Exploring The Principles Of Genetic Research In Genetic Eye Disease - Part 1 | Episode #18

Episode 18

Exploring The Principles Of Genetic Research In Genetic Eye Disease - Part 1

This episode embarks on a journey through the world of groundbreaking research with our special guest, Dr. Kimberly Drenser, who holds the prestigious title of what is called a double doctor (i.e. she holds two medical degrees).

Additionally, Dr. Drenser engaged in a two-year retinal fellowship with associated retinal consultants Dr. Anthony Capone and Dr. Michael Trese. 

Your host, Dr. Patrick Droste dives into this captivating three-part series that covers innovative and promising research for the future. In part one, we will explore the fundamental definitions of principles that underpin genetic research and particularly genetic eye disease. Part two will navigate the captivating landscape of research development challenges, and part three will investigate pivotal moments that shape the trajectory of a scientific breakthrough from early-stage investigations to rigorous experimentation.

  • 0:00:09.3 Patrick Droste: Welcome to the Through Our Eyes Podcast that takes you on a journey through the world of groundbreaking research with our special guest, Dr. Kimberly Drenser. Dr. Kimberly Drenser is what we call a double doctor, this means she has two medical degrees. She has a MD degree or a degree in clinical medicine, which allows her to take care of and operate on patients. She also has a research degree, which she did basic science and qualifies her as being a research scientist physician. She did... Dr. Drenser did her medical school at the University of Florida, and she also did her PhD at the University of Florida, combined MD PhD program. She did two years of medical school, three years of clinical research where her PhD thesis was on gene therapy for retinitis pigmentosa. Completed her medical school two years afterwards, and graduated with an MD PhD. This was done at the University of Florida and also at the University of California, San Francisco. Dr. Drenser then went on to do internship and residency at the University of California, Los Angeles.

    0:01:17.7 PD: This was a five-year program, then she did a two-year retinal fellowship associated retinal consultants with Dr. Anthony Capone and Dr. Michael Trese. So utilizing the baseball analogy, which I like to do, a baseball player is evaluated on the five skills. Does the baseball player run, hit, hit with power, catch and throw a baseball? And if he can do all those things and do them all well, ends up in the Hall of Fame. So Dr. Drenser has already established the fact she hits them all well, and she's our Hall of Fame special guest tonight. I'm your host Dr. Patrick Droste and today we embark on a captivating three-part series that delves into the realms of discovery, innovation and the promising future.

    0:02:01.4 PD: In part, we will explore the fundamental definitions of principles that underpin research and particularly genetic eye disease. In part two, we'll navigate the captivating landscape of research development, challenges, triumphs and pivotal moments that shape the trajectory of a scientific breakthrough, from early-stage investigations to rigorous experimentation. And finally in part three, we'll fast-forward to the future. A future fueled by hope as we examine groundbreaking drug currently fueled, currently used, as we try to correlate a new drug with the treatment of inherited retinal disease. So please sit back, relax, and get ready on this tremendous journey with us and share the five-skill player in baseball analogy, Dr. Kim Drenser.

    [music]

    0:02:50.2 PD: Welcome, Dr. Drenser, and thank you for taking time to talk to us, we're accompanied tonight with Luisa Recchia, Nicole Gudicci, Andrea Bennett, also members of our podcast team, and we invite them to ask any questions as we go along. We've divided this podcast into three parts, one is basics 'cause we're not really sure what general audience knows about genetic eye disease. And then we're going to a little bit more specific on your passion in this area and what led you into doing research, and then lastly, about the concept of translational research, which means taking a drug, applying it to disease and then having it available for patients to cure genetic eye disease. So everybody uses the term genetics, can you give us an idea what in your mind, genetics is?

    0:03:41.Dr. Kimberly Drenser: Absolutely. To me, genetics is kind of the broad term used to describe how our chromosomes, our DNA, and that special code that makes us each individuals interplays with each other to make us similar and unique. And it drives all of the characteristics that make us what we are. And so I think that being able to understand genetics and use it to improve our management of disease, our treatments of disease, and even just our basic understanding of why things happen is a very powerful tool.

    0:04:24.8 PD: Now, they say that Deoxyribonucleic acid, or DNA, is the building block of our general makeup and all genetics. Can you comment a little bit about the importance of DNA and genetic disease and particularly genetic eye disease?

