S3E04: A Look Into the Eye
We know very well. How about the instruction works out of visual cycle work now. The big challenge is really trying to understand how h related. Macular degeneration comes about and trying to solve that i think is is a very big deal it john rogan and i'm a scientist specifically an immunologist so someone who studies how the immune system works one key part of my job as a scientist is to communicate ideas with other now the scientists and also with people outside of the field one of the cool things is this podcast allows me to do for the past few seasons. I've had the privilege to speak to. Some of the brightest minds minds in research but i'm not done yet this season. I'm going back into the bar to see what my colleagues are doing to research some of the most complex diseases and see what they're up to so. Grab your favorite favorite drink. Get ready to unlock your science brain and join us for to find this walk into a bar do you. You have to think about how your eyes work. No not really i mean we studied at some point. Don't remember like how it works village study about it back in the day for granted. Sometimes i mean i. I remember him like biology class. We had courses on on human anatomy and stuff just thinking back on science experiments. I know the white parts like made from the same thing as the expert weirdly enough. Sometimes i think about what in our eyes get so hot. They become hard boiled eggs. Welcome back everyone in today's show. We're going to take a deep dive into the the is something very unique and it's a protected organ within our body. That's protected from a lot of common inflammatory responses however there are certain diseases that are very specific to the i am one of these is natural degeneration ration- so today we're going to unpack that and we have with us men of and lebron companion every such specialist in the field of biology and interestingly also in neurobiology elegy and immunology now. How does that all come together. Welcome in a i want to start really high level and get a picture of what the i is. It's perhaps you could help. Describe the i is physically the i is focusing the lights on the back of your eye and the back of your eye is for retinitis and more specifically the macula macula is extremely important for because central vision and it's also where we have most visual acuity which means that that's what we used to drive a car or to recognize faces or watch t._v. The other part of the it's the vitriol the vitriol it's cavity built filled with that with a viscous material to keep the retina to the back and also feel to a delight as solid as components that are very clear <hes> but keep a very strict path between the lens in front of your eye and retina so you have to look at retina as projection screen but it has to be positioned except in the right distance to the lens to get very clear are your projection so that's keeping everything in focus so the lights coming into the lens it goes through the victorious. It's picked up by the roman coins which and this information is conveyed to the brain out through the optic nerve at the back of the that's correct so so once that a light is converted into electrical signal that electrical signal is relates to what's called retinal ganglion cells and a very long excellent said go all the way through the optic nerve to visual cortex and that's the perception of that vision is create non-human primates have macular species aren't for many species. The sensation is not the most important thing you can for example imagine that the mouse has to have the ability to see as well to to to the to the to the sky so needs his peripheral vision that we don't need as much necessarily uh-huh and also nocturnal animals they <hes> they need less of of of this daylight vision they need night fishing where to have much better off off using the total retina so there is definitely differences between us having this macula and species that don't in what the requirements are for for for his vision letter most important survival tactics are just fascinating that our vision has co evolved served with us as a human species so that we have central vision this. Maybe it's also it's very important for us to recognize each other. You never look at somebody that you prefer retina and it's also extremely important to make sense of what you see so there is a lot of things that via species have evolved to do and so also monument privates. Will you need your central vision even to working with tools. I hand coordination and pretty exactly now. It's so fascinating and for the audience what exactly are bolton coins so cones they are there to to for your daylight vision asian and for color vision routes used those when it gets dark. I have to just ask. How do they get these names. Do they look like they look like brooks and likely brought are pretty straits cones. The cost structure is he's really destructive. That's a nice thing is maybe i'm also fascinated by the either's visual to it so the rods and cones are have these these inner segments in other segments. They're specialized in their own and the other segments is referred to transaction takes place and what does instruction this process this for life gets converted to electrical signal and that's been feeds into the brain center embiid electrical signal goes all the wave travels all the way three optic nerve to the brain took visual cortex so regulating that photo conversion must be very well chewed and obviously very important very important very well described right so it's it's really a combination of an obscenity and vitamin