Inside the Lab with Dr. Michael Risner and Dr. Luis Villa-Diaz

 Luisa Recchia: Welcome to Through Our Eyes, a podcast from the Pediatric Retinal Research Foundation, where we share stories, information, and promising research related to pediatric retinal disease.

I’m Luisa Recchia, and today’s host is our very own Annie Rubin, who is joined by Doctors Michael Risner and Dr. Luis Villa-Diaz, researchers at Oakland University. In this episode, we explore the fascinating world of mitochondria, the tiny structures that provide energy to our cells, and how transferring healthy mitochondria into damaged or stressed cells could potentially open new doors in retinal research.

Doctors Michael and Luis help us understand this complex science in everyday language. They explain how mitochondrial transplantation works, why collaboration between different areas of expertise is so important, and what this research could one day mean for people affected by retinal disease. While this work is still in the research stage, it offers an exciting look at how scientists are approaching some of the most difficult questions in vision research.

Doctors Michael and Luis, welcome to Through Our Eyes.

Annie Rubin: So Stephanie told me that she met you, Michael, at the Hope for Vision Walk. 

Michael Risner: That’s correct. 

Annie Rubin: What inspired you to show up that day? 

Michael Risner: As I understand it, I’m just now getting to know and understand the PRRF, but they have a strong connection with, uh, Rochester through the affiliations with, uh, Dr. Capone. 

Annie Rubin: Yes. 

Michael Risner: I heard about the PRRF, of course, through, um, the pilot grant, um, call last year, and then I became aware of the, the walk-a-thons they hold, and I thought it was incumbent of me just to show up and show that I and my lab and other people care. 

Annie Rubin: Oh, that’s beautiful.

Well, we’re so glad that you came. I was hoping you could each introduce yourselves and then tell us what drew you to pediatric retinal research.

Luis G. Villa-Diaz: Sure. Michael, you want to go ahead? 

Michael Risner: Sure, I can go first. As you have introduced me, my name is Michael Risner, and, uh, I feel like I’ve always been a scientist, even as a, a [00:01:00] little kid. But, uh, through my education and training at Western Kentucky University, University of Alabama at Birmingham, and Vanderbilt University, I became a credentialed scientist.

And through my education and training experiences, I have a broad knowledge of vir- the visual system, from genetics to behavior under typical and pathological conditions. And most of my prior work has focused on understanding the pathophysiology of glaucoma. And the preexisting partnership between the Oakland University Eye Research Institute and the PRRF, my previous research into retinal ganglion cell differentiation, and Dr. Villa-Diaz’s ongoing research in retinal organoid development drew me into, uh, the pediatric retinal research realm. And through the funding of the PRRF and other agencies, I hope to continue our work to understand and develop treatments for pediatric retinal [00:02:00] degenerations.

Luis G. Villa-Diaz: Okay. Um, hi, my name is Luis Villa. I am associate p- assistant professor in the Department of Biology and, and the Department of Bioengineering here at Oakland University. And, um, uh, just as Michael say, I’ve always been intrigued to science. And 20 years ago, uh, about 24 years ago, I start working with, uh, pluripotent stem cells with, uh, um, and induced pluripotent stem cells.

And more recently I become doing certain work with the differentiation of these cells towards the lineage of the eye, specific, uh, to s- two cell types that are heavily involved in interconnecting and providing vision. And then, looking into other research that we were doing in, in the lab, we f- we found a connection that, uh, could be applied to certain diseases, that are affecting [00:03:00] the retina early in life, uh, early for children.

And of course, I found great collaboration with Dr. Risner and with many other, uh, professors here in the Eye Research Institute, all with the support of, of the foundation. So very thankful for that. 

Annie Rubin: Well, beautifully said. Thank you both. Um, my next question is going to be to ask you to walk us through what it’s like a day in the lab as a scientist, but with the caveat that I would love it if you could explain it to me like somebody who’s never studied science, never been in a lab, never opened a science textbook.

Just as simply as you can describe what the process is like in a day-to-day research. 

Michael Risner: I’ll go first. You know, the typical day is really not that exciting in the laboratory. The typical day is spent executing a plan that you’ve already conceived of, and that’s… [00:04:00] The typical day involves applying technical skill sets.

The more exciting part of lab is that planning stage. It’s when we get together our lab, other collaborators’ laboratories get together and really start to hash out how we’re going to execute the plan. And so it’s the, it’s the camaraderie that we have and the ideas that we share in forming a plan for our study is the really exciting part.

It really leads to novel ideas that we actually execute on the day-to-day. 

Luis G. Villa-Diaz: Yeah, I would agree with Michael. I will… but anyway, your question is more like in the daily day what we do and, uh, uh, so it’s a lot about, going back and forth, again, communication with our students or, or with our personnel and with colleagues.

