add certain cues to push towards
an early brain.
And then over a period of time,
we then played them back down,
so that they go from being a suspended aggregate
to being stuck down onto a plate.
We switch the cues that we provide them,
again, trying to mimic development.
And over time, we see them form these
kind of very interesting radially oriented cellular colonies
with almost like a little hole in the center.
And we could take those off. We can actually pick those off,
Like this.
And so, when we pop them off,
we leave behind all the cells that stay stuck,
and we pick off these little
circular structures which we call golden cheerios,
and they're actually vesicular little
aggregates of cells,
and they're about perhaps the size
of a coarse grain of salt, if you look at them in your hand.
So, these are small.
And so, we can pick them up,
grow them on mass and flasks.
And if you look first at what's left,
so instead of
looking at those golden cheerios,
which is what we'll spend time with for the rest of my talk,
if you look at what's left behind, so that's the hole
from where we picked off one of these
vesicular type structures.
And if we let it go over time and we treat it just right,
we'll find that, that skirt
around where those golden cheerios used to be
will become retinal pigmental epithelium.
And they will form the retinal pigment epithelial cells,
not only in terms of what they look like,
but they also can do all the same functions that we see
in a normal eye.
And we can make these, and this is now being done
by many laboratories around the world.
It's also in clinical trials now,
and I'll talk about that at the end.
But it's really remarkable, we can make it, essentially,
an unlimited supply of retinal pigment epithelium.
So, the spare part, at least for that support layer
is not that hard to make, it turns out.
and it kind of wants to do it.
You have to almost make a mistake not to get this.
So, that's nice.
Not the same for photoreceptors as I'll show you.
So let's go back then to the little golden cheerios,
the little vesicular structures that we picked up.
So these are hollow balls.
These is under a microscope,
so it looks kind a phase bright and golden on the outside,
but envision that they're just hollow.
They're hollow balls.
But are these really optic vesicles?
Are these really those early structures
that I showed you earlier in my talk
that are budding off of the developing brain?
And to be able to show that,
I've have to be able to follow these over time,
and see what they make.
And so, let's take a look at one of these.
So if I take a section of this,
so if I take it and I cut it in half and look at it,
and I stain it with something that turns
primitive retinal cells,
in this case, kind of a red or green color,
you could see that it's completely formed
by these primitive retinal cells called progenitor cells.
That's important because it could be that
there's some retina in there and some brain.
It could be a mixture of different things.
As it turns out, they grow separately,
so that we can pick them apart
from all the other different cell types.
So this then is the purification step
that's really important.
We can pull it away from the retinal pigment epithelium,
also if there's any brain in the dish,
or anything else that might be growing,
we can pick it apart,
so we can reduce the amount of contamination
that might be there.
If we let it go another week or so,
we start to see that it layers out.
So those cells that make those progenitor cells,
which have to make the entire retina,
all those different layers, they move back and forth,
and they start to make the cell types
that are normally found in the retina.
So here in the purple are the ganglion cells,
so those output neurons.
They're born first, normally,
when the human retina is being formed.
and they're born first in the dish as well,
and they form a layer like you see there.
Then a little bit later on,
we see production of primitive photoreceptors.
So, in red and yellow
are particular fluorescent markers
that home in on cells that have
early characteristics of photoreceptors.
So these wouldn't be able to detect light yet,
but they've already decided
that they want to become photoreceptors.
The question is how close to being a mature photoreceptor
will they ultimately become.
And so, it takes a long time.
We have not found a way, very well at least,
to be able to accelerate the process.
So, one of the downfalls of this--
From a developmental biology standpoint, it's great,
because we love to be able to follow development in a dish.
But from a cell manufacture standpoint,
we haven't been able to overcome the clock.
So these cells march along from immature to mature,
but they take their own sweet time.
And essentially, the amount of time it takes
is almost identical to what it would take
in a developing human embryo.
So, it's really kind of remarkable that the timing,
that clock stays the same.
But here at 200 days in a dish,
so this is more than half a year,
it's gotten big.
Not this big, but it's gotten bigger.
