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2019 GRF Annual Dinner Keynote: David Calkins, PhD

Glaucoma Research Foundation held its 2019 Annual Dinner with the Board of Directors, staff, volunteers and donors, on April 23, 2019 at The Olympic Club in San Francisco, CA. The keynote speaker was Dr. David Calkins who spoke about "The Catalyst for a Cure Initiative to Restore Sight."

David J. Calkins, PhD is the Vice-Chairman and Director for Research for the Vanderbilt Eye Institute and the Denis M. O’Day Professor of Ophthalmology and Visual Sciences at the Vanderbilt University School of Medicine. In addition, he serves as Director of the Vanderbilt Vision Research Center. With Glaucoma Research Foundation, he serves as Chair of the Research Committee and the Catalyst for a Cure Vision Restoration Scientific Advisory Board.

Video Transcript

Thomas M. Brunner: It’s now my pleasure to introduce Andrea Epstein, who will introduce our keynote speaker. Andrea is a member of our Development Committee and also chaired our Patient Summit steering committee. In March we held our first Patient Summit right here in San Francisco. Thanks to Andrea’s leadership, it was a tremendous success. Ladies and gentlemen, please welcome Andrea Epstein.

Andrea Epstein: Thank you Tom. I just want to give a few little intro remarks and then introduce our keynote speaker tonight. Like many of you here tonight, I became involved with the Glaucoma Research Foundation because someone very important to me has glaucoma.

My husband David was diagnosed with glaucoma 33 years ago when we were first married. Though he has been a diligent patient, adhering to regimens of eye-pressure-lowering drops followed by multiple surgeries, his vision has continued to deteriorate. With his professional life in high gear, I went on the hunt for organizations that were funding the most innovative research in both glaucoma treatments and advances that might lead to an eventual cure.

I found myself here at GRF and specifically at Glaucoma 360 about five years ago. I was there to learn as much as I could about what research and advances were on the horizon. Like many of you, my husband and I also became donors to advance this research.

I also realized from attending these meetings that there just might be a cure for glaucoma in our lifetime. As part of the committee that helped launch the first annual Glaucoma Patient Summit last month, we were gratified to see close to 200 people arrive on a Saturday morning, coming from as far away as London and Canada.

Some were newly diagnosed, looking for support and resources. Some, like my family, were looking for information on the latest advances to manage low vision, but without a doubt, all the attendees wanted to find more information about what is on the horizon in terms of vision restoration.

What became clear from talking to the Patient Summit attendees is that families touched by glaucoma want support and information, so they can be empowered to help themselves or those they love.

The Summit filled a void for the glaucoma patient community seeking collaboration, information and support, but what we also confirmed, which is no surprise, is that no matter where you or your family member is on the glaucoma spectrum, the fear of permanent vision loss is real, and yet, so is the hope for a cure.

It is that hope that propels every person, family member, caregiver, or friend to keep pushing forward with their own care and to manage what vision they still have left, because we hope that at some point vision restoration will become a reality. Clearly, that is our shared hope for the work of the new Catalyst for a Cure initiative. That brings me to why we are all here tonight.

It is an honor to introduce tonight’s keynote speaker, Dr. David Calkins, to highlight the next phase of the Catalyst for a Cure initiative and the initiative to restore sight. Dr. Calkins is the Vice Chairman and Director for Research for the Vanderbilt Eye Institute and the Denis M. O'Day Professor of Ophthalmology and Visual Sciences at the Vanderbilt University School of Medicine. In addition, he serves as the director of the Vanderbilt Vision Research Center.

He attended the University of Michigan for his undergraduate degree and completed his PhD at the University of Pennsylvania School of Medicine. He then completed two post-doctoral fellowships in brain research. Dr. Calkins is a leading authority on neuroprotection and regenerative medicine for conditions that affect the retina and visual pathways.

In addition to recognition from GRF, he has received many accolades, including awards from the Alfred P. Sloan Foundation and BrightFocus. In 2011, he was awarded the Lewis Rudin Glaucoma Prize of the New York Academy of Medicine.

Most recently, he won a 2013 Senior Scientific Investigator Award from research to prevent blindness, and I’m sure even though this sounds like a lot, it’s probably only a small recap of everything that he has accomplished to date. Ladies and gentlemen, please join me in welcoming Dr. David Calkins.