    0:04:42.6 KD: Yep, absolutely. So one of the things that's very interesting about DNA is that DNA really is the backbone of our genetics. You have four distinct nucleotides, G-A-T-C, and the combination of these four nucleotides together speak a language. And it's amazing that these different, millions of different iterations of how you can put just those four nucleotides in different patterns creates unique genes. For instance, what your eye color will be, what your hair color will be. Some of them are very straightforward and the one gene very highly correlates with one characteristic, but there are other characteristics that are multigenic, meaning that the interplay of more than one gene creates that characteristic. So it can be very, very simple and elegant and it can become very, very complicated depending on the interplay of how these genes work with each other. Ultimately, what many of these genes end up doing is working together to create particular pathways. So one gene turns it on, one gene turns it off, when it turns on the pathway other genes get activated, other genes get turned off or suppressed. That interplay of these genes is what determines when eyes, we'll stick with eyes, when eyes do what they're supposed to do when they develop the correct way, when they see the way and function the way they're supposed to versus eye diseases.

    0:06:22.7 KD: And eye diseases can be, for matters of what we're discussing here to better understand genes, we're really looking at inherited diseases or a change in that DNA alphabet that causes a gene to not behave correctly. And that can lead to being born, so having a congenital problem, so you can be born with an eye disease or you can develop that eye disease, it can be progressive over your life. So you might be born with something and you see normally, but then you start to lose that function throughout your life. And that's how genetics in the eye plays a role in what we see people having problems with.

    0:07:06.8 PD: Oh, I have a question. If DNA is what defines the genes, malfunctions or let's use the term mutations in the DNA causes changes in the gene. Does that show up in chromosomes or does that show up in the final product or both?

    0:07:27.6 KD: All of the above. So before we could really do genetic analysis, the earliest analysis was chromosome analysis. So, and it's actually very, very pretty, and also looks a little bit like a different alphabet. It's 23 chromosomes, so you have 22 chromosomes which are what they call somatic, you get one from mom and one from dad and the two work together. Each chromosome of the somatic chromosomes has the exact same genes, so it has the exact same set, there are variations in the DNA in each chromosome, which is why your offspring, your children will have characteristics of both mom and dad and characteristics of each other as siblings, but they're not identical, because again, it's that interplay. The sex chromosomes is an X and Y and that's what determines whether you're a male or a female. So a female gets two Xs and a male gets an X and a Y and these can also... The X always comes from the mom, so any sort of X-linked disease will always come from the mother and the Y always comes from the father. So the father can donate either an X or a Y, so it's always the father that determines the sex of the offspring.

    0:08:47.9 KD: And then the mother has two Xs, so often times mothers can be carriers states, because only one X chromosome can be dominant in a female. And so that's how DNA makes up is that they would take a, basically a blood sample and isolate, break down the chromosomes, break the cell open to look at the chromosomes, and they spread them out and they all have very defined shapes and sizes and the right density and size that they're supposed to be. And so you can look, the earliest analysis was looking at just alterations that you could see in these chromosomes from what they should normally look like. That's when people started to become more sophisticated in saying, "Well, there are literally thousands of genes on each chromosome. How can we analyze instead of these kind of macroscopic changes that we're seeing in the chromosomes, how can we see the detail of what's really changing in these chromosomes." Which would be for being doing the DNA analysis.

    0:09:46.8 PD: That brings us to, you mentioned thousands and thousands of genes make up a human being. And in 1990, the Human Genome Project was launched where we tried to list all of the hereditary information in genes in a human being, with the variability that you've just described, this study lasted until 2003. Can you tell us a little bit about that study and what it means for medicine?

    0:10:20.6 KD: Yep. So the Human Genome Project was a really, really amazing project, and I was actually in college when it started and then in medical school and graduate school all the way through, really through residency while it was being completed. And it dramatically changed our understanding of human disease and the genetic causes of it. So prior to 1990, if you wanted to try to isolate a gene, you would take... You'd actually have to try to isolate it in what they would call libraries. So let's just say that you were working with a virus and you wanted to know, and this is something obviously very small compared to the human chromosome. Let's just take a virus, you would take their DNA and you would chop it up into small pieces and put it into a clone or plasmid, that you could sequence these little chunks and then you'd write them down and you'd have them overlap and you'd figure out the way that they work together, so that you could better understand these small little pieces of these small genomes. Well, once we understood how to do that, it was very obvious that rather than having Dr. Joe over in one small lab and Dr. Kim over in another small lab working on a little tiny fragment, we could actually maybe piece the whole thing together if it was put on one server and everybody shared the data.