And you see on the edge, a lot of little hairs.
Perhaps you can see it.
I hope it conveys well on TV as well.
But there are these kind of little hair-like structures that
cover the outer surface.
And if we cut these again in half,
and we look at mature markers now.
So now we're looking at markers, fluorescent tags,
that tells us whether you're not just a photoreceptor,
but are you a cone or are you a rod?
In red here are the cones.
In blue are the rods,
and green is kind of a mixed marker,
so it's kind of both.
And so, not only does it make cones and it makes rods,
these are red green cones,
but they actually form the right layers.
Cones are usually on the very outermost portion
of the photoreceptor layer.
Rods tend to be on the inner portion.
So we're not doing this. We're not moving things around.
We're not taping anything. It's just doing it on its own.
So it kind of knows where it wants to be
relative to other cells as they're being born.
And if you compare this now to,
in this case, a human retina,
so this is not grown in a dish, but an actual human retina,
and overlaid here,
you could see how close it is.
So, the little red structures are a little bit longer
than what we see in the dish,
but the relationship is all there.
And in some cases, it's kind of hard
to tell the difference between what's growing in a dish
and what we can see in a donor eye,
for instance, from a cadaver.
Okay, so our interest then was piqued
because we see that they're separating out like they should,
their relationships are correct,
they also make long processes that form
synapses that I'm not showing, but they do that as well.
But what I was particularly interested in
was these little hair-like structures,
because is possible that these could be
early outer segments,
so this little antenna that detect light,
because that's really critical.
If we put a cell into somebody's eye
and it can't make an outer segment,
then it's essentially just
maybe a cell that survives and hooks up,
but it has no ability to detect light.
And this is an exceedingly specialized structure
that only photoreceptors have.
So we kind of looked at that really carefully,
using electron microscopy,
and sure enough, that's what they are.
So, they don't look great. We call them little pod people.
But this is actually,
this is what outer segments look like
when they're first born.
They don't start out long
with perfect stacked disks ready to catch light.
They start out as these little pods
which then elongate and grow.
And we have older ones that do date 250 days up to 300 days,
where they do get longer
and the disks starts to stack appropriately.
But this little area here,
if I can get it to work,
is called the connecting cilium,
a very specific structure
that then ends in an outer segment.
So these are all--
We were just amazed when we saw it.
And again, we're not doing too much.
We're providing it some cues,
but for the most part, these calls are
pre-programmed to go this route
once you get them going in the right direction,
which is wonderful because,
ultimately, if we put them into a person's eye,
we're not going to be there to squirt them
with a bunch of different factors every three minutes
to make sure that they do what they're supposed to.
To some degree, we're going to have to
set them on the right path,
and they're going to have to do the rest of it themselves.
And it looks like that, in fact, can happen.
So, if it has the right properties
and the right morphology and structures to detect light,
can it actually detect light?
For this, we collaborated with a wonderful
electrophysiologist here on campus, Bikash Pattnaik,
who's in the Department of Pediatrics.
And he could actually lower an electrode
onto one of these cells, here shown in red.
We got all the photoreceptors in this culture to glow red.
And then we recorded from it,
to see whether or not it would respond to cues
that a photoreceptor usually responds to.
Now, we cheated a little bit here,
because we bypass the need for light.
We instead gave it a chemical
that's one step beyond the detection of light,
but it responded.
It responded just like a normal photoreceptor cell.
We could mimic the light being on
and the light being off, and it would turn on and turn off
just like a photoreceptor cell normally does.
And then another collaborator, Dr. Canto Soler
from Johns Hopkins
who's in now at the University of Colorado.
We collaborated with her; she took it a step further
and actually looked light impulses
with a little more mature cell,
and showed that they in fact
can respond to light with an electrical impulse.
And this is the first time that any photoreceptor had been shown
to respond to light in a dish.
Even if you take a real photoreceptor
from an animal or a human,
and take it out of its natural environment, put it in the dish,
it will no longer respond to light.
So, this was the first time
that any photoreceptor from any source in a dish
had shown the ability to respond to a photon of light.