David Calkins, PhD: Thank you very much, Andrea, for that beautiful, beautiful introduction. Can everyone hear me okay? Alright. I’m going without a script. Bill, how are you doing? Alright. It’s good to see you. How’s the vision? Doing okay? Okay. Thanks for coming. Thanks for coming.

Well, folks, glaucoma. How many in the room think that this is a disease about the eye? Raise your hand. Come on, don’t be shy. Exactly. That’s what everyone thought in 2002 when Catalyst for a Cure began.

What I’m going to tell you tonight, though, is that glaucoma is like a disease of the brain, like Alzheimer’s disease, like Parkinson’s disease, like Lou Gehrig’s disease, okay? This is because of the Catalyst for a Cure. My friends Ted and Melza Barr asked me, “How did you get involved in this?”

I said, “Well, don’t you remember? You gave me a grant through the Glaucoma Research Foundation, and I transformed my laboratory from one that studied the nuts and bolts of the visual system to one devoted to understanding degeneration in glaucoma and ways to preserve sight.” What we are doing tonight has an effect. It has an effect on scientists. It has an effect on physicians, and it will have an effect on everyone who suffers from glaucoma and everyone who could suffer from glaucoma.

Okay. Let’s get started. Alright. What is glaucoma? I've got a bunch of statistics here for you. This is a bad disease, okay? Many of you in the audience are aware of some of these statistics. Glaucoma is a disease of the visual system, not just a disease of the eye. The eye is the beginning of the visual system, but it's not the whole kit and caboodle.

Age is the greatest risk factor, increasing sevenfold by 55 years of age. Guess what? We are all living longer because of advances in healthcare, social and economic reasons. As we get older, the risk for glaucoma gets greater and greater. My friend Harry Quigley at Johns Hopkins University predicts that by 2020, not so long from now, 80 million worldwide will be afflicted with this horrible blinding eye disease.

There’s also a higher incidence in African Americans. This is a disease that involves racial disparity for reasons we do not understand. In the U.S., annual direct costs for treatment of glaucoma are now in excess of seven billion. (This is an old slide. That was an old study from 2013.) On the right-hand side I've listed for you how the costs associated with healthcare for glaucoma compare to other leading blinding eye diseases.

Now, when you go to the doctor and he says you've got glaucoma, he’s going to tell you about pressure in the eye. In fact, pressure is one of the risk factors for glaucoma. In the pictures that I'm showing you, I'm showing you how fluid in the middle of the eye normally flows. In glaucoma, there are problems with the regulation of that fluid. It doesn't mean that it’s always going to elevate eye pressure. It means that it can elevate pressure.

The important part is that if this is untreated, glaucoma will cause loss of vision. However, even when treated, many people, as many as 50 percent depending on where you live, will continue to go blind from the disease. The only thing we have to treat glaucoma is to lower pressure.

We do it with topical eye drops, which many of you take. Then we do it with surgery. Then we do it with both and we keep doing it and doing it and doing it and doing it, but in fact we do not have any tool to stop the loss of vision, and that’s why we are here.

Now, the way that I think about glaucoma, and this was really a paradigm shift when we started this research in 2002, is that while glaucoma is a disease of the front of the eye, it damages the back of the eye. In this graphic, what I’m showing you is that the eye connects to the brain by a structure called the optic nerve. The optic nerve is the thing that causes you to see. It sends signals from the eye to the brain, and our brain interprets those signals as vision.

In glaucoma, as I said before, it’s not elevated pressure necessarily. It’s sensitivity to pressure. The back of the eye is sensitive to pressure of any magnitude. There are people who can survive with having pressures of 40 or 45 and never get glaucoma. The back of their eye is less sensitive to pressure. There are people with pressures 11, 12, 13 who will have glaucoma because the back of their eyes is more sensitive to pressure.

That’s what this mathematics is showing you in the lower left-hand corner there. There’s a distribution of people who will go on to suffer vision loss because of pressure and sensitivity to pressure. The vision loss will manifest itself by starting out as a black spot in your peripheral vision. Then it will fill in towards your central vision.

