Glaucoma researcher seeks deeper understanding of the eye disease

Upstate Medical University in Syracuse, New York invites you to be "The Informed Patient with the podcast that features experts from Central New York's only academic medical center. I'm your host, Amber Smith. An Upstate researcher for the Center of Vision Research won a grant recently that will hopefully help lead to a better understanding of glaucoma. Here to discuss his work is Dr. Samuel Herberg. He's an assistant professor of ophthalmology and visual sciences. Welcome to "The Informed Patient," Dr. Herberg.

[00:00:32] Samuel Herberg, PhD: Thank you very much. Good morning everyone.

[00:00:35] Host Amber Smith: Now I understand your grant is from the National Eye Institute, and it's to help build something. Can you explain what you're making?

[00:00:43] Samuel Herberg, PhD: Yes, that is correct. The grant we received is an R-21 grant, which is a two-year grant. And the purpose of this project is to build a device that will enable us to study the biology of a tissue that is important in normal pressure regulation. But if this tissue becomes impaired, it does play a role in glaucoma.

[00:01:08] Host Amber Smith: So is this model that you're making, is it going to look like, will it be like a physical eye, or is it a model, like a computer model?

[00:01:17] Samuel Herberg, PhD: It is a physical model, but not of the entire eye. The tissues that we are interested in are really small.The trabecular meshwork and the Schlemm's canal, these are the two principle tissues we are interested in. They're located in the front of the eye, and they're really, really small. So for the purpose of the modeling, we focus on the tissues that we are trying to understand better, and we recreate a version of the tissue in vitro (test tube experiments) so that we can do experiments in the laboratory.

[00:01:49] Host Amber Smith: I see. Now, before we get too far into this, I feel like we ought to describe glaucoma. Can you tell us how many people are affected by glaucoma?

[00:02:00] Samuel Herberg, PhD: This is a disease group. It's not one particular disease. It's really more of a group of diseases. Currently the number is approximately 80 million patients suffering from a version of glaucoma worldwide. And the predominant cases of this disease are characterized by high pressure in the eye. So there are other versions or other manifestations of the disease, but the majority of all glaucoma patients are being treated for high pressure.

[00:02:33] Host Amber Smith: Is the high pressure, does that cause pain in the eye?

[00:02:37] Samuel Herberg, PhD: Surprisingly not. There're very few manifestations that you could physically feel as a patient, and that is part of the problem with the disease. It has very few symptoms, and if that makes the diagnose relatively difficult to diagnose. And also, treating later on is somewhat challenging if the patient is not being seen by a provider.

[00:03:03] Host Amber Smith: Is this the kind of thing if you go for an annual eye exam, would they be able to detect it?

[00:03:09] Samuel Herberg, PhD: Absolutely. This is exactly what's being done clinically, by an optometrist or an ophthalmologist at the office as a routine part of the exam, the pressure is measured within the eye. And if there's any indication that the pressure for any given patient is outside of what is considered normal, then there would be follow-up examinations looking more closely if there are, in fact, any sort of evidences for disease.

[00:03:42] Host Amber Smith: So if it is diagnosed, and they think that the person has glaucoma, is there a way to treat it?

[00:03:49] Samuel Herberg, PhD: Yes, there are treatments available. It is important to note up front that as of right now, there is no cure. The disease can be managed clinically, and this is exactly what we are doing. However, there's no cure.

Part of the reason is, that it is really a multifactorial disease. It's not a single cause. It's probably more of a group of causes. And they're likely dynamically affecting each other. So as of right now, we do not know what causes the disease. High pressure that I mentioned a little bit earlier is considered a risk factor. So if a patient presents with elevated intraocular pressure, the attending physician or the care team is then making arrangements to lower the pressure in the patient's eye.

That does not necessarily mean there is optic nerve damage. So the nerve that transmits the visual inflammation to the brain so that we can perceive our environment is really what is being damaged in the disease. So it's a neurological disease, a neuropathy. So if that occurs, the patient would lose vision irreversibly. So that's why lowering pressure is the first line of treatment, although the patient may or may not already have symptoms of impaired vision.

[00:05:14] Host Amber Smith: So researchers haven't figured out what causes this. Are there other major pieces of the glaucoma puzzle that still need to be discovered?

[00:05:25] Samuel Herberg, PhD: Yes, there are a list of sort of well known and relatively well understood risk factors. Some of them are unchangeable. We cannot change a person's age, sex, or race. There are also a few changeable, potentially changeable risk factors such as the diet, the environment that the patient is in, and ultimately pressure as one of the most important risk factors that can be treated if it elevates in the eye.