So, we're obviously very thrilled.
But along the way we're thinking,
"Well, our ultimate goal--"
Now, it's wonderful that we can use these,
like I said before, to model disease,
so we can take, for instance,
a patient that has retinitis pigmentosa
from a genetic defect that affects the outer segment.
And now we can grow those in a dish,
and try to see if we can find
drugs or other therapies that might help that patient.
But if we want to take that cell,
once that cell is gone,
there's no way that the drug is going to help them.
So, if we're going to take the cells that we're making
and put them into that patient,
we have to move out of the laboratory at some point.
We've got to find a way to take what we do in a dish,
and convert that to a method
that's suitable for use in humans.
And that's an exceedingly difficult thing to do,
but we're unique suited to do that
here at the University of Wisconsin,
because we have a biomanufacturing facility on campus.
And in fact, it's two floors down from my lab.
My lab is the sixth floor here on the Waisman Center.
It's on the far western portion of the campus,
on the medical campus.
And then the biomanufacturing center
is here on the fourth floor.
And it's a world-renowned center for producing
self-therapeutics, also gene therapies,
and pharmacologic therapies as well.
And I had the privilege
throughout the course of my career here,
as I'm developing these cell types,
to walk down and talk to the people there
and say, "Okay, well, how do I ultimately convert this
"to something I can help a patient with?"
And most people can work 20 years
until they finally get to talk to somebody
that has that kind of expertise,
and then they find out they have to do everything all over again,
because they made critical mistakes along the way,
unbeknownst to them.
Whereas, I've got people coming up and say, "Don't do that.
"That's not a good way."
"If you've got this choice, choice A and choice B, go B.
"A will never get into a human, B will."
And so, it saved me a lot of time,
and I'm very grateful for that,
one of many things I'm grateful for,
to be a scientist here at the University of Wisconsin.
So, with the collaboration with that group
at the Waisman Biomanufacturing Center,
they were able to recapitulate our method
using techniques that are compatible for human use.
And so, you could see lots of
these little optic vesicle structures.
These green yellow and red dots
are all photoreceptors that have been broken apart
from these optic vesicle structures as they're grown.
So, we grow them up, and then we kind of piece them apart,
so we can get kind of a, for lack of a better term,
a little handful of photo receptors.
And so, it's possible now
to be able to not only create the photoreceptors,
but do them in such a manner
as to make it compatible with human use.
That's all cell production.
And so, if you think of a Michigan analogy, a Detroit analogy,
that's making the spare parts.
But ultimately, what about installation?
And I'm bringing that up at the rear
not because it's less important.
It's actually as important, if not more important,
and an even greater challenge.
It's great that we're at this position
where we're now thinking about how best to install the cells
because we actually have the spare parts now,
which 10 years ago we didn't have,
but it's still a large hurdle to overcome.
Taking a cell that's brand new and putting it
not just into another human's eye,
but a diseased eye.
So, it's an environment then that's going to be slightly toxic.
The cells have degenerated away.
There can be scarring.
There can be remodeling
of other cell types within the retina.
So there's a lot of factors that need to be considered
when talking about putting the cells back into an eye,
and getting them to hook up and restore vision.
Thankfully, we're ahead on the curve on this
simply from the fact that
the surgical tools and the surgical skills
are pretty main stream.
So when you think about trying to put in
dopaminergic neurons in the middle of somebody's brain,
boy, cell replacement in a brain hasn't been done very much.
But the eye is very accessible
and the surgical techniques and tools
are all pretty main stream.
So a lot of retinal surgeons,
when dealing with retinal detachments
and other types of diseases
are pretty comfortable getting underneath the retina
and manipulating things.
So, the approach is relatively quick,
and the risk is pretty low.
Plus, you're dealing with two organs, right?
So, you got two eyes, not one,
so you kind of have one to play with maybe,
especially if neither one of them work, right?
And if there's an untoward effect,
like everyone worries about tumors,
it's an encapsulated organ,
so you're less likely to run into trouble.
And as much we hate to do it,
we can take that eyeball out.
