Episode 037: Ozzy Mermut
Assoc. Prof. Ozzy Mermut of York University’s Centre for Vision Research investigates the diagnosis and treatment of age-related eye diseases using lasers. Her work on biophotonics harnesses the power of light to provide new insights into the structure and function of the eye, with the promise of new diagnostic tools and minimally-invasive treatments for serious eye diseases.
Transcript
Cameron: "The eye is the window to the brain." So says my guest today, Dr. Ozzy Mermut from York University's Centre for Vision Research. Dr. Mermut studies how light can be used to diagnose and treat vision diseases, particularly those that affect the elderly. Her research combines physics, chemistry, biology and mathematics to diagnose and treat vision diseases at the cellular level. It's a field that holds great promise for people who face the loss of their eyesight. I hope you enjoy our conversation.... Ozzy, welcome to the podcast.
Ozzy: Thank you so much for having me on this podcast. I'm excited to be here. And hopefully by the end of this, I can convince you how biophotonics methods and technologies are a vital piece for managing devastating age-related generative diseases of our visual systems.
Cameron: Well, you don't have to convince me. I've looked at your research, and I'm amazed. So let's just talk about this whole notion of vision research, because York University is something of a hotbed for vision research. You've got your own lab, there's the Centre for Vision Research as well which you're a part of, and you're also part of this huge interdisciplinary project called VISTA, which is Vision: Science to Application. That has 38 core researchers, including yourself, 33 associate members, and 34 affiliate members. That's huge. What makes vision research such a hot topic at York?
Ozzy: Cameron, this is an excellent question. And I think I can probably sum this up by saying that both the Centre for Vision Research, CVR, and VISTA have a unique ability to be able to collaborate and collaborate so effectively across a broad range of fields. This includes faculties of health, science, engineering, so electrical engineering, computer science is combined with neuroscience and kinesiology, health, physics, psychophysics, psychology, and even philosophy. So I think that is one of our unique traits here, is our ability to combine these science sectors together so effectively. Perhaps I can also state that one of the important outcomes of that is that it allows us to be able to solve important complex problems over a broad landscape that we call vision. And this is hard, actually, if you think about it. It's very hard to get folks out of their comfort zone and siloed expertise fields. So we've been really successful at collaborating effectively and producing some tangible opportunities in terms of new discovery and research and vision science. We've got about 1,500 publications, international publications from our collaborative research, about $120 million of individual PI funding, 37 patents filed. So yeah, I think this is a real hotbed because of our ability to collaborate so effectively, and also bring in trainees. In July, we're going to be having a CVR summer school that brings in internationally top candidates, brilliant young minds in the cutting edge of vision research into our summer school, and working alongside some top tier PIs here.
Cameron: So when I listed all the fields that you're working in, which one is your comfort zone?
Ozzy: Oh, that's a great question. Yeah. So biophysics is very transdisciplinary. So from day to day, my physics lab gets integrated with folks from the chemistry labs. So we're designing sensor molecules that can be used to look at biosensory disorders at a molecular scale. We're looking at building instrumentation, so physics and optics instrumentation. I'm working alongside neuroscientists. Professor Jennifer Steeves is a fantastic neuroscientist in psychology. And combining optics with neuroscience is turning out to be a really interesting navigation space for looking at things like depression, for example. So yeah, biophysics is inherently very transdisciplinary. And vision science is inherently transdisciplinary. So it's a really nice fit between my research and what we do at CVR and VISTA.
Cameron: What kinds of diseases do you study?