And then once we are in the lab, [00:05:00] uh, the students or ourselves because we’re still working in the lab, still doing experiments, still doing actually hands-on experiments, is really developing some skills and putting those skills. But in simple terms, think about if you were cooking, as you were in the kitchen, and basically, as Michael said, you have to plan what is that you are going to cook, what is that you need, put it together, and then skills, right?

Uh, okay, we’ll do this with these ingredients and so on. So we do it obviously with cells. Uh, we do it with, uh, chemicals and reagents that we… that help us to explore certain questions. And so it’s basically that. The students and us, we go, and we look at the cells or, or the organs and, start doing the experiments that we want to do.

Uh, I have to say our [00:06:00] experiments in both cases are very long, so what we do in a single day really it has a big impact, but we are not going to see an effect right away. Most likely the effect and for… this particular experiments that we are doing with retina is about three or four months of continuous work and finally to be able to reach the moment in that we are able to do the final experiments, and then we can start extracting data.

So it’s, uh, it’s time-consuming, but it’s exciting. 

Annie Rubin: No, that’s really well said, and you do a really good job breaking it down for us. Well, I wonder, Dr. Villa, you and Dr. Risner had worked on a pilot grant, and in simple terms, what were the questions that you wanted answers to when you set out on this research project?

Luis G. Villa-Diaz: Yeah. So yeah, I very fortunately [00:07:00] to collaborate with Michael and also very fortunate to get to obtain funding from this pilot grant that allow us to do our research. And the question is a little bit simple. I will try to put it in simple terms. So we are looking into a disease that affects the retina, affects the function of, of a cell type in the retina, and is– this is due because a certain component of those cells the mitochondria, is an organelle a piece of the cell, which is the cell, the, the factory of energy of the, of the cells, are not working well.

So we have the theory that we can replace that mitochondria in th- in those cells by transplanting mitochondria from healthy cells to them. So we want to test that. Uh, we think that once that we replace that unhealthy mitochondria, then the cell is going to start working as should be, and that will help to [00:08:00] restore or to maintain vision in, in, in the patients if we get to that point, right?

Uh, right now do it– we are doing it in, at experimental conditions in the lab, in, in better conditions, and we are evaluating certain conditions, uh, certain parameters to see whether this will work.

Annie Rubin: What an incredible question that you’re asking, and that we have the science to be able to take mitochondria from another cell and place it in. I wonder what would a breakthrough look like for you two, and have you seen any breakthroughs so far in this research? 

Luis G. Villa-Diaz: Yep. We have preliminary data, uh, that we’ve been obtaining with the funding, in which, uh, one parameter that we look into, as I say, the mitochondria is the energy factory of the cells.

So we can measure how the energy levels are in the cells that are affected by the disease especially the [00:09:00] cells that we already differentiate and are part of the retina. So we know they are kind of low compared to normal cells. And then when we transplant that, uh, mitochondria in this, at least in this parameter, we can see now the energy levels goes up, right?

So as early indication that there is, uh, integration of the transplanted mitochondria, and that integration results also in functional mitochondria, and that at least is helping in that parameter to, to the cell. Now we need to look into the other important parameters to verify that this is functional.

Annie Rubin: Incredible. How did the PRRF pilot grant make this work possible? 

Michael Risner: Well, it certainly helps with, um, funding for reagents that we require for these experiments and also the [00:10:00] students, working in the laboratory. The funding was essential for those two factors that are, of course, essential for the completion and doing the work. 

Annie Rubin: And now I know you two are applying for funding with the National Eye Institute that you’ve submitted a grant to? Yes. 

So what would that funding allow you to do that you haven’t been able to do yet? 

Luis G. Villa-Diaz: There are more evaluations that we need to do and more experiments that we need to do in the long term to verify multiple conditions that to test our hypothesis. So again, uh, the funding from NIH, uh, if we are able to obtain it, will allow us to test all of these and to finally, uh, get a strong data to continue with our research and then make future questions, uh, related to this disease and, and, and potential treatment.

Annie Rubin: Yeah, and can you speak to the lifetime of research? Because I think [00:11:00] a lot of people in our community are really eager to find cures, severe retinal diseases, but how long can it actually take? 

Michael Risner: Well, I think it– that depends really about how much funding there is for a certain disease or, for example, we just, what, what was it? Six years ago, we went through COVID, right? A development for a vaccine for this virus occurred relatively rapidly because there was a huge push from the government and other foundations to, um, bring that therapy, that treatment to the fore. And also there’s the, uh, the workforce behind those, uh, therapies, and the workforce has to be there.

And for the workforce to be there, there has to be continual funding to generate those new master’s degree students, those new PhDs who are working [00:12:00] for, uh, to treat human diseases. So I think, uh, funding from the government and the– and other agencies such as the PRRF are essential in the development of the workforce and of course the, the s- the funding for doing the actual work.