Worst case scenario, you can't take your brain out,
but you can take your eye out.
And then lastly, we have the tools to look at
what's going on in real time.
We don't have to put you in an MRI machine
or a PET scanner to see what the cells are doing.
We just dilate you and take a look.
We have all kinds of instruments that can give us
3D images of what's going on
underneath that transparent retina.
So it's not behind a curtain, it's right there in front of us,
so we can follow what they're doing
from a functional standpoint,
as well as an anatomical standpoint in real time.
So, all of these things have led the eye
to be really on the forefront
for cell replacement therapies
using stem cell technology.
Here's an example of where we took
the donor human photoreceptor cells
derived from IPS cells are in red.
This is actually in a rat that has a disease
that causes all the photoreceptors to go away.
And so, there are no photoreceptors in this rat.
The blue and the green are the remaining layers of the rat
that still are there.
These are blind rats.
And you can see how we can inject the cells
and get them to at least reform a layer.
It also forms connections and synapses
with the host rat as well.
We have to manipulate the immunology of the rat,
because it's a xenograft.
It's a human into a rat,
so that rat tends to destroy it.
So we have make to sure the rats don't have
a proper immune system to do that.
So, there's some manipulations that have to occur,
and a rat is not a human.
So, it's promising, but ultimately until we get into humans,
we aren't really going to know.
But that approach is really just taking out
that gemisch of photoreceptors
and injecting that into the subretinal space,
which is awfully crude, right?
We're making them. We're really proud. They make outer segments.
But I showed you a way in the beginning
that these photoreceptors
aren't just randomly interspersed in your retina.
They're tin soldiers.
They have an up, they have a down,
they have an interconnection between one another.
They have a particular orientation
that's important for them to work correctly.
So if we're just randomly squirting them
into the subretinal space
and hoping just to sort themselves out,
yes, it's shown some promise,
but it's awfully inefficient as you might suspect.
So, we're looking ahead and saying,
"Okay, well, how can make a version 2.0?
"How can we work on version 2.0
"while we're still trying to push 1.0 along?"
And one way to do that
is to put them into a prefabricated bioengineered scaffolds.
And reason number 305 at the University of Wisconsin,
we got a great bioengineering group,
and they're very collaborative,
and they love this sort of stuff.
So, you walk to them, you say, "This is what I got.
"I got these cells, but they're all kind of randomly dispersed
"when we disassociate them out.
"Yes, we'd love to put in the whole retinal structure,
"but they're not quite the right shape,
"and they're hard to manipulate or deliver."
"What we'd really to do is get them to stand up and pay attention
"and do what we want them to do."
And they say, "No problem."
And the make us things like this.
And so, this is
an electron microscopic view of one of the scaffolds
that was especially custom designed for us.
And each one of these little holes you see there
is a receptacle for a photo receptor cell.
And this was not easy to do; It's done by Yei Hwan Jung,
and with Sarah Gon and Jack Ma in her laboratory.
And this is kind of what it looks like on a little bit
lower magnification.
It's flexible. We can cut out--
This is probably enough to treat hundreds of patients,
and it is pennies to make
with the manufacturing process that they developed.
And so, here's a-- You can't see the actual scaffold.
We've kind of removed that from image manipulation.
But each one of these red lines is a photoreceptor
that has a particular process that's oriented correctly in it.
So, we're able to exceed them
into each one of those little wells,
and we're able to course them to know
which way is up and which way is down.
So, this would not be a first line treatment,
because using a scaffold is a whole another
series of FDA headaches.
But if we can get this working well,
then we're positioned to move quickly
from our baseline treatments
to something that perhaps more sophisticated
and more likely to restore meaningful vision.
So, I'm kind of wrapping.
You guys are probably happy about that,
but a couple other things that I want to mention are,
as I said earlier,
whose stem cell do we use?
We have IPS cells, we have ES cells.
ES cells obviously are not going to be
from a particular patient,
but IPS cells can be.
So, if we have a population,
one thought is,
"Well, we can make IPS cells from every individual,
"so why don't we just do that?"
So if a person needs a cell replacement,
we just personalize it for that particular person.
