Stemming vision loss with stem cells: Dennis Clegg at TEDxUCSB


Translator: Robert Tucker
Reviewer: Tanya Cushman Thank you and thank you for inviting me. I’m going to tell you about efforts
ongoing here on campus and in a team of researchers
across California to try to use stem cells
to treat a blinding disorder called age-related macular degeneration. But before I get started, I wanted
to put up this slide for inspiration. This is a newt, and you know how
when you make a PowerPoint, you go to Google Images and search? When I searched, I found this image. (Laughter) And, in fact, that’s
the first thing that comes up. Then I started thinking about – I was comparing the Newt on the right here
to the newt on the left, and this guy’s pretty powerful, you know. He’s not running for president anymore, but he was, and here
he is on Meet the Press, but in some ways the newt on the left
is actually more powerful because the newt on the left
can regenerate body parts after injury. The Newt on the right cannot do that. (Laughter) Even parts of the eye can regenerate. Just amazing. And here’s a picture
of a limb that was lost, and it regrows over a period
of about three months. So, this is really the field
of regenerative biology, or regenerative medicine, that has a lot of people very excited. If we can figure out
how the newt does this, and regenerates here,
over three months’ time, a limb that looks pretty much
exactly like the original limb, we could maybe benefit and treat
our own disorders and diseases. So, I’m going to tell you about that, starting with a little bit
of background about stem cells. And I am a teacher,
and I know a lot of you are students, so you probably didn’t know this,
but there’s a pop quiz. So, I’m going to start. This is your midterm, and I hope you all brought
blue books and No. 2 pencils. But I don’t see any out there,
so I’ll make it multiple choice. Here’s your first question: What is a stem cell? Here are your choices: a) a cell from the stem of a leaf, b) the latest cell phone from Apple, or c) a self-renewing cell capable of
differentiating into a specialized cell. (Audience) c) c), very good, although I think a)
would also receive full credit. I think that’s actually – that’s true. No, those are the two things
that a cell has to do to be a stem cell. First of all, it has
to be able to self-renew, proliferate, make more copies of itself, and then second, given the right signal,
usually during development, it differentiates or changes
into a specialized cell type. And if you think about
types of stem cells, there are pluripotent cells that can give rise to
most cell types in the body, and multipotent cells
that have a more limited repertoire and can give rise to a few cell types. The types of stem cells
that we’re going to talk about today are neoblasts, embryonic stem cells, and induced pluripotent
stem cells or iPS cells – those fall in the first category – and multipotent cells that can give rise
to a few cell types, adult cells. So, what are neoblasts? Well, I brought, actually,
an organism here that has some neoblasts. I don’t know if you can see this. This is a flask, and maybe if we can zoom in here
with the camera over here, you can see these are planaria. Planaria are amazing. They’re little flat worms,
they live in the pond, and they’re crawling around here. They are full of stem cells. and you can take a planaria – It’s actually a fairly complicated beast, it has all these internal
organs shown here. You can take this and cut it in half, and each half will regenerate
into a complete worm. You can actually cut it up
into 279 pieces, and each piece
will regenerate into a worm. Turns out, they’re full
of these neoblasts. Every tenth cell
in the organism is a stem cell, and that stem cell
is actually pluripotent; it’s actually totipotent. It’s recently been shown that a single cell
can regenerate an entire worm. So, that is the champion
of regeneration, the planaria. We’re not quite as good as that. I guess our equivalent of a neoblast
is an embryonic stem cell, and I wanted to spend just a few minutes talking about where embryonic
stem cells come from – there’s a bit of misinformation out there. If you go to a developmental chart
and look at development, after five days, we have about 128 cells,
and we form what’s called a blastocyst. And there’s one little cluster of cells
in this little hollow space in the middle called the inner cell mass. And the inner cell mass [ICM]
actually gives rise to the entire embryo, the rest of the cells make the placenta
and other extra embryonic tissues. But this ICM is amazing. Maybe, you know,
a cluster of 30 to 50 cells – that makes the embryo. So to grow embryonic stem cells, those cells are extracted with a pipette