Ozzy: If you think about the nature of the conferences that our students end up going and presenting in, it's always a challenge to figure out whether you're going to go into photonics for ophthalmology or photonics for dental or photonics for cancer or neurophotonics. And so I would classify our research more on the biophotonics approaches rather than the actual disease itself. But if you wanted to put an umbrella around it, I would say that our general area of research is really related to diseases of biosensory disorders and age-related degenerative diseases. And one of those that plagues us and a big part of our aging population is AMD, that's age-related macular degeneration. And this is a maculopathy that affects folks 60 or 65 and above. And it affects about 10%, almost 10% of the world population. And it's only going to get worse, because people are living longer. And the quality of our lives is severely hampered by our incapacity, our inability to perform everyday activities. So that's one area of interest for our research, for our photonics research. We're also interested in looking at neurological disorders through photonics, things like depression, which as you can imagine, during times of COVID, has become ever increasingly important to investigate and study. So we're looking at new treatment modalities for depression and how we can use optics and light to look at the mechanisms of different types of neuromodulation technique. So, this is something I'm really passionate about. I have family members afflicted by depression. So this is a passion of mine to try to see how we can look at biomarkers, optical biomarkers of the brain, and how we can effectively treat depression in our elderly.
Cameron: Can you define photonics and biophotonics for me?
Ozzy: All right, yeah. So biophotonics comes from the Greek words phos and bios. So it's light and life combined together. So we're using light to probe living systems, or effect and treat living systems. And we can do a variety of different things for these diseases that affect our eyes, our brain, cancer, with light, interacting light with biological or living tissue. We can use it to screen for diseases. A big part of this puzzle is early detection of some of these diseases, and looking at the biomarkers of expression early on so that we have more effective treatment strategies. We could also use light to treat these diseases. So we want to see how we can interact light in very specific ways so that we can target this disease, lesions, and leave the healthy tissues alone, because that's effectively what we would like to do, is targeted, personalized treatments that are effective and detected early on so we have the best possible outcomes for patients.
Cameron: So in simple terms, at the diagnosis stage, you're shining light on tissue that may or may not have the early markers of some sort of pathology. And if it's healthy, the light will be reflected or refracted in certain ways. And if it's got those markers for the disease, it would have a different pattern of light emitting from it or transmitting from it. Is that the basic idea?
Ozzy: Yeah, that's exactly right. We're using a variety of different light-matter. And in this case, matter is tissue or cells or molecules, in fact. A variety of different mechanisms are used to either probe or treat the tissue. And you named a number of them here. We've got light interference, we've got light reflected, refracted, absorbed. And of course, when light is absorbed, a variety of other different processes can happen, photochemical mechanisms. In fact, that's how you see the world around you. You have a photochemical mechanism at the back of your retina. Light enters your eye. It hits the retina, then this information cascades through your optic nerve. And then your brain does all the hard work of signal processing. And voilà, your vision. So, a number of these processes ... once light, once those photons are absorbed into tissue, a number of different interactions can happen biologically. And if we can tune how light is interacting with a tissue, we can produce the desired treatment outcome; or if you're looking at imaging, you can image the various biomarkers you're interested in visualizing and seeing.
Cameron: So you're shining lasers on this tissue?
Ozzy: Yeah. Yes. Okay, so light can come from a variety of different sources. Lasers, thanks to the work of our Nobel prize winner, Professor Dr. Donna Strickland, have become very powerful in terms of high speed, very high power lasers, and their ability to do a variety of cutting-edge biomedical treatments, either for surgery or treating visual diseases. So lasers are one such option that we could use as a source of light. One sector of my research is focused on how we can make these technologies and devices accessible to remote communities, and perhaps those that cannot reach very sophisticated settings where you can set up very fancy lasers. So one of our goals is to use lower cost, miniaturized sources, such as LEDs, light-emitting diodes, as an illumination mechanism. And you could imagine, this can facilitate a whole bunch of device development that is oriented towards point-of-care delivery of medicine. So thinking about, for example, the remote communities of Canada, it's like bringing the lab to the community as opposed to the community having to come to a centralized center for getting the diagnostic or treatment that they need. So yes, lasers are very, very powerful, but I think it's really important that we think about how we can make these technologies eventually accessible to a broader community.
Cameron: This is happening basically at the photon level. It doesn't require necessarily a huge apparatus to actually have the effect that you're after. Is that correct?