So how long does it take? Well, like I said, it depends on the interest and as much interest as you can, as you can gather up. Well, that further supports the, um, how long it’s going to take to get a treatment for a particular disease. So the more interest that you can gain, the more funding, the more workforce you can get behind having a therapy brought to the patients that are in need of it.

Whether that’s two years in the case of COVID or, you know, for more complex diseases such as Alzheimer’s, Parkinson’s. Those are very, uh, complex diseases, and sometimes the complexity [00:13:00] is the, um, the, uh, the barrier that you just have to go through and figure out through time and effort. 

Luis G. Villa-Diaz: If I can add as well all of that is extremely correct.

But, uh, also we need to take in consideration the nature of the biology, right? How is that, uh, cells and organs and tissues take time to mature to get to the stage where we can do the research. Also, it takes time for us to optimize the conditions, right? So it’s a lot of moving parts that are involved in research.

It’s lengthy, but I will say both the students and us, we are excited.

And we have to continue, and we hope the public understands and also supports and is patient also with us to get to that point.

Annie Rubin: For each of you, I wanna know a little bit more about your personal history. What got you into this line of work? Of all things to [00:14:00] study, why were you attracted to this? And, how does it feel personal- on a personal level to be in the lab working on th- these, uh, these types of studies?

Michael Risner: To me, it was always about what’s going on in the brain, right? Uh, I’m a neuroscientist by training, and initially I saw the eye as just what it is, a projection of the brain. It has all the same neurochemistry, proteins, lipids that the brain does.

Except the nice thing about experimentally, the nice thing about the retina is it, you can dissect the… In a mouse, of course. Uh, you can dissect the retina from the eye and have an intact circuit, and you can understand part of the brain using the retina, except with this intact circuit that you can, uh, analyze the circuitry of the retina and understand the deficits that occur in disease [00:15:00] states.

Whereas in the brain, experimentally, you’d have to do performed sections of the brain, and with any kind of b- manipulation, such as sectioning, you’re going to, um, disturb the circuit. So you’re really not understanding the intact brain, but rather a disturbed circuit. So u- that’s the reason that the retina and the optic nerve always was appealing to me, is to understand the brain using the retina as a format.

Now, as I’ve, um, matured scientifically, uh, I’ve come to appreciate that vision is one of our most powerful and essential senses, and it brings us so much.

It makes our life fuller. It makes our life complete, vision does. And with that appreciation, I then use the retina to understand what happens in those disease states to bring back vision to those who’ve lost it.

Luis G. Villa-Diaz: In my case I, again, um, my [00:16:00] training as a stem cell biologist, uh, and working with pluripotent stem cells and with all the potential that these cells has for regenerative medicine, for future medicine, personalized medicine, and so on, it’s always been fascinating, right?

Try to, It’s happening in real life. Uh, in the 20 years that I’ve been working with this, it’s more or less the same time that we start, scientists start working with this field. And one of the first clinical applications that was done for these cells was in the eye, uh, was to treat another disease, uh, macular degeneration and, uh, a Stargardt disease.

Uh, both disease affect the cell type that we are now working for this current syndrome, the retinal pigmented epithelium. It has been demonstrated that with these stem cells we can produce functional retinal pigmented epithelium that can be [00:17:00] transplanted into the eye and restore certain function in the case of macular degeneration and Stargardt disease.

Right now there are very advanced clinical trials, so I mean, it’s now no longer in experimental phase. It’s now moving into demonstrate safety in clinical application. Hopefully in five years there is now a treatment that could be done for that uh, those diseases. But that help, uh, was interesting, right?

And then now looking into, again, the same cell type but with a different characteristic, a different, uh, malfunction, also could be a, a quick transit- quick, again, uh, relatively quick. Uh, uh, as I say, everything may take five, 10 years. But a potential treatment for a particular disease that affect many, many, many kids.

Annie Rubin: Do you have peers [00:18:00] who are doing similar research that you communicate with? And how do you all work alongside other investigators in this process? 

Michael Risner: So I never trust a, a one-off, you know, finding. I get excited, but that excitement is quickly subdued by, well, I gotta repeat this finding.

And then once it’s repeated, then of course we take it across the hall to our peers in our community or our colleagues at other universities and say, “Well, have you seen this before?” You know, it’s, it’s very, uh, it’s not as formal as one may think during this pre-publishing, you know, period where we then start discussing amongst our friends and colleagues about our findings, and then we try to publish those results.

Once we’ve satisfied ourselves and our colleagues internally, we then go out to people we don’t know, the reviewers of manuscripts in, of scientific [00:19:00] journals.