[00:05:59] Host Amber Smith: The risk factors you mentioned -- race, gender, agewhich ones are more at risk?

[00:06:07] Samuel Herberg, PhD: That's a very good question. So age is probably one of the strongercorrelative readouts for developing the disease. But there's also a good amount of literature on race. African-American populations are at a higher risk for developing the disease.

But this is really not something that I particularly study in my laboratory. I'm not a clinician. I do not see or treat patients. So we read the literature and we take in the information. but that is not something we address in the laboratory.

[00:06:42] Host Amber Smith: This is Upstate's "The Informed Patient" podcast. I'm your host, Amber Smith. I'm talking with Dr. Samuel Herberg. He's an assistant professor of ophthalmology and visual sciences, and he's doing research that hopefully will help us understand glaucoma.

So getting into your project, can you explain the drainage system of the eye?

[00:07:03] Samuel Herberg, PhD: Yes, the drainage system that we are interested in is located at an angle that is formed between the iris and the cornea. So these are two tissues that are located in the front part of the eye, and in most of us, this drainage system works just fine. However, in patients that have underlying conditions that are not fully worked out, the outflow pathway might become impaired. What that means is that the tissues that are responsible for filtering the fluids outside of the eye to maintain a balance between production of fluid and drainage of fluid. If that tissue becomes impaired, there would be an imbalance of fluid maintenance within the eye, raising the pressure over time, and that tissue responsible for doing this is located in that angle.

The principle components are the trabecular meshwork, which is sort of a fenestrated filtering type tissue with various layers. And the biology of that is complex in itself. And then immediately adjacent to this tissue is an endothelial vessel, a little bit like a blood vessel, but it is a more of a lymphatic vessel, so it does not contain blood. The fluid that comes from the underlying trabecular meshwork is then being filtered into the lumen of this vessel, and from there it exits the eye into the venous circulation.

So it's really a two componenttissue, let's say. But there's other parts of the outflow tract that can be dysfunctional. In my laboratory, we really focus on the conventional outflow pathway. The majority of fluid goes through this tissue, and therefore a lot of my colleagues and myself included focus on the trabecular meshwork and the Schlemm's canal.

[00:09:03] Host Amber Smith: When we're talking about a drainage system in the eye, the only thing I think of is tears. But that's not what you're talking about.

[00:09:11] Samuel Herberg, PhD: That is correct. So this would be an intraocular, so within the eye. So you can think of the eye, like a fluid-filled pressure vessel. There's continuous fluid production from tissues within the eye, and that fluid needs to exit to maintain a normal homeostatic level of intraocular pressure, pressure that is responsible for maintaining visual acuity and that we can perceive the outside world in an unobstructed manner. So this is fluid that is being produced from inside the eye and is then shuttled outside of the eye.

[00:09:52] Host Amber Smith: So this fluid keeps the tissues moist, it sounds like?

[00:09:56] Samuel Herberg, PhD: It keeps them nourished. Several of these tissues that are located in the front of the eye are avascular, so there's no blood supply to certain parts of this, which is important to maintain clear tissues, that the light can enter the eye in an unobstructed way.

Imagine if we had blood vessels spanning the front part of your eye. Light would not be able to enter the eye in the correct manner and then be focused using your lens onto your retina, which is the tissue responsible for carrying this information forward into the brain using the optic nerve.

So the tissues are avascular, and thus the fluid is partially nourishing these avascular tissues. It contains various nutrients but also contains byproducts of cellular turnover. And these waste products need to exit the eye. And this is also part of the responsibility of this fluid.

[00:10:56] Host Amber Smith: So with the research you're doing, does the drainage system of the eye malfunction and cause high pressure, or does the buildup of high pressure cause the drainage function to malfunction?

[00:11:08] Samuel Herberg, PhD: Probably both. It is very difficult to identify the onset because patients who suffer from the disease do not present with major symptoms until a significant loss of vision. So there's no pain associated with developing outflow problems. And then for researchers like myself in the laboratory, we rely on cellular material that we can explant from donor eyes, so patients or normal individuals who have passed away and donated their eyes for research purposes. These are the sources for our cellular materials. So we get the cells, and then we can study them in a controlled environment in the lab.

What we cannot control at any given experiment is if this patient had normal or high pressure, and if that was a result of dysfunction, and if this was amplified by the high pressure. So the general consensus is that it is very likely that the tissue itself becomes impaired. And then as a result of this, the pressure rises, and that will likely have some feedback information in exacerbating the dysfunction, so to speak.