either. It's called eleven sis retinol eighteen all that is converted into all transformational <hes> and that conversion creates that electrical signal and when you when you create that all transfatty now there's a moment you have to supply new eleven sis retinol to keep that photo construction going so there is a moment where you have a very intense use of vitamin a. that you don't see anything that's reflective lights. It is when you're driving dark in a car with headlights into i or somebody makes a flesh picture of you and this this moment so you see a dark and go bleaching so that's where you have no ability to supply north of your vitamin a derivative of your your eleven retinol to due to produce that split second i it's just a second and then quickly have to refill the reservoir the right and the reservoir is filled by dispatching a pigment epithelial cells so this really gets to how important these photoreceptor the cones and the retina pygmalion sales are goes that both are important for default addressed actions in the retina <unk> yourself is a very important process several enzymes that convert eleven cities to transfer back in a process the visual cycle. Unfortunately it's these two cells. The photoreceptors cones arpey cells that die in a._m._d. So so these most important parts of retina that you absolutely need to create a vision have got lost concepts concepts the light ones though cells are destroyed. They can't photo convert that information to the brain so what you get left with his literally black hole it correctly he wellington epithelial cells appear similar to the ones that we've talked about another podcast in the intestines intended to finding finding them as a selye. They're all epithelial cells however these cells organize themselves slightly differently or at least different factors depending on the environment. Let's talk about diseases within the macula particularly something called metro degeneration which can be devastating especially in aging populations. Could you walk us through what that is so in in macular degeneration. That's where you lose. Photoreceptor votes counts which are critical for instruction and you also lose a very very important layer which is called vetting pigment epithelium at works very closely with these photoreceptors to convert this process official transaction shen so those sales fortunately our cells that give up and we still have very little knowledge that happens so why do you lose these photoreceptor the receptor <unk>. Why do you lose these photoreceptor retinal pigment <unk> that are required absolutely required for the survival survival of these photoreceptors and hadas macular degeneration or actually as we <hes> some people will know it as a._m._d. Or age related macular the generation. How does it present itself. What is it kind of quote. Unquote look like so in early stages before you even notice notice anything in your vision you you get larger numbers of deposits <unk> present in the macula and he's threes are really composed of i mostly lipids and proteins and the forum just on their these retinal pigment yourself. Do we know how these gruden's form is. It just protein aggregation shen or is it driven by certain signals so we think the driessen is products at the secreted by arpey cells that are not very happy to the epithelial cells yeah and and the jerusalem are they tend to grow over time and they also produce some stress against these r._v. Sales so it's part of driesen maybe being toxic to cells directly but also part of forming a physical barrier between aetna pigmented yourselves and the koran which under the drew sonora under the the membrane on which the r._p._g.'s cells lie lays of giving you all stacked on each other and that's were barrier is is extremely important because on one hand that keeps blood vessels from going into the vetting but it also makes sure that nutrients supplied by these blood vessels get to these photoreceptors photoreceptors. I am not directly vascular is you don't want to have escort cheer in an area ever you need to create vision because it will disturb division as the disease progresses what happens and so eventually you will lose retinal pigmented you yourself and then two things can happen. You will have some compensatory satory vascular ascension cop neo vascular sation which is good because now you supply the photoreceptors and the r._p._o. East sales with blood vessels salsa with everything that blood can't supply but on the other hand. It's a big disadvantage because he also disturbed division so this form of macular pitching rations called wet h related macular degeneration divaesque utilization which is kind of coming in to provide nutrients and help prevent event the damage at the same time. It's kind of causing some of the damage correct that's correct because the vascular through leaky and that leanness that call the dima is this is very disturbing for division vascular function. Try and tell yes and this is a really natural process. The body tries to make new blood vessels missiles after damage or whether it's trying to reap refuse damaged tissue and this is what's going on i in this case and so you're getting you blood vessels that are being formed but when you don't have a strong protective barrier when those epithelial cells have broken down it allows for leaky so the the blood. That's coming coming in the new blood. That's coming into phone. The vessels does start to leak out into the eye as well so that is the webcam day and how does that compare with dry naturally degeneration attention so dry a._m. The loss of retinal pigmented