How New Drugs Are Developed
Hi, welcome back to the healthcare trash podcast this healthcare. Chaz podcasts in all podcast. Sponsored by Indiana University school of medicine whose mission is to advance health in the state of Indiana. I'm beyond by promoting innovation and excellence in education, research and patient care. I school medicine is leading Indiana University. First grand challenge the precision health initiative with bold goals to cure, multiple myeloma, triple negative, breast cancer, and childhood sarcoma and prevent type two diabetes and Alzheimer's disease. Table going to be talking about Alzheimer's disease, specifically drug development. I'm super excited today because our guest is dance Grabotski president of Lilly research laboratories and chief scientific officer for ally Lillian company, I've known Dan for years. We actually went to medical school together at the university of Pennsylvania school of medicine. Did you graduate with us in nineteen ninety eight or was it later took me a little bit longer because I stayed on to get a PHD as well. So for seven years. Oh, well, let let's start with that. I'd love. To talk about how you got to this position given that we both started in the same place, which was at university of Pennsylvania in nineteen ninety four. So when I took off in one thousand nine hundred eighty eight what were you doing? So I was working towards my PHD working in neuroscientist on basic mechanisms of Alzheimer's disease them, what did you do after getting your PHD and MD? So I continued my training through residency and surgical pathology. And then I went onto