Ozzy: Well, it does require somewhat of a large system, at least in the prototyping stage. So we are using some quite sophisticated lasers that can produce photons at different wavelengths and different energies. And because these lasers can emit photons at variable wavelengths and variable energies, again, we can tune our work around that light-biological matter interaction. So the nature of the interaction that we desire comes from the power that we put onto a tissue over some spot size of tissue, and the duration in which we're delivering that laser energy to the tissue. So if you can modulate along the spectrum of possible wavelengths and energies and the way that you're depositing those energies, you can facilitate different types of therapeutic mechanisms. And indeed, they're happening at the photon level. But to produce those photons comes quite a bit of sophisticated technologies from lasers.
Cameron: What kind of wavelength works best? Is this on the visible spectrum?
Ozzy: Yes. Yeah. So when we're talking about biophotonics, that can have a variety of different meanings for different folks. We are talking about non-ionizing radiation, which is inherently damaging. So we're talking about the light that you and I see, the spectrum of light that you and I see, from blue, and a little bit further down into the red, so near-infrared energies and wavelengths, because the wavelengths in the near-infrared allow light to penetrate through tissues much more effectively than, for example, blue light. So you get much higher energy with blue light, but the tissue penetration of that light is much lower. And it's an exponential decay through the tissue. Whereas with red and near-infrared light, a little bit beyond our visual spectrum, we're able to go and probe tissue much further and much deeper into the tissue. And we call this the optimal therapeutic window. There's a nice window in the near-infrared where light can effectively target the various chromophores that we're after, and also penetrates deep into the tissue so that we can reach the target that we are trying to treat.
Cameron: So for macular degeneration, for instance, it's not right at the surface, it's behind the surface of the retina?
Ozzy: That's right. So if you think about how you are treating the retina in, for example, age-related macular degeneration, the photons have to take quite a path from your cornea and your lens and through the vitreous fluid. And most of this is optically transparent because there's not a whole lot of absorbers that interfere with that. And about 55% of the light actually reaches the retina by the time it gets through all these interfaces and tissue layers. But then we hit the retina, and that's an 11 layer structure. So the light has to be absorbed by these very uniquely shaped rods and cones, photoreceptors. And there's a variety of different interactions that can happen along that pathway. And so it needs to be able to reach the various layers to produce these cascading signals from the photoreceptors. And luckily, the eye happens to be a really a good organ, I guess, to probe and treat tissues, because it's mostly optically transparent until you hit the retina. And that's when you get all these other chromophores that absorb the light, which is what it's intended to do, in fact, to produce vision.
Cameron: With the laser, then, as it goes in and it hits these cells that you're after, what are the kinds of reactions that you can produce with the laser? How are they therapeutic?
Ozzy: Well, for a very long time, and now, we have been relying on, well, perhaps I can say a little bit archaic methods for treating lesional tissue. So perhaps I start a little bit further up in the discussion, that age-related macular degeneration results in neovascularization, that's weird, abnormal vascular growth. And this proliferates through that tissue, that beautiful architecture that we have in the retina that preserves our vision. And so what happens is, in wet AMD, you end up getting a lot of these leaky blood vessels. And you want to seal these vessels so that you don't have retinal detachment, and the disease doesn't progress any further, separating this architecture and the structure that is necessary for proper vision. So, one of the methods that's that's commonly used is photocoagulation. And it is basically what it sounds like. And what you do is you essentially heat the tissue where you would target those leaky blood vessels, and you cauterize, essentially effectively cauterize the tissue with heat. The problem with that is that heat is very diffusive. So the thermal energy goes well beyond the target of the tissue that you're ... the diseased lesion or the diseased part of the tissue that you're after in sealing. So, what we're trying to do is new, more selective approaches, things like selective retinal therapy, where we can confine that thermal diffusion in other ways and other mechanisms. So we try to do this spatial, thermal-mechanical confinement. And the way that we do this is by varying the rate at which we deliver laser energy so that instead of heating and just thermally diffusing that area, that leaky blood vessel, we are trying to produce a small cavitation event. And a cavitation event is a really, really small microbubble. It's a vaporized microbubble. And you can limit the size of that cavitation, which then limits the spatial extent of that damage to only the target, ideally single cell, if you can get there, ideally to a single cell, and limit the damage to the surrounding photoreceptors that are absolutely healthy and that you would like to preserve. So we're trying to move away from these non-targeted diffusive thermal techniques like photocoagulation, to selective retinal therapy, which is based off of this thermal-mechanical confinement of laser energy to very specific targeted regions of a disease.