    0:11:56.6 KD: So anytime somebody sequenced something, they just put it in and shared it into this big server. And so over a relatively short period of time, the entire human genome was mapped, sequenced, mapped. And we learned a lot, not just about the techniques and how to do that, but we learned a lot about the alterations that we see in all of these different genes that we still don't know what the majority of the genes that have been sequenced actually do. There's lifetimes, careers worth of data in that Human Genome project. But it also now created a server where you could now find genes and the genes were linked to citations, I got this gene from a family of six with this rare eye disease. So you look up how they described it and what the gene was, and that's what started leading us to all of these understandings of the correlation between changes in the genes and in their genetic makeup and how it was impacting the structure, the function, the development of different tissues in the eye.

    0:13:07.3 PD: That's just... That's absolutely extraordinary. That brings us now to the core thing we wanna talk about is namely, making the transition between a disease entity, for example, Familial Exudative Vitreoretinopathy. We know that it is a genetic eye disease and we know that it has genes and we know that it has mutations that cause abnormal function of the retina. And so we devise ways to study these genes and then come up with a way to get a medication or a vector to change the genetic code back to something that's normal. And this is kind of what we refer to as translational research, go from the problem to the research and then to the remedy, namely medication. Can you talk to us a little bit about that?

    0:14:07.5 KD: So this is the most... In my opinion, the most important aspect of advancing the understanding of genetic diseases and in particular understanding rare diseases. One of the things that's interesting is that the original mutations in genes associated with Familial Exudative Vitreoretinopathy were generally found by finding families that had enough members without eye disease and enough members with eye disease to be able to look for that candidate gene and then identify it. Back in the early days, this was really painstaking, you could spend a decade on one family in isolating the gene and then getting the sequencing and really understanding it. We've advanced now to an area where we can evaluate multiple genes at one sitting, it's very... It's much faster, it's a rapid throughput. You can also do whole chromosome sequencing if that's what you really wanna do. You can look at the whole genome. So there are a lot of different ways to look at that now. But fever was a very fascinating pathway to look at, because what these genes started telling us as we started to see them and compile them is that they were all related to a single pathway that was very, very important for the normal development of retina. And by better understanding those genes, how they're affected and how they affect the function and structure and development of the eye, allowed for a better understanding of how we can intervene.

    0:15:49.7 KD: And when we talk about therapies, there are a lot of different ways that you can tackle this. The most common way to tackle this is to do, to identify the pathway and learn how to kind of fake out the pathway, either turn it on or turn it off, depending on whether it's overactive or under-active or mal-active, it's going in the wrong direction. So how do you kind of modulate that pathway? Gene therapy really speaks to the cleanest way to do that is gene replacement, this is a bad gene, I'm going to put into that DNA, I'm gonna put the normal gene and I'm gonna introduce that by a vector, thereby fixing the problem. That works for certain things, it doesn't work for a lot of things. There are some other genetic therapies that have not truly come to fruition yet, but are definitely being evaluated and researched heavily, which is what they call gene altering. So can I actually go in and cut out the bad part of the gene and replace it with the normal one? It's not a traditional gene therapy, it's really a gene editing, it's a splice and repair rather than a replace. But all of those are really at the goal of understanding the genetic disease is to understand how we can intervene and change that trajectory to, in this case, a healthy eye or in fever, a healthy retina.

    0:17:18.6 PD: Thank you very much. That is very, very helpful, you've taken us through the basics, starting with Deoxyribonucleic acid, genetics, chromosomes and research in how we surgically excise bad parts of genes and replace them with good parts. That'll conclude part one of our three-part research series on Through Our Eyes Podcast. We hope you enjoyed this deep dive into the basic definitions of research, if you have any questions, thoughts or ideas you would like to share, we would love to hear about them. Please forward them to us via our website, via our social media, via our subscription newsletter or via phone call. The podcast is called Through Our Eyes. Make sure to like and follow our Facebook, Instagram and TikTok and let us know if you have any questions or have a topic you would like us to cover. We have tremendous things planned and we hope you tune in again for our next podcast. This is Dr. Droste saying night to all of you. On behalf of our staff, the PRF, thank you.

    [music]