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Regenerative Medicine In Ophthalmology At The Fox Center For Vision Restoration, JOE S.
SCHUMAN, MD
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So I’m going to talk about regenerative ophthalmology and very little of what I’m talking about is
my work and I’ll try to let you know who is doing what when I’m talking about specific things. But
we’re going to cover a fairly wide swath as we do this. One of the most mature areas that we are
doing work in is in cornea and Jim Funderburgh’s lab is really a leader in corneal stromal
regeneration so Jim Funderburgh and Yiquin Du who is in the audience you’re going to hear from I
think next, discovered a stem cell that is for the corneal stroma and basically that stem cell can
rebuild cloudy corneas in mice. So if you take a mouse that’s lumican deficient it has a disorganized
cornea, the cornea is cloudy, you inject these stem cells into the cornea, the cornea will reorganize
into its proper structure and the clarity will be restored. And these are human stromal corneal stem
cells and they take up residence and they stay there and so that’s what you see here. So these are the
human corneal stromal stem cells sitting there. In a in a translational effort Funderburgh’s lab has
paired with a group in Hyderabad, India that LV Prasad Eye Institute and ______ from the LV
Prasad spent a year in Jim’s lab and has taken the technology back to India where they will attempt
to use this technology in patients. And so we should know in the near future the efficacy of this
technique in patients, but it would be very exciting to be able to take a cornea like that in a patient
and with the application of these stem cells be able to restore corneal clarity.
Another area of stem cell work in the cornea is work by D.P. Dhaliwal and Kira Lathrop. So Kira
working with Larry Kageamann from our group was able to image the corneal the palisades and
identify the areas where corneal epithelial stem cells reside. And so I think everybody in the
audience knows the effect of the stem cell deficiency and this is the imaging of the corneal palisades
Regenerative Medicine In Ophthalmology At The Fox Center For Vision Restoration, JOE S.
SCHUMAN, MD
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here. So this is human clinical in vivo OCT and processing the OCT you’re able to see the
substructures. And just the way that Larry Kagemann showed the 3 dimensional reconstruction of
the aqueous outflow system you can similarly do a reconstruction of the palisades. Finally in the
cornea for the endothelium we created a program called the OTERO Program at Louis J. Fox Center
for vision restoration and so the Fox Center is a part of the department of ophthalmology and it’s a
collaborative effort between ophthalmology and the McGowan Institute. The McGowan Institute for
regenerative medicine is one of the highlights of the University of Pittsburgh. It’s a fantastic
organization if you don’t know about it I would encourage you to look on their website but we were
able to pair with them to create the Fox Center and what the Fox Center does is to provide an
infrastructure for clinicians and scientists of varying backgrounds to work together. And the
OTERO Fellowship is specifically designed to take people who are in disparate fields let’s say a
bioengineer and a clinician or a bioengineer and a basic scientist who’s a molecular biologist or cell
biologist and pair them together to train a post doctoral fellow and that post doctoral fellow then
learns the regenerative techniques that are being done outside the eye and can apply them to
problems in the eye so that when their fellowship is completed they’ll be working on ocular
regeneration. And so this is one of those projects and this is a project that’s a collaboration between
Adam Feinberg who’s an engineer at Carnegie Mellon and Jim Funderburgh and Rochelle Palchesko
is the OTERO fellow and OTERO provides $70,000 for a year of post doctoral fellowship training
plus supplies and what they’ve found is that by changing the firmness of the substrate on which the
cells grow they can stimulate the growth of corneal endothelial stem cells. So they’re not supposed
to divide right and yet they have been able to get the cells to proliferate by changing the firmness of
Regenerative Medicine In Ophthalmology At The Fox Center For Vision Restoration, JOE S.
SCHUMAN, MD
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that substrate. So that’s very exciting and we’re looking forward to the work that will be done but
there’s a lot more work to do.
I won’t spend really any time on this because you are going to hear from Dr. Du about her work but
I’ll just say that Dr. Du was able to identify stem cells – was able to identify stem cells in the
trabecular meshwork and was able to prove that those stem cells when injected into the eye will
home to the trabecular meshwork and specifically if you’ve injured the trabecular meshwork that it
will home to those areas of injury. Now the next step is will it repair those ares of injury and we’ll
hear something about that but the first two things there are stem cells and they’ll home back to the
trabecular meshwork I think is quite exciting and I’m – I’m really excited to be having the
opportunity to collaborate with Dr. Du.