Cameron: You sent me two papers that I think are related to this. One is called the “Potential of Sub-microsecond Laser Pulse Shaping for Controlling Microcavitation in Selective Retinal Therapies." The duration we're talking about is very, very short, right, the duration of the pulse, right?
Ozzy: Yeah, that's right.
Cameron: But you're saying it's not just the duration of the pulse, it's how much energy. I mean, it's a very, very short burst of laser, but it's not all the same intensity.
Ozzy: Yeah. So what we're trying to do is not only deliver light in pulses, but how we ramp up those pulses in energy is important. And we know that this is important because this controls the cavitation, that microbubble size, and the threshold in which that cavitation is generated. And so if you ramp up the pulses in different patterning mechanisms of laser energy delivery, so for example, you can imagine a ramp going up or a ramp going down, the way that we ramp up or ramp down that laser energy will control the cavitation properties. And we're trying to effectively produce that cavitation, but not let that cavitation expand, so that we're not disrupting the surrounding photocells. And you can do that by the time-dependent deposition of that laser energy. And that's what we're finding. We can get about a 30% variation in how we can control the thresholds of producing this cavitation, but also the size of the cavitation region. So that's pretty effective, if you're trying to preserve those healthy cells, the photoreceptors that you'd like to keep around for your vision.
Cameron: So you're making this very, very tiny little microbubble, which then, what, collapses?
Ozzy: That's right. That's right. And actually, you come to a really important aspect of this, which is you can use the expansion and collapse of that bubble to listen to the sound of light in a similar mechanism, through photoacoustic dosing.
Cameron: That's what your second paper is about. Let me give the title of that paper so we can refer to it in the show notes. It's called the “Effect of Laser Pulse Shaping on Photoacoustic Dosimetry in Retinal Models." So, photoacoustic: how do you listen to an event that small?
Ozzy: Great question. And again, you need some fancy lasers, shall we say, to be able to do this at this point in time, but what we're looking at in terms of photoacoustic dosimetry is ... Okay, so let me go walk through the mechanism. We have the absorption of light. And usually, that absorption of light comes through vascular chromophores, so things like hemoglobin, your blood, hemoglobin chromophores. And this absorption of light produces heat. And this heat generates a pressure differential, and it expands and cools, so you have this contraction mechanism. And this generates a sound wave. So you have light being converted into a sound wave that you can detect through a transducer, and you can measure how much energy then you have delivered, and dose effectively that energy that you've delivered to the tissue. Because again, the name of the game here is to deliver just the amount of energy you need to effectively treat the lesion and no more. So, that is what photoacoustic dosimetry and detection allows us to be able to do, is to listen to those cavitation events, because of this pressure wave that's generated from the bubble generation, and then eventually the collapse of it. So we can say, "Aha, we produced a cavitation event. We can move on spatially into another region of treatment."
Cameron: Tell me a little bit about the process of research, because obviously, you don't start with shining lasers in people's eyes. So you must have access to the appropriate tissue. Does that come from donors?