and grown in culture. That’s where they come from. And it turns out
excess blastocysts are generated during the process
of in vitro fertilization. And it’s estimated that there are over 400,000
frozen-down blastocysts in IVF clinics that will eventually be discarded. So, that’s where these lines are derived. And once you derive a line
by extracting the cells growing them, they propagate forever,
as far as we can tell, and you can freeze them down,
thaw them out and keep growing them. So, that’s where these cells come from. They were first isolated
by this man, Jamie Thomson, who, at the University of Wisconsin,
figured out how to get these from monkeys, and then went on and figured out
how to get them from humans. Here he is on the cover of Time magazine. Dr. Thomson has a partial appointment
here at UC Santa Barbara, where he serves as a co-director
with myself and Tom Soh in our Center for Stem Cell
Biology and Engineering. Here’s what they look like. This is a figure from
Jamie Thomson’s 1998 Science paper, and what you see here
is a colony of embryonic stem cells. One cell is about that size. So this is thousands of cells. They grow as a colony, and they’re actually growing on a carpet
of irradiated mouse embryonic fibroblasts, these stretched-out cells. So, it’s very difficult to grow them. Some people even think
there’s a bit of artwork involved. You have to be able
to look at your cultures and see if they’re happy or sad. And, actually,
in preparation of this talk, I found evidence that it is artwork. And I found this on
the University of Wisconsin website. There’s stem cells
and there’s Vincent van Gogh. He may have been a stem cell scientist … maybe he was trying
to regenerate his ear, I’m not sure! (Laughter) Okay, so that’s embryonic stem cells. Now there are also adult stem cells, and a number of our tissues
have lurking within a population of multipotent stem cells. The bone marrow, for example, makes blood, and it has stem cells,
hematopoietic stem cells, that can make all the blood types. Can’t make other types,
but can make all the blood. And there are already
therapies, as you know, using bone marrow transplants
and other types of adult stem cells. The newest kid on the block is this type of cell called the iPS cell
or induced pluripotent stem cell. And in 2007, two groups reported that you could take
normal, old skin cells, add in a cocktail of four genes, and convert it to what looks like
an embryonic stem cell. So it’s induced pluripotent. It was first reported
by Shinya Yamanaka in mice, and then jointly by Yamanaka
and Thomson in human. Thomson used a slightly different
cocktail of genes, encoded by viruses that infect
this boring somatic cell and turn it into this really cool,
embryonic, stem-cell-like cell. Ian Wilmut, who cloned Dolly,
called this an astonishing experiment. Somebody likened it to cellular alchemy. You’re taking lead
and turning it into gold here. So, there’s a lot
of excitement about these. You don’t even have to use blastocysts; you can take your skin
and make what looks like a stem cell. So a lot of people
ask which stem cell is best. Why do we need embryonic
if we have iPS or adult stem cells? And the answer is we don’t know yet;
we need to do more research. Embryonic stem cells
have the greatest repertoire; iPS cells, there’s still
some questions about them; and adult stem cells may work very well
for some things but not for all things. A lot of research still needs to be done. Well, as you know, stem cells
is kind of a political football, and if you remember back in 2001, George Bush said that you couldn’t use federal funding
for any new stem-cell lines, you had to use the existing lines, and he limited research in this country. Then, out of the surf, came Barack Obama, and he lifted this ban in 2009, allowing federal funding for a number
of different embryonic stem-cell types. And then in 2010, along comes
a judge in Washington DC, and he put the freeze back on
in even more draconian fashion. So it’s really difficult for researchers
working at the lab bench to try and deal with this
when the football is moving around, and your funding, all of a sudden,
one day, is cut off – it’s difficult to do the work. In California, you may remember, in 2004, we passed Proposition 71
for state-funded stem-cell research, and it created the California Institute
for Regenerative Medicine, or CIRM. And here’s the state of California
made entirely of stem cells – there are the Channel Islands right there. And UCSB benefited from grants from CIRM and founded this stem-cell center, where we’re doing