[00:12:24] Host Amber Smith: Who are your collaborators, and what are their roles?

[00:12:28] Samuel Herberg, PhD: So for this project, I have two main collaborators on board. One is a colleague from Syracuse University. His name is Dr. Pranav Soman in biomedical and chemical engineering, and we've been working together for a while. His expertise is really on biofabrication using high-end techniques and state-of-the-art manufacturing to build devices.

And the device we are using is really made in his laboratory. It's called a microfluidics chip, a little platform you can imagine, almost like a little bioreactor that we can fill with human cell material. And then we can study the response of the cells to fluid flow that we can simulate using small tubing and controlled fluid pumps so that we can simulate the normal aqueous humor outflow.

And to validate this new model that we are attempting to establish with this grant,the model to use to balance or validate it against is a model developed in a collaborative lab at Indiana University School of Medicine, Dr. Weiming Mao. And he has agreed for us to come and see the apparatus necessary to build this. And then we can relatively easily set this up in my laboratory to have a tissuemodel system that we can sort of benchmark our new completely bio-engineered system against to determine if the values we obtain are comparable to in vivo or tissue level measurements, and ultimately enhance the physiological relevance of these bioengineered tissues.

[00:14:12] Host Amber Smith: So you said this is a two year grant. If everything went perfectly, what would you hope to have accomplished after two years? What do you think might be practical?

[00:14:24] Samuel Herberg, PhD: This is a tough question because a lot of times when we write these grant proposals, especially for a two year mechanism, the NIH and the National Eye Institute in particular, they're interested in funding quote, unquote "high risk, high reward" projects. So this is a mechanism for which projects receive funding that are really trying to push the envelope with a greater risk of failure. However, if we are successful in executing our goals, we should be able to really generate a new model system that would facilitate mechanistic studies of cell biology. And that can then also be done outside of my lab. This can be transferred to other laboratories if they're interested in setting this up themselves. And this is an area that we are interested in helping others as well.

[00:15:18] Host Amber Smith: Before we wrap up, I'd like to ask you which advances you think we'll see -- in the quest to find a way to prevent or cure glaucoma -- which advances do you think we'll see next?

[00:15:31] Samuel Herberg, PhD: Research is really focused on the front part of the eye, where the fluid balance is maintained. I think from studies in that area, we can expect that more and more researchers will go into using high throughput types of techniques that will allow us to study genetic or epigenetic changes, proteomic changes, and even lipidomic changes. So not just simply chasing one pathway or one molecule at a time, but really trying to include more unbiased approaches to studying the biology simply because what we've done so far over the past few decades, while we have improved the understanding of the disease hasn't led to targetable sort of pathways that we can really address this disease. So that's where I think the anterior part part of the eye research will go.

But we cannot underestimate the connection between the front part of the eye and the back part of the eye. As I mentioned earlier, glaucoma is a disease of the optic nerve, so it's a neurological disease, and our colleagues who study the back part of the eye -- the retinal ganglion cells, those are the ones that will ultimately be impaired and eventually die in the disease, those are extremely tricky to study, and I think there's going to be a huge shift to focus more on the neurological side of the disease and implement, maybe by engineering as well, and then improve the model systems we are using to study the disease in an ex vivo, sort of outside of the eye, context.

So it's really difficult to make predictions, but I think it's. it is very possible that we see a shift with more researchers coming in from other fields, like myself. I did not train formally in vision research. I came in from a bioengineering perspective. And bringing in colleagues with expertise outside of the traditional vision sciences has facilitated, sort of, maybe incremental steps, but also slightly larger steps. And I imagine this will happen in other areas as well.

[00:17:52] Host Amber Smith: Well, Dr. Herberg, I appreciate you taking us into your lab and telling us about your work. Thank you.

[00:17:58] Samuel Herberg, PhD: Thank you very much.

[00:18:00] Host Amber Smith: My guest has been Dr. Samuel Herberg, an assistant professor of ophthalmology and visual sciences at Upstate. "The Informed Patient" is a podcast covering health, science and medicine, brought to you by Upstate Medical University in Syracuse, New York, and produced by Jim Howe. Find our archive of previous episodes at upstate.edu/informed. If you enjoyed this episode, please tell a friend to listen too. And you can rate and review "The Informed Patient" podcast on Spotify, Apple podcasts, YouTube, or wherever you tune in. This is your host, Amber Smith, thanking you for listening.