patil yourselves photoreceptors without having this new recession and it's very possible because you don't have this new station you have a porn rapid progress of loss of these retinal pigment photoreceptors thor's time you start with a few dropouts of cells and increases with large areas that that dropout so concentric way it's spreads through the macula and in about five to ten years time people go from having no noticeable effect on vision to be legally blind so that's a big problem that's great biological description but felicitous who are familiar with the disease is their way into scribe what a._m._d. Aimed looks like when you have it or when you're developing it yeah so so it's a bit more difficult to do it for new way because nevada in views is a blurred vision. It's like looking through a bottle of water for geographic atrophies explain. It's really like put put two fists in front of your eyes and then try to see so so you have still your peripheral vision to some extent depending how close your eyes but you're central vision is is lost so you can't see the center. Actually we cannot see center. Yes so you just see darkness and then the vision so recognizing faces is very difficult because suit. You're used to see that in your central vision driving a car meter central vision watching t._v. into central vision watching newspaper so the quality steve live in asia so i just want to shift gears and ask you how to take the drug into the eye so parentally the only way we can undo this is ben jackson so useless very small needle and injects the drug which safar is an antibody antagonist in the eye behind the i. It's it's a canoe tyrod the white part of your eyes when you look at it and and you reject it in vitrolles so in that cavity filled with <hes> with with this more viscous components and then the drug brooke states there for about a month. I usually have to reinject okay so that was hard to listen to so why do you need to inject it locally as opposed to other therapeutics where you can just dr we began to show talking about how the is unique and one of the unique aspects of this is a so-called immune privileged organ so it has various various to the immune system because you don't want general inflammation to come in there you want it to be quiet in this possible and you don't want to have your vision head through through inflammation that my call swelling for example and so the result of protecting the eye from the systemic circulation is that you can on inject drugs systemically in have them penetrate the eye so it's really important for some of these treatments is that you need to deliver the drug into that particular organs and case the back of the eye. What's the pathophysiology of michael degeneration. What are the causes associated with aging but that could be due to many different and finance well. Genetics is extremely important and we know that now that we have been able to secrets of patients and copan of its controls so genetics genetics drives over fifty percent of the disease which is quite substantial looking at other diseases. So what do you mean by that. I mean that that this certain the genes that are affected and when you have polymorphism so single nuclear sites that changed in these genes. You have a much higher risk of getting a._m._d. And so far about thirty six genes that have common polymorphism that associated with with a disease with the risk of disease and to these common polymorphisms help you and your colleagues in the field focus research into certain areas them absolutely early because that's the way we can understand human disease better. These genes that are affected are obviously very important for the health of your retina looking looking to look at the the function of a number of these genes have been identified and one of them that i know you have worked on for very long time. Something called compliment. What is compliment so so complement is a series of proteins that we carry in plots that are extremely important to fight pathogens by poking holes through what we call a membrane rain at tech complex and they also elicits immune system activation so they're bringing immune cells that eat these pathogens this factor santos these pathogens kind of like a tree or a signal that something's going on so it's very important that we have compliments because without have compliments you will get infections but not wanting the wrong place like the i if it gets in the wrong place in the example i mentioned to you have nervous conversation or you have a break in the barrier dan <hes> these neurons get the tax. <hes> photoreceptors counts get the tech the same way as his pathogens get the tax so complement pokes wholesome them brings immune cells in their particularly mona sites macrophages and i start attacking the i have thinking this is another pathogen so why not just remove the compliment from the eye and that's the strategy to to block complement meant activation in the eye again. There's certain challenges that because compliments very abundant to to have enough drug any i <hes> <hes> you will also have to have the drug at the right place because now you're really looking at the interface of the eye and blood and that's a challenge so you can argue view yes if you could looking compliments systemically in the blood. Maybe the best way to go about it but this comes at the safety risks so we cannot do that. Whereas has the fuel going in terms of delivering drugs into the eye with biomedical devices delivery devices what's new well. There's several things that are being explored right now. One of them is the device you