a number of different studies. I’m going to finish by telling you about one very exciting piece of work
going on at our center. It has to do with the eyeball and that disease I mentioned
at the beginning, age-related macular degeneration. Let me just tell you
a little bit about the disease – but first, you need to take
your final exam before you can go on. So here’s your final exam question: What is a macula? Here are your choices: the newest version
of the Macintosh computer, a Scottish cousin of Count Dracula, (Laughter) or c) the central-most part of the retina,
responsible for detailed, sharp vision. Anyone? Audience: c) Very good, very good. You all get an A
for this class. Congratulations! Yes, that’s this tiny part
of the back of your eye that’s responsible
for very high acuity vision. Here’s just a cross-section of the eye
showing you this tiny little part. It’s 0.1 inches in diameter,
chock full of cones and photoreceptors, and it’s really important for your vision. It’s right at the center
of your visual field. If you’re reading small print,
or threading a needle, or even doing normal tasks, you use this part of your eye. For some reason, this disease
only affects that part, and if you go into the doctor
and look at an eye chart, it may look like this. You see this blank spot, or sometimes it appears like a dark spot
in the middle of the visual field, and it could progress to legal blindness. It’s actually one of the leading
causes of blindness in people over the age of 55. It’s characterized by this loss
of the central part of your visual field, so if you’re looking out at a scene,
it may look something like like this. Now, we know a little bit
about the disease. It turns out there’s a key cell type
in the back of the eye called the RPE, the retinal pigmented epithelium,
or retinal pigment epithelium, and when that cell dies,
pretty soon the photoreceptors die. So, let me tell you about the RPE. If you look at somebody’s eyeball,
and you look into the pupil, it’s black. That’s because you’re actually
looking at this cell layer, which is in the back of the retina. As light passes into the eye,
it’s focused on the retina, and here are the rods and cones, and right behind the rods and cones
is this pigmented monolayer, very important, because without that layer,
the rods and cones die. So, the RPE is an essential support cell
for the photoreceptors. Now, why does it die? We don’t know all the reasons
that it dies in this disease. It takes sometimes 70 years, and we’re still trying to figure that out, but we think that it might be
a good candidate for a stem-cell therapy. The reason is we know that the death
of those cells causes the disease, and we know that you can take
human embryonic stem cells or iPS cells and turn them into RPE. These cells could then be implanted
in the eye and replace the damaged RPE and prevent the loss
of the photoreceptors. So we’ve gone forward to try and do that. And before I go into our work, I wanted to tell you
about some of the challenges that anyone faces in trying to make
a therapy for a disease using stem cells. There’s a lot of hype in this field, and there’s still a lot
of really difficult challenges to solve. First, the cells may not
integrate in the tissue. And if – You can imagine, if the tissue
is too far gone, too far damaged, it will be really difficult for a cell
to go in there and fix everything. Second, if you’re using
a cell type from somebody else, it would be recognized
as foreign and rejected. So it’d be like a heart transplant;
you’d have to use immunosuppressive drugs. iPS cells may solve that problem
if you start with the patient’s own cells. And then third,
the cells may form a tumor. These cells like to grow,
they like to proliferate, and the danger is that if you get
an undifferentiated cell in there, it could form a tumor. Now, that all being said – well, there’s also one other problem
that you may know about, and that’s there are these unregulated,
unproven foreign stem-cell companies that prey on desperate patients
and offer to fix you for $10,000 with something that’s not even proven. So you have to be really careful. And I wanted to point out the CIRM website that has a lot of links to companies
that have been investigated so you can find out about any company
you’re interested in. Okay, all that being said, the eye, I think,
is a good place to start. And the reason is we know
how to get in there and do surgery; there are good ways to image the cells
after you transplant them. If you’re injecting cells into the heart,
it’s hard to see where they go. But in the eye, the ophthalmologist
can use non-invasive imaging to look inside and see where they are. We can also measure function very easily, and it’s not a very big organ