Annie Rubin: That all makes sense. For someone who doesn’t know about the makeup of the eye, what makes the retinal cells different from other types of cells? 

Michael Risner: Most of the cells in the body do not respond to light, and that is the unique property of the retina. Of course, the cells in the pineal gland do respond to light.

But the photoreceptors, rods and cones in the eye, they’re the cells that, uh, absorb the photons of light from our environment, and there’s a particular type of ganglion cell that contains a photopigment called melanopsin. It can also sense light, and those cells are more involved in the regulation of our circadian rhythms.

So if people, uh, have a visual disability where they’ve lost their sight, they can often maintain their circadian rhythm. They know when it’s day and night, um, through [00:20:00] those intrinsically photosensitive ganglion cells in the eye So in addition to sensing light, um, the ability to accommodate the ce- the cell’s, uh, neural activity to the different lighting conditions, right?

You can take the typical example of say you, you go watch a matinee movie and you exit the theater, and all of a sudden it’s very, very bright outside on a sunny day, uh, after you’ve been in the dark for a period of time. And then all of a sudden things appear normal again. Your, uh, cells in your eye adapt to the different lighting conditions.

Uh, so those two factors make the retina of the eye very, very unique. 

Annie Rubin: Yeah. I wonder if you were to connect the dots for donors on how this work helps to develop rare disease cures, how would you [00:21:00] explain it to that audience?

Luis G. Villa-Diaz: It’s a common goal, right? I mean, the general public has an interest in resolving a problem that could be personal or familiar or just in general, right? But the interest of resolving, or creating a cure, and everybody contributes in whatever ways it does it, right?

The public contributes supporting research, uh, just supporting verbally or supporting monetarily. And, uh, and for us, well, is, uh, the interest, uh, the desire to contribute in certain way could be small or big. We all think that our contributions are huge, but the reality are, are, are little, but they keep adding, right?

And that’s the, the, the key part here, that every single new discovery will add to another ones, and eventually the puzzle will be complete. But yes, we need the [00:22:00] support with this. This, uh, takes time as we’ve been discussing it. It takes a lot of, uh, econo-economical burden. It requires the collaboration of the public, the government, the institutes, uh, the institutions and the scientists, the com-communities and, uh, scientific community for a common goal to move forward. 

Annie Rubin: Thank you. We talk so much about research and researchers and the scientists who are working in the lab, and it’s really, really rare to get the opportunity to actually speak to people who are seeing this side of the work. What, if anything, would you like to say to them about, you know, what, what hopeful things that you’re seeing to give a family a sense of what we have to look forward to?

Michael Risner: I think there are, there, there are many great advances and, and, um, the, the development of new therapies for many [00:23:00] diseases and pediatric retinal diseases as well.

I think some of the future things that… Some of the things that people are using today will have tremendous impacts accelerated development of therapies. For example, the use of AI, I think it will be an important supportive f- factor in accelerating our understanding of how different chemicals bind to different proteins, uh, that we can use to develop safer and more effective therapies.

Uh, I think that the development of new ways to encapsulate therapies through nan- nanoparticles where they will increase the bioavailability of therapies to make them more effective, longer-lasting, will… Is a… Are those two things that I, [00:24:00] I really, uh, am intrigued by in science that I think will, um, really accelerate better and safer therapies for many diseases.

And that’s where these pilot grants really play a key role in encouraging those collaborations from people from different backgrounds that have different conceptual and technical skills and knowledge. And those pilot grants are the fuel that bring those new ideas and potentially new therapies to the public. 

Annie Rubin: Well said.

Michael Risner: I’d like just to add on a bit. What really was surprising and heartening to me, uh, attending the PRRF walkathon was how many people showed up who had children affected by retinal degenerations from out of town from many parts of the U- US, and they were so interested in what we’re doing, and I really look [00:25:00] forward to sharing our, our findings with those parents, those donors at the next at the next time we gather.

That’s the thing about scientists, I think, we’re just normal people interested in answering questions that will benefit humankind. And, um, we’re just normal people, and I find it so rewarding to find people interested in our work ‘cause a lot of times it feels like I’m working in a very closed environment.

So when we have people come in and are interested, and we see that interest, it really invigorates and motivates me to dig deeper, to work harder.

 Luisa Recchia: Dr. Michael and Dr. Luis and Annie, thank you for joining us and for making such a complex and exciting area of research easier for all of us to understand. Today’s conversation reminds us that some of the most promising discoveries begin when researchers from different fields come together, ask new questions, and are willing to explore possibilities that once might have seemed impossible.

To our listeners, thank you for joining us for this episode of Through Our Eyes. To learn more about the Pediatric Retinal Research Foundation, the research we support, and resources available to families, please visit prrf.org. Until next time, thank you for helping us keep research, connection, and hope in sight.