You’ve heard a number of presentations from our Glaucoma Imaging Group, this is a sort of an old
photo but it gives you a sense of the group and of our basically faculty and students. And you hard
from Larry Kagemann who talked to you about imaging the aqueous outflow system and this should
turn just like it did for Larry. And so Larry has been able to image the aqueous outflow system and
this is a 3-D reconstruction, a part of which Larry showed you before but it gives you a sense of the
outflow system in a actually human cadaver eye, and so this is what the outflow system looks like in
that eye. And since that time Larry has gone on to create reconstructions in living human eyes but
not 360 degrees. And the reason is that it is very time intensive, and it’s not easy.
Regenerative Medicine In Ophthalmology At The Fox Center For Vision Restoration, JOE S.
SCHUMAN, MD
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We have two scientists who are working on retinal regeneration, so you may ask yourself well if a
newt can regenerate its – you know its arm or leg or if it can regenerate its eye or retina why can’t
we? The machinery must be there, why can’t we do that? And so if you look you know you have
these stem cells that will proliferate ad infinitum in a newt or a salamander, in a fish you can
regenerate the retina, in a chicken you do have stem cells, how about in vertebrates?
Well in mammals you may or may not be able to regenerate the retina and there are stem cells that
are in he retina in normal humans and this is work from Hongjun Liu who just joined our department
and Hongjun Liu has identified a subset of amacrine cells that are what’s called Lgr 5 positive. And
these, that’s a marker for stemness, so these are stem cells in the human retina. Actually this is in
rats. And this is showing you the Lgr 5 positive cells and where they are located. These are all
nuclei, here you see the Lgr 5 positive cells. And they are not ciliary body cells, there was this
hypothesis a number of years ago that there were stem cells in the retina at the area of the ciliary
body in humans but we do know that that exists in lower animals, not in vertebrate mammals.
And then here is evidence that these are in fact amacrine cells. So what Hongiun Liu has shown so
far is that the stem cells exist in adult mice, that they are amacrine cells and they possess all the
properties of differentiated neurons and yet they can proliferate and generate other retinal cell types
that in fact they are stem cells both in vitro and in vivo and that the mammalian retina has plasticity
and these cells can function as adult retinal stem cells.
Regenerative Medicine In Ophthalmology At The Fox Center For Vision Restoration, JOE S.
SCHUMAN, MD
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Another scientist who is working on stem cells in the retina in our labs is Igor Nasonkin. Igor is the
Assistant Director for the Fox Center, he is the Salvati Assistant Professor of Ophthalmology. I
should mention that Jim Funderburgh is the Associate Director of the Fox Center and so as the
Salvati Professor Igor is running the Retinal Regeneration Laboratories which are soon to be
unveiled as the Snyder Retinal Regeneration Laboratories thanks to the generosity of the Snyders
and he is basically running 3 projects. One is grafting stem cells to the mammalian retina for cell
replacement, another is using epigenetics for retinal regeneration and finally doing retinal genomics
for personalized therapies for vision loss and this is an example of grafting photoreceptors and here
you see the stem cell graft to regenerate photoreceptors and you can see that there is the integration
of some of these cells.
And this is a very brief cartoon about methylation and how epigenetics works but basically you have
the machinery but it may be on or off depending on whether or not the chromosome, that area of the
DNA is methylated. So the methylation controls the access to that DNA for translation. And so
there are these epigenetic mechanisms that play a role in plasticity of the cells in the retina and here
is a brief description from Igor as far as how he plans to use this as an approach to regenerate retina.
We do also have a scientist working on optic nerve regeneration, he came out of Jeff Goldberg’s lab
and this scientist Mike Steketee is using a couple of different approaches to work on regeneration of
the optic nerve. Up until I don’t know a year ago I probably would have said that it’s very unlikely
that we would see optic nerve regeneration within the next 10 years. We had a meeting here this
Regenerative Medicine In Ophthalmology At The Fox Center For Vision Restoration, JOE S.