When it wipes out half of your vision, it’s going to jump and it’s going to do the other half. That’s what these visual fields, how many have had visual field measurements done? A lot of fun, isn’t it? Right. I see some hands of some very, very young people.

The visual field, this is how we measure it. Really, it’s the only way to measure loss of vision in glaucoma. The point is that sensitivity, the back of the eye is very sensitive to pressure. That means the optic nerve is sensitive to pressure, and so in glaucoma it’s that relationship between pressure and damage to the optic nerve that causes you to lose vision.

What does this look like? Now I'm showing you in the middle, in the yellow picture, this is what the optic nerve looks like. Each one of those cables sends information from the eye to the brain. Normally you have about two million of those individual cables going to the brain. These are called axons in neurobiological terms. Each axon carries a different kind of visual information to the visual centers.

I’m showing you then a cross section through the optic nerve under the electron microscope. That’s the pretty picture that’s called ‘Healthy Optic Nerve’. You can see the integrity intact for each one of these individual axons. Lower right-hand corner: look what happens to the bundle of fibers in glaucoma — they degenerate.

Sensitivity to pressure kills the optic nerve. Without the optic nerve, you don’t see. It’s that simple. Why is degeneration a problem? Degeneration is a problem because the optic nerve, like the brain, like the spinal cord, is part of the central nervous system. Nerve cells that comprise the central nervous system do not regenerate.

Happily, you damage your liver after years of abuse, a little nub of liver will grow back into a beautiful, healthy liver. There are other tissues in the body, your skin naturally regenerates. It does so almost weekly. You can replace these tissues. Once you lose a nerve cell in the brain, it’s gone. It’s not coming back.

Lower left-hand corner: I'm showing you what a brain from an Alzheimer’s patient looks like. You can see the massive loss of tissue. Because these cells in the brain do not regenerate, because the optic nerve does not regenerate, once you progress to a little bit of field loss, to a lot of field loss, it’s not coming back because we can’t regrow that tissue.

Now what I want to do is, I want to take just a little bit of a deeper dive into what the optic nerve looks like. This is one of those horrible pictures. If you just squint, it looks really, really, really good. I like to make my own graphics. I like color. I don’t proclaim to be an artist. However, there’s your eye.

Now I’m taking a sliver near the optic nerve and I'm blowing it up for the middle graphic. The cells that you see that are orange in color are the retinal ganglion cells. These are nerve cells that send their axons into the optic nerve. Just like the optic nerve has about two million axons or fibers, there are about two million retinal ganglion cells. Those signals then are sent to the brain and we see.

Now, in glaucoma, the sensitivity to pressure in the back of the eye kills these retinal ganglion cells. Because they degenerate in glaucoma, the axon goes away. The optic nerve degenerates and we lose our vision, alright? The challenge in glaucoma isn’t then to lower pressure, to manage pressure. We’ve been doing that. We can do that until the cows come home.

The challenge in glaucoma, from my standpoint, is to make pressure in the eye irrelevant. We want to be able to go to the doctor and say, “Hey, I've got glaucoma. I'm going blind. My pressures are 50.” “Don’t worry about it. Don’t worry about your pressures. Take some drops. Pressure will go down, but here’s what we’re going to do to treat your optic nerve.” That’s where we need to be focusing.

Let me tell you something else. Everything that we discover about optic nerve degeneration and ways to stop it, ways to replace it, we can then apply to Alzheimer’s disease, Parkinson's disease, ALS, spinal cord disorder, paralysis, and any other thing that kills nerve cells in the central nervous system. That is because these diseases are all similar.

Because of that similarity, the tools that we are building through the Glaucoma Research Foundation and the Catalyst for a Cure will have a rippling effect throughout the medical field for anything that affects the central nervous system.

The first FDA-approved gene therapy, does anybody know what disease it was? Retinitis pigmentosa, retinal degeneration, gene therapy to rescue the cells that catch the light in the retina of the eye. That is still the only FDA-approved gene therapy.

We have proven over the decades that research into visual diseases leads the way, and yet the budget of the National Eye Institute, which I'm going to show you in a second, is very, very small compared to the other National Institutes of Health. I want you to keep that in mind.