The problem with that is sometimes you need them right away.
Let's say you had a heart attack and you need cardiac myocytes.
You don't have two years to grow them in the lab,
and it's millions of dollars.
So, if you're not really, really, really wealthy,
and you have a lot of time to wait,
then it's not really going to be very practical to do,
especially not when you look at healthcare worldwide.
The other option is to say, "Well, one size fits all.
"Let's have one cell that we can give it
"to anybody that has a disease."
Therein lies the problem with immune rejection.
Because now you have a cell
that's not necessarily immune matched
to the recipient that's going to get it.
And so, that means you probably are going to need
some immune suppressive drugs,
which in elderly population could be a lot of problems.
Not that, that might not be the best way to do it,
and certainly would be the simplest and most economical,
but we're kind of looking at an in between strategy,
and that is to develop a series of cell banks,
about 85 to a hundred different cell banks
that are immune matched to large segments of the population.
So, with about five specially chosen IPS lines,
you can match almost 20% of the US population,
like you would for a kidney transplant.
So, not perfect.
It's not exactly like that person, but it's close,
like you might look for a good match
or a beneficial match for a solid organ.
And if you move it up to 85 or a hundred cell lines,
you can cover over 95% of the population.
And that's the strategy that Opsis Therapeutics
and Cellular Dynamics International here in Madison
is adopting.
So they're working with the Blood Center Wisconsin
to produce these banks,
so that they'll kind be kind of an off the shelf.
So, a person walks in, and you say,
"You're closest to line 42."
And so, you start there.
We don't know, however,
whether that's necessary or sufficient.
But for us, that's what we're gearing towards,
because we think that it's a nice bridge between
dealing with the biologic problems,
and dealing with the economic problems.
So, in terms of actual stem cell trials
or what's going into patients these days,
the eye is, as I said, leading the way.
Almost all the stem cell trials right now going on humans
are in the eye,
and they're all with the retinal pigment epithelium.
"Why," because, as I said way in the beginning,
they're easy to make and they grow in large swaths.
They can be purified easily,
and then they can be placed into the subretinal space.
They don't have the same orientation problems
that the photo receptors do.
They need to be oriented, but they tend to grow oriented.
The downside of it is RPE don't detect light.
So, when they die,
the photoreceptors then die afterwards.
So if you just replace the pistons
and the carburetor is missing,
or the catalyst converter is missing,
then you're not really going to get the engine to start, right?
So you're only replacing one of the two cell types.
So, California Project to Cure Blindness
has an ES cell-based RPE clinical trial that's ongoing.
Advanced Cell Technology, which is now Ocata, now Astellas,
also has one.
Riken in Japan is starting up one again
with IPS cell derived RPE.
And the National Eye Institute, Kapil Bharti,
a friend of mine, is also doing one with IPS derived RPE.
So, a lot of energy is being put into putting
the RPE cells into patients to see if they will help
individuals with RP and AMD.
But that leaves out
what I think are the real critical players in this,
and that's the photoreceptor cells
that were the subject of most of my talk.
The good news is that we're making good progress
enough that, not only here at UW, but around the world,
but the National Eye Institute recently
established their audacious goals for the next 10 years.
And they feel strongly enough that this will actually occur,
that they've kind of put their money down,
and said, "This is actually what we're looking for
"over the next 10 years."
And that is to be able to restore vision
through regenerating cells of the retina,
particularly photoreceptors and also ganglion cells.
So, that's very encouraging.
And it's an audacious goal, which means it's not easy,
but it also shouldn't ridiculous.
So, we got a long way to go, but it's not so far-fetched
that they would look silly at the end of 10 years,
because there's no possible way that they can attain that goal.
And so, we at the University of Wisconsin,
and there's the website there if you want to
read more about the audacious goals.
I recommend folks do that.
And we at the UW are playing a prominent role.
So, at the McPherson Eye Research Institute,
we have a number of members.