Ozzy: Yeah, so this is a really interesting question. And Cameron, you bring this topic to another area of research, which is, how do we simulate tissues that we're interested in so we can study these laser effects, without having to rely on either animal explants, retinal explants that are come from animals, particularly rabbits. That's what I've been working with. And donors are really hard to find. So, another area of our research is to try to develop artificial biorealistic models of the retina, where we can control, in a very systematic way, the optical properties of the tissue, so that we can see what is going on with different, let's say, laser deposition methods that we are developing. So you can imagine, if you go and get rabbit eyes or even a human donor eye, you have a fixed set of properties. So the optical properties is different between your eye and my eye, and same thing with animal studies. So we have no way of controlling or understanding of how the laser-light interaction differs between, for example, your eye and my eye. And by developing artificial realistic models, and this is a materials project that's happening in my lab right now, we're able to systematically define a series of properties and study these various laser patterns and how effective they are, depending on the personalized optical properties of that particular tissue. And yeah, so our research has been funded to look at how we can develop these artificial retina models so that we can more quantitatively and systematically study a variety of different properties that we might encounter in vivo when we're actually treating the eye in humans down the line.
Cameron: You're moving beyond research on the eye in your work with Jennifer Steeves. You are looking at how all of this might apply to depression. Now, I understand how lasers could relate to eye diseases. You're going to have to explain the link to depression to me.
Ozzy: Okay. So this is a really fascinating area of research that I think is just unfolding, new to the community. There's this very interesting new method that's based on electromagnetic induction. So transcranial magnetic stimulation is a new treatment modality. And through a magnet, an electromagnetic induction, we can reset the circuitry in our brain, either from a stimulatory perspective or an inhibitory perspective. So we can reset that circuitry and treat things like anxiety, depression and PTSD, a variety of different psychiatric and mental diseases. And so, there's a lot of questions as to how the mechanism of this actually works. We have this magnet that's put on your head, and again, through the magnetic field, you generate electrical field and you stimulate the nerves, and that produces some neuromodulation. And this has been a mechanism for treatment since 2008, I believe, in the US, and in Canada, even earlier. But again, nobody really understands the fundamental mechanisms. And Prof. Steeves, my wonderful colleague, has been working on looking at MRI to see, for example, how blood flow and perfusion changes in the brain from stimulating. But you can imagine that when you're doing this, we don't really have access to an MR to be able to walk around and visualize what's going on. And it's very challenging to do these experiments with an MRI, because we're talking about magnetic stimulation and an MRI instrument; they're not quite compatible. So, what we're trying to do is to stimulate the brain and optically probe, just as we would the eye. There's absorption that's happening because of our oxy- and deoxyhemoglobin. These are our chromophores in our blood. So just as we would treat the eye to produce either photocoagulation or to produce this micro cavitation, we're probing the brain with more or less the same type of light interaction. So the light would penetrate through the brain, superficially albeit. And what we're interested in doing is looking at the variation in the oxygen demand as we're stimulating. So we're looking at oxy- and deoxyhemoglobin as we're stimulating the brain, because this oxygenation is very much linked -- well, we hypothesize that oxygenation is very much linked -- to what's going on fundamentally when we're doing this neuromodulation. So the treatment itself is electromagnetic induction, but we're looking at it optically by using this near-infrared methodology that can look at the blood oxygenation and blood flow in the brain. So I think this is going to be very promising in terms of how we can evaluate the treatment as we're doing the treatment, in a very quantitative way.
Cameron: There's just one piece I'm not following here. How do you see the brain? Are you talking about patients whose skull is exposed? Are you going through the eye? Are you somehow penetrating through the skin?
Ozzy: Okay, so we are definitely not going through invasively. And I think this is what makes this a really unique methodology. We can imagine putting a cap on top of the head. And you have fiber optic probes that are situated around the region of neuromodulation. And the fiber optic probes diffuse through the tissue, light is diffusing through your tissue. Just take a laser point and shine it through your finger, and you'll see, light just diffuses through the tissue. And you look at the back reflection of that diffusion to measure something about your oxygenated or deoxygenated blood. So this is completely noninvasive, and you can put this in the form of a cap. And this is what we're doing right now and developing as a prototype. You can situate fiber optics around the region of the stimulation and measure the oxy/deoxyhemoglobin change as you're stimulating through your stimulation protocol. So, yes, we definitely do not want to slice up the brain in order to do this. That would be not very patient-friendly.
Cameron: I'm greatly relieved to hear this because I couldn't imagine what it would take to get through ethics approval.