Because these cells don’t regenerate and because it’s so important to replace them in glaucoma, the focus for the Catalyst for a Cure initiative is very simple. I want you to look at the cells that are green. Those are brand spanking new retinal ganglion cells. The focus of the Catalyst for a Cure vision restoration initiative is to save vision in glaucoma by restoring, replacing or outright regenerating damaged retinal ganglion cells and their axons in the optic nerve. That's the goal.

The way that we’re going to do this is by bringing to bear some very, very talented (I apologize) ‘junior scientists’ to do the work. Now, before we do this, you’ll see that I put in a paragraph there with an asterisk. This is what makes it really, really, really difficult. Engineered ganglion cells must not only be inserted to the retina where they must survive, but those fibers need to grow through the optic nerve and into the brain.

In the brain, they need to find their appropriate targets because we really don’t want to replace a retinal ganglion cell and have you smelling roses instead of seeing red. Okay. It’d be an interesting experiment, perhaps for an undergraduate, but not something that we want to bring to the clinic.

Alright. Let’s take a look at the team that we’ve put together. Folks, this is an all-star team. Anna La Torre, school of medicine, University of California Davis. Anna is an expert in the genetics of ocular development, the genes that cause embryonic cells to grow into an eye, to grow into a retina, to grow into a retinal ganglion cell.

My friend Derek Welsbie sitting here is a glaucoma specialist. He's a clinician scientist. He sees patients. He's also an expert in getting axons to grow. My friend Xin Duan, there you are. You thought I forgot about you? He's here in San Francisco, UCSF, he is an expert in ganglion cell physiology and anatomy, and my friend Yang Hu from Stanford who’s actually involved in building the little railway cars that deliver genes for gene therapy.

This is a great team. Each one of these individuals went through a rigorous process whereby we interviewed them, we screened them, we talked to them, we challenged them in these interviews. They also share a common interest in collaboration. Folks, that is the key, collaboration. These are friendly folks who like to talk. They like to share ideas, and that is how we do things in the Catalyst for a Cure.

The Catalyst for a Cure. This is actually the third incarnation of the Catalyst for a Cure. Part one began in 2002, with 11 years of funding. Monica Vetter, who has been a member of the [Glaucoma Research Foundation] board; my friend Philip Horner at the University of Washington, he's now at Houston Methodist; myself; and Nick Marsh-Armstrong, who was at Johns Hopkins and is now at UC Davis.

We began in the Rita Loskill era of the Glaucoma Research Foundation with a really, really generous grant in partnership with Steve and Michele Kirsch through the Kirsch foundation, and we had a lot of fun. We had a lot of fun. We would travel together to different laboratories in different cities, and we would share our data. I think when this thing started I was 34 or 35 years old.

It was just a new way of thinking for all of us. Here’s the cool part. None of us had any experience at all in glaucoma: zero, zip, nada, nothing. No experience in glaucoma, but we all had a certain expertise. That's why we transformed this field from focusing on pressure to focusing on the optic nerve in the brain.

The second incarnation of Catalyst for a Cure also did not start out local, but when Jeff Goldberg became the chair of ophthalmology at Stanford, he consolidated things. It’s just better that way, alright? Alf Dubra is an expert in imaging. Andy Huberman is an expert in axon regeneration. Jeff Goldberg is not only the chair of ophthalmology but one of the world’s leading experts on the genetics of retinal ganglion cell development. Vivek Srinivasan, who is an engineer building new imaging modalities to see things in vivo. These two groups, really, they are joined naturally by the progression of what we wanted to do with Catalyst for a Cure.

Our focus in Catalyst for a Cure 1 was really defining what the disease was. What are the key events in glaucoma? We also developed new experimental models of glaucoma that are now used by virtually every laboratory across the world who’s studying glaucoma.

Importantly, we tested very, very mechanistic hypotheses in the laboratory and showed that if we abated certain pathways, we could slow progression in our experimental models. That led us then to CFC 2 with its focus on what we call the Biomarker Initiative. A biomarker is a fancy word for something that indicates a moment in progression — a diagnostic tool, if you will.

They focused their efforts on developing new imaging tools to follow how ganglion cells in the optic nerves were degenerating through time in human patients. They also have new non-invasive therapies involving visual activity that show some promise for slowing progression.