compared to the heart or the brain, very small number of cells
would be needed, we think, to make a good therapy. So, we formed a team with a number
of universities in California, and we have a grant from the California Institute
for Regenerative Medicine, to go after this disease. The project is actually headquartered
at USC Keck School of Medicine and led by Mark Humayun, who’s an MD PhD retinal surgeon
and actually sees patients. Here at Santa Barbara, we’re sort of
the cell factory or cell farm, we’re growing the cells and transferring them
to USC to do experiments. The City of Hope down here is where we’re going to be
making the cells in what’s called a GMP facility, where people in bunny suits
work to make the cells. And Caltech is helping
with other aspects of the work. What we’re imagining is sort of a contact lens
for the back of the eye, a contact lens coated with cells
that is implanted by the surgeons, similar to what’s shown here
in cartoon fashion. And here’s actually a scanning EM picture
of cells on a substrate. Here’s an implant in a rat showing the substrate with human cells on
placed exactly in the back of the eye where we would hope
to put them in humans. How do you tell if the rat can see? We’re actually testing this in rats, and there’s a test you can do
called the optokinetic response. You can try this at home
if you have a pet rat. Put him in a jar
and make some bars go by and watch the rat’s head. It’ll start to track those bars. You can tell not only
that the eye is working, but that it’s hooked up to the brain. So, that’s an easy test
to tell if a rat can see. We used a rat model
that loses vision with time, called the RCS rat. What you’re going to see next
is a blind rat that doesn’t have any transplanted cells
and has lost its ability to see. He’s more interested
in sniffing the ground, and then he actually tries to get out. He’s pretty smart, but can’t see; he’s not tracking the bars at all. Now what you’re going to see is a rat
that actually has an implant of our cells on this plastic synthetic substrate that’s been surgically transplanted
into the back of the eye before the photoreceptors
have all disappeared in this model. And what you’ll see, a blind rat here implanted
with stem-cell-based therapeutic, and the green bar indicates
the time when he’s tracking, and it’s scored by several people, and you can see
some rescue of his vision. It’s not as good as the original rat,
but he’s starting to see. So, we’re also going forward with this
and developing surgical methods. And here’s how we think it would work. A patient would go in,
a slit would be cut in the eye, the vitreous body is removed –
the jelly stuff in the middle of the eye – and then a little bit of fluid is injected to lift the retina
away from the damaged RPE. Then a little slit is made, and our contact lens with cells –
which looks like a band-aid here – is inserted back there
to replace the bad RPE. Now, how do you work this out? Well, turns out the pig has an eyeball that’s very similar in size
to the human eye. And here’s an actual surgery done by Rodrigo Brant,
last March, down at USC. What you’re actually looking through is a microscope
that’s placed over the lens, and there are little holes
in the side of the eye where they can go in with tools
to first remove the vitreous, now inject some fluid
to lift the retina away from the RPE, and then cut a little slit in there – and what they’ve done down there is developed this tool
to pull the implant into a cannula. This is our implant –
looks like a squished bottle – it kind of rolls up like a taco shell and then gets inserted into the eye and extruded out. It’s a little difficult to see, but you should be able to see it now going in behind the retina
and then unfolding back here. In just a minute,
you’ll be able to see it. There, it just came out, and it unfolds and lays down
in the right place in the eye. Now, they think they can do this in humans
in about a 45-minute outpatient procedure, and we’re going forward to hopefully start
a clinical trial in 2015. So, someday, we hope
to have this commercialized and available to patients, and maybe someday we’ll be
a little bit more like the newt. And I heard newt
is in the building, actually. Here he is. These are amazing creatures – hopefully they can zoom in – but these little guys
know something we don’t, and maybe we can do what they do
using stem cells and tissue engineering. Thank you very much. (Applause)

4 comments

  1. I need help to help my son he is blind in one eye and blurry in the other eye from diabethic rethnapathy please help me thank you

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