can <hes> plug a device in the eye that you load which drug and device will slowly release the drug over time hi so instead of having to come back to the doctor's office every month. Now you can <hes> give the patient can feel that this device every half year every year the other way <hes> is is gene therapies so if you're able to supply a gene that that that creates a protein that temple blogs complement activation you can put a gene in the i <hes> through a vector virus or an isolated virus lies to the i know the i can get one injection. Maybe get out years and that's been very successful. Mona janik disease is not so much. Gotcha age related macular degeneration but if you have one gene that you want to bring back and restore the system. That's a great way of getting around around having to give monthly injections just means. It's one gene associated with a disguised as opposed to multiple correct. The other part field is really going is trying to find out can be approach. H related macular degeneration differently by cell therapy so when the people lose <hes> yourselves photoreceptors can be replaced by other cells and there's now clinical trials ongoing the stem cell therapies clinical trials would put sheets of retinopathy <unk> yourselves back in areas where they got lost. I so this is another area. I think is really promising because now you really think about restoring function when you treat with therapeutics takes you can halt disease but you cannot restore. It's very lost jannik hansen easier to treat than one involving multiple. Yes amona genetic disease. Aziz really is just a disease. It occurs because we tation in a single gene so if that's single gene can be corrected for example with gene therapy that would be <unk> simpler than a multifactorial multi gene disease. It has so many different components to it that it becomes complicated to dissect and then target and in this case it's not just multiple genes that are out of whack. It's multiple cell types as well. It's also thinking about the retinal pigment epithelial cells the photo receptors <unk> as well as the complement and vascular ization that we were talking about earlier. It's very complex. I think the the biology of the eye and the you know therapeutic treatment of disease really points to how i think the field across all different diseases going in terms of trying to get a drug to someone that's disease very specifically and not have any other toxic effects systemically. Yes yes and of malaysia is is a great area to do that because you can see what you're doing. You can with a slim look in the back of your eye and see how your therapy works. You can do surgery to find now that your cells growing in the right direction and covered the rye patch that has lost cells so so you can really do a very targeted cell based therapies because this is very different from something like athritis or even in kansas because in order to look at the changes in the disease you either have to wait over time so your joints swelling as march or your cancer shrunk but you can't really look intimately along the way whereas you can with this so that's i think why my cell based therapies and also gene therapies are taking off any optimally space so it's really exciting area to be working in. I really want to go back to your story. How did you end up working in the eye because 'cause i know you actually know you as an immunologist right when you first started working on compliment but you didn't stop it. How did you decide lied to get into science. And when did you start well. The training wasn't neurobiology fascinated with neurons then and when i came to the minority departments we discovered a new complement inhibitor so combined combining my background's neurobiology my doc interests in the minority the i was a great place for me to work. It's a huge convergence right. You've got the immunology part with the complement then the neurobiology biology because it's all about getting the right signals from those photoreceptors back into the brain you know is also part of it the nation with how the eye works and it's such a well organized system as a mention. I think we know very well. How photog- instruction works additional cycle work work so there's a lot to go from and then now the big challenge is really trying to understand how h related macular degeneration comes about and <unk> and trying to solve that i think is is a very big deal given that the disease is increasing in terms of incidents with the aging population understanding why that is it's increasing because our life span is getting longer so we have higher into the risk increases with age hence the name so above sixty you get a thirty percent chance that you that you get a better knowledge invasion especially you have the genetic factors against you working against which increases the risks and over eighty it. It's exponentially increase so that's that's really the reason becomes such big problems how do you how does field studies when the human is the only place where the disease manifests itself. What's really the best way to study. The disease is to study human disease and studied humans and i think what has been a tremendous tremendous. <hes> instill development is the imaging center you can get access by vitit imaging modalities to do the retina optical coherence tomography is a way you can see all the layers of the retina and find out what happens over over time it's noninvasive and those imaging technology some also fluid scene and geography we can fill the basketball cheer the die and you can now visualize those very important and