SCHUMAN, MD
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June specifically on regenerative ophthalmology and Larry Benowitz and Jeff Goldberg were both
here and presented really exciting data showing robust optic nerve regeneration, really just very,
very fascinating and exciting. And so Mike is following up on some of the work that they talked
about but a number of original projects that he’s working on including collaborative work with Steve
Badylak looking at the role of extracellular matrix in promoting the growth of ganglion cell axons.
This is work by Matt Smith, so Matt Smith is doing very basic science in a nonhuman primate model
and what he is looking at is visual perception. So when the nonhuman primate is shown an object
what neurons fire in order to understand – for that monkey to understand what it’s seeing. And so
he’s doing single cell recordings 100 cells at a time using these Utah rays. And so you might say
well you know what does that have to do with regenerative medicine? Well we have a kind of a
crazy project going on and that crazy project involves the head of neurobiology and also the head of
the neuro technology center and so that’s Peter Strick and Andrew Schwartz. And Dr. Schwartz is
the person who is responsible for the quadriplegics being able to use their thoughts in order to
control a mechanical hand. I don’t know if any of you saw that it was on, it was in the popular
literature as well as the scientific literature and it was also I think on 60 minutes or 20/20 or one of
those T.V. shows and it’s very exciting, it really is. I mean it’s the first time that you could basically
use your thoughts to control an external object except for the people who can do telekinesis and
that’s outside of the scope of this lecture.
And so instead of recording single cells, if we can
understand how the brain interprets visual information in order to make a visual construct we would
be able to provide a true vision back to people who have lost it and so this visual neuroprosthesis
Regenerative Medicine In Ophthalmology At The Fox Center For Vision Restoration, JOE S.
SCHUMAN, MD
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project is crazy, exciting, it will take a long time to do and a lot of money. But we’re very excited
about it and if you don’t set out to do it you’ll never accomplish it. So this is a priority project for
our group.
Can you pause that for just a second. Okay, so the person you just heard and you’ll hear it for a few
seconds is Amy Nau. Amy Nau is our head of optometry, she’s an optometrist, clinician, scientist
and she is working with sensory substitution so there’s a company very close to Paul Kelfman which
is called Wicab. Wicab was started by Paul Bach-y-Rita and Bach-y-Rita had this idea that you
could use a part of the body other than the intended sensory portion of the body to provide sensory
information and in this case we’re taking people who are blind and by blind I mean light perception
or no light perception and giving them visual information on their tongue. And so there’s a video
camera that feeds to a computer that feeds to a tongue stimulator and it’s completely you know noninvasive and fairly simple to use. It doesn’t provide true vision to the patients but it does provide
enough visual information to them so that they can experience the visual world independently. So
now can you put the video on.
VIDEO PLAYS
So in this brief presentation I don’t have enough time to share with you all the data that Amy has
gathered but she’s done a fair amount of scientific study to show the efficacy of this device but also
to show where the information is processed and this will kind of blow your mind. As it turns out in
Regenerative Medicine In Ophthalmology At The Fox Center For Vision Restoration, JOE S.
SCHUMAN, MD
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people who are blind the information from this device once they’re trained which is about a week or
two of training and use, is processed not in the tactile portion of the brain but in the visual cortex.
And if you take a group of healthy people who are normally sighted that doesn’t happen and it’s
really a fascinating aspect of neuroplasticity in the visual system which we all were taught we’re
hardwired, but in fact you know part of the brain can be used that’s not being used and the brain’s
even smarter than we thought it was maybe. Let me show you 2 other short videos. So here’s one,
can you start this one please?
VIDEO PLAYS
So that’s somebody who’s LP or NLP and was able to do that. Then the last video that I’m going to
show you is Eric Weihenmayer who’s a blind climber I think he was the first blind person to climb
Mt. Everest and it’s a vide from the NIH. And he’s the person on the bottom right. The PET CTs
are what you’re seeing up on the top right. Amy has now done studies with Kevin Chan the person
who’s working with Ian showing similar findings with FMRI. And this is where she sees things
going now instead of having a tongue stimulator we foresee the stimulator being applied to the hard
palate and you can put your tongue up against it at any point and then it would be wirelessly
transmitting the information. Obviously having something that you take in and out of your mouth
interferes with your daily activities, this would be a little bit less intrusive. Okay can you start this
video please?
Regenerative Medicine In Ophthalmology At The Fox Center For Vision Restoration, JOE S.
SCHUMAN, MD
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VIDEO PLAYS
Thank you very much.