Ozzy: Yeah. No, thankfully these are noninvasive techniques. But again, all this comes back to fundamentals of light-tissue interaction. Thankfully, light can, in the near-infrared wavelengths -- I think you asked about that earlier -- can probe sufficiently deep down that we can actually look at the vasculature in the brain as we're doing this neuromodulation method; and in fact, correlated to some of the measurements that we're seeing with MR.
Cameron: There's one other aspect of your research I wanted to touch on before we wrap up, and that's the role of patents. I am not used to getting patents for my research, I don't know many people in the academic world who are, and yet patents seem to be quite important to your work. So what's that all about?
Ozzy: I think it's part of the clinical translation piece. At least for me, I leave it to the commercialization folks to go after the business and financial side of things. But I think if you want to translate stuff into the clinic or any kind of medical device, I think patents are an important part of it, and innovation; not just discovery, but innovation and materializing technology into devices that can be implemented in the clinic. So I think patents come in tandem with publications, and this is the path for translational research. And in fact, I think we have over 40 patents in VISTA and CVR that's enabling things like startups to happen. And these are feeding the translational pipeline so that we can effectively bring the stuff that we're discovering in a lab into the clinic, and effectively treat patients. So, yes, of course there's always a profit motive for someone down the line, but again, the way that I look at it from our research, we're really interested in utilizing innovation as a way of translating our understanding of these new treatment modalities and delivering it to patients.
Cameron: It's publicly funded research, by and large. The patent is held, what, by you or by the institution?
Ozzy: At York, we're very fortunate that we are owners of our IP [intellectual property], but at the same time, we have various commercialization arms that help support the efforts for taking these technologies and devices to the market. Of course, I'm not involved in this. Our research, as you say, is publicly funded. We have been working with industry partners. And they're interested in uptaking some of these technologies and licensing them downstream for their companies. In fact, LiveView Technologies is a company that I work with out of Ottawa, which is a medical device company looking at various types of oral lesion cancers. So yes, there is the private element to this. But again, my research is really focused on the proof-of-concept discovery, and in fact, going up to the stage of prototyping so that someone else can engineer this and materialize this into real life technologies and devices that can be used and ultimately treat people. That's my goal.
Cameron: It's a very, very comprehensive research program, right, from the most basic research out to the edges of commercialization. I don't know how you keep up with all the advances, let alone just doing your own work. It's a very dynamic field. Must be very exciting to work in that field.
Ozzy: I think so. I think so. And biophysics is very strong and prominent at York, and again, in large part to do to our ability to be able to collaborate across those silos that we've built over time as scientists. So I find myself in a variety of different conferences just trying to understand the basics of neuroscience. And I will never become an expert at it, but thankfully, our ability to collaborate with experts in the field allow us to be able to, I think, make impactful research. So you really do have to get out of your comfort zone and go from, as you said, discovery to engineering. If you really want to make that impact, you have to be comfortable with being uncomfortable in a variety of fields and a variety of stages of development of these devices and techniques.
Cameron: Well, thank you for sharing your insights into your research. And I look forward to seeing what happens next for you.
Ozzy: Thank you so much, Cameron. I think that was a really great opportunity. I hope I was able to share a little bit of my passion for biophotonics and how we can use it to better manage diseases that are profoundly impacting our lives as we age.
Dr. Ozzy Mermut with students in her lab (image by Tania Cannarella Photography)
Links
Ozzzy Mermut’s faculty page at York University
Her article on the "Potential of Sub-microsecond Laser Pulse Shaping for Controlling Microcavitation in Selective Retinal Therapies"
Her article on the “Effect of Laser Pulse Shaping on Photoacoustic Dosimetry in Retinal Models"
MiBAR, the Mermut integrated Biophotonics Applied Research laboratory
Credits
Host and producer: Cameron Graham
Production assistant: Andrew Castillo
Photos: York University
Music: Musicbed
Tools: Squadcast, Audacity
Recorded: May 26, 2022
Location: Toronto