understanding the disease because they tell you exactly where the problems are and how they develop over time and i think that together with the human genetics which has also been a recent development. It's only the last ten years that we start understanding. The genetics of age related macular degeneration ration- if you combine these these developments in imaging with a better understanding of the human genetics you can start understanding sees better better and start in the standing. What are your targets and how do you go about targeting the need to increase or decrease certain advice so the last ten twenty as being like rhythmic in terms of the understanding of the disease. Where do we go from here. What are you. What are you in the field goal from how well we're were. I would go and my lap ghost is really trying to understand the genetics better and <hes> we have a lot of excess for clinical trial data ah from our own but also from natural history studies to to really link the genetics with the imaging and see see how patients respond to certain therapies but also see how dare a._m._d. Develops over time and as a result of having certain genetic attic profiles and we can start on the standing which are the genetics that drive the neo vascular part of the disease. What is the genetics that makes six photoreceptors survive less well or retinal pigment salves so i think we need to start looking into that more and more and one way to study that is <hes> to to to closely study post mortem is so you get is from donors that you really want to understand what is what is the pathophysiology what our buddy pat. I look like an another way to study. It is really from from human stem cells and grody stem cells out to become retinal pigmented patil yourselves or even or gun rights which are small mini ice mini eyeballs that you can filter in addition. You can now study how these eyeballs that's right. They just have have many of the features so there have been so you've got some of those layers of the onion formation and then you can start to to play around with pathways right while you can knock out certain genes you can look at at at certain genetics of the stem cells how the <unk> posted a disease etc so what does the future look like beyond just tagme ice sculpture or compliment so technologies that the now available to to approach the disease regenerative therapy were you are able to reconstitute the cells where lost for example right now does clinical trials and have been successful that can insert a sheet of retinal pigmented a peculiar cells my right. It's mind blowing. How do they do that. Do is retinal pigment. Patil your cells that grow on the membrane naturally. It's called the brooks member so the way you do that. You can make an artificial brooks membrane with composition very similar in in addition retinal cells from amona layer and now you you make it the size proportions of the area that brady's greatest epithelial cells are lost band-aid size roads right exactly so you you you asserted micro surgically retina and on the books yeah you partly you layer it on the books membrane and then let it grow back <hes> and now retina it could very well be that photoreceptors are lost above those r._v.'s cells but now you can also turn retina and turn the better part of the retina above these cells with all of these advances. Will we have this cute in the next ten twenties. He's one of the reasons why it's it's very difficult to to cure the disease. That disease is still the very heterogeneous we call it. H related macular degeneration but there's several ways that the degeneration happens so talk mostly about about genetics. Have you know there's several different pathway said there are a fact that <hes> we also know that apart from genetics environmental factors that can affect the the risk of getting the disease progression of the disease so there's not a one fits for all type of therapy available so i think the you're making progress i think the progress has to come from these new technologies but also having better ways of delivery therapies more convenient less invasive and also by finding ways nice to treat the disease really early on maybe even before people noticed that they have lost visual acuity. That's only again. That's not what's like typical for the only but again you can follow patients from very early on and see how to respond to therapy <hes>. Do you have to just capture this patient. You have to predict who is going to get the disease and start treating them early. Such strong genetic says the possibility to be able due to really identify who those patients might be absolutely. That's the strategy to feel to stake so meno. It's been such a delight talking with you today it. It makes me want to go and retrain as an eye surgeon. Thank you so much for talking with us and good luck with the rest of your research eurokom. We've all been listening with your ease but now i. I know you're thinking about your eyes. I certainly am. I think it's really fascinating certainly as an immunologist when you think about how the immune system is attacking something. That should be in privilege in this case. That's the eye and how an understanding of. I envision inflammatory. Pathways genetics together can help help us understand and you've disease and come up with new therapeutics which means for me. I think i better get back into the lab and in the meantime please keep telling you science fans about us like us on facebook and twitter download the podcast from your favorite podcast app and rate us on. I tunes. Thanks for listening and for me. It's back to the left.