We have two large grants that we're working on
with University of Rochester, Johns Hopkins, and Harvard,
to band together
large teams with specific expertise
to try to overcome these hurdles,
not just of cell production,
because we're moving along quite well on that,
but also cell installation,
making those connections and restoring vision,
and making it a meaningful restoration of vision.
We have to manage expectations along the way.
Super computers weren't made overnight.
We had little clunky things that took up whole rooms.
And then over the course of decades,
we ultimately have our little cellphones now
that can do more than those
whole room computers could do at the beginning.
And similar to this type of technology,
we have to crawl before we walk before we run.
And so, when I talk to patients, I'm always quick to say,
"You can't really expect to go from
"blindness to reading the New York Times.
"It's going to be an iterative process where we learn along the way."
And if we ask the right questions, and we're careful about it,
and we're safe about it, that's number one,
we'll be able to make those steps
and hopefully arrive at a product
that's really meaningful in the foreseeable future.
And...
All right, this is the bane of my existence.
But, stem cells, they cure everything, right?
And you can get on and--
Don't go on the website and just Google stem cells.
You'll get all kinds of things,
and they'll claim everything under the sun.
And the rule of thumb is
if they ask you to open your pocketbook,
it's probably a sham.
At the state that we're at right now with this technology,
we have to pay you,
we have to search out the patients
to come in and participate,
and we're going to pay for your travel,
and we're going to thank you profusely,
and you're going to get a gift certificate to Panera.
If they're asking you to drop $40,000,
then they have a conflict of interest.
They're making money off of you, right?
And if the scientist that are really in the thick of it
are saying, "We're working, but it's not a miracle cure,"
and somebody turns around says,
"No, no, it's a miracle cure for 40 grand."
Then all the bells and whistles and flags should go up.
There are plenty of very, very wealthy people in this world
that are blind or have low vision.
If there was a way to pay
to get your vision back right now,
they would do it.
So don't fall for those traps.
And that's the best way to sniff them out.
If they ask you for money, don't trust them.
So, just to finish up here
before I thank all the people that actually do the work,
the technology exists to build human retinas in a dish.
That's amazing. That gets me up every day.
And like many areas of stem cell technology,
UW-Madison is a leader in that field,
and the McPherson Eye Research Institute
is playing a huge role in that.
Installing these new cells that we can make
and that we're so proud of ourselves about
still remains a large challenge,
but the expertise and resources
and all the accoutrements that are necessary
to really address these big challenges
are here on campus or with our collaborators.
And more importantly, the atmosphere
is such that we like to work together.
We like to take what I know best
and meld it with what somebody else knows best,
and come up with better ideas
and build a better mouse trap, and it makes it fun.
So, to finish up, here are credits.
These are the actual people that I want to make sure
that get highlighted.
My laboratory as changed a lot over the years,
and the people have been wonderful.
They work very, very hard, and they're brilliant.
Beth Capowski and Joe Philips deserve special recognition.
Beth did a lot of the work
on the three-dimensional structures that you saw,
and Joe runs our transplant program.
Without these two individuals,
there's no way I would be anywhere close
to where we are right now.
And of course my laboratory is just one of
hundred plus that are part of the
McPherson Eye Research Institute.
I have them all interconnected here,
because we talk with one another,
we exchange ideas, we exchange resources and expertise.
And that allows us all to move ahead
faster and safer,
and that's the important thing.
And so, our motto is to pioneer science, medicine, and art
of saving sight.
We're very serious about our support of art.
Because ultimately, what are we trying to save?
We're not trying to save the ability to see
a white dot on a black background.
We want to save or restore the ability of people
to appreciate the visual world around them.
And I have collaborations across campus.
These are just some of them.
Jamie Thomson is there, Bill Murphy, Sarah Gong.
I can't name them all, but just tremendously talented people
that are willing and enthusiastic to work with us.
And of course we have a lot of sources of support
that I'm very grateful for,
particularly, I mentioned Dr. Monroe and Sandra Trout,
and David and Nancy Walsh
who have been very instrumental
in getting a lot of this work going,
as well as our other source of funding.
And with that, I want to thank you for listening to that.
And I'll take any comments and questions you folks have.
(audience applauds)