Why is this model so important? Well, this model’s important because it’s a new way of thinking about biomedical research. Not only do studies of glaucoma inform other age-related degenerative diseases of the brain, but how we are doing the research itself through Catalyst for a Cure is changing how we approach research.

In this slide, what I'm showing you is the traditional model. The National Institutes for Health in Bethesda, Maryland, they have a pile of money, and that’s in the middle. The different laboratories across the country have to compete for that same pile.

Now, the way that you get promoted in the American academic system is to garner success in gathering extramural funding. So, when I get a grant from the NIH, that means somebody else didn’t. That’s good for my career. Not so good for his or her career, but good for my career. That's how we do business.

The problem is that in real dollars — the NIH appropriations have the appearance of going up year by year, but it’s been flat — and it’s actually below what it has been in terms of the inflation-adjusted dollars. That’s a problem. That budget isn't going to be what it needs to be anytime soon. And so: less dollars, more people competing for less dollars.

Finally, there's another problem: it’s such a difficult system to compete in. The average age to get your first grant from the National Institute of Health: 45 years old. Yes, 45 years old. That’s crazy, right? 10 years later most people in the United States are thinking about, “What am I going to do for retirement?” Well, you’re 55 in biomedical research, you’re just getting started.

Young people with their fresh ideas have difficulty competing against senior investigators. That age of the first award keeps getting higher and higher and higher. This need to compete to establish your career really removes the incentive to collaborate.

The CFC [Catalyst for a Cure] model is much different. In the CFC model, each of these four labs is given the same resources. We stipulate with these dollars that they are to collaborate. That is our mandate. The goal through this model is that through collaboration [the research team] is to create results that are greater than the sum of their individual parts. And the unrestricted funding that we give allows them to try new ideas.

There is oversight. We have a Scientific Advisory Board that I chair. My colleagues and I meet with the team once or twice a year. We have conference calls, and we review written reports. We make certain that the collaboration is happening in order for the next year’s funding to come in.

I am very, very, very proud that since we’ve been doing this since 2002, not once have we failed to pony up for that next year, because the model works. It is exciting for the scientists to collaborate. It’s an exciting thing just being in the room when they meet during the weekend of Glaucoma 360 and the gala to show their new results. There’s an awful lot of synergy, and it’s a beautiful thing (and there’s salmon as well, which I’m a really big fan of).

The way that I think of Catalyst for a Cure, really, is innovation through collaboration. That’s what I want you to think of tonight: innovation through collaboration. That’s the way we ought to be doing things. The CFC really, really does work. What I’m doing [for] you here is I'm just giving you just a few examples of some of the successes that we’ve had.

CFC 1 with its focus on progression: disease begins in the axon to the optic nerve, not in the retina. That was brand new. Degeneration involves oxidative stress, inflammation and decrease of metabolic resources. We also established meetings, conference calls and an annual review to show these things. That was new. Targeting the pathways in glaucoma really, really helps.

CFC 1: our research has resulted already in nearly 8,000 citations by other scientists. A citation is when someone in another lab writes a scientific report and they reference your papers in that scientific report. 8,000 times that has happened.

CFC 2: inventing new ways to see dying retinal ganglion cells in human patients. Identified which retinal ganglion cells are susceptible first; this was a big one because if we can rescue the most susceptible, then it should be a lot easier to rescue the other retinal ganglion cells as well. Inventing new non-drug therapies using computers and virtual reality. The research has already resulted in two new clinical trials to protect vision, so this thing really works.

Finally, we get to CFC 3: restoring vision in glaucoma by replacing retinal ganglion cells and their axons. Right now, these are questions: Can we build new retinal ganglion cells and their axons? Can we re-grow the optic nerve?

Now, I’m like everybody else. I like to pick a winner. I like to put my money on the winning team. I’m here to tell you that I think, because of this initiative, because of the novel way in which we do research, because we are focusing on the right problem — replacing and regenerating retinal ganglion cells and their axons in the optic nerve — the question that I've written here is: can we finally cure glaucoma?

I wouldn’t be standing here tonight talking to you if I didn’t believe deep in my heart and as a scientist that yes, indeed, when this is done we can finally cure this blinding eye disease. Thank you very much.

End Transcript.

Last reviewed on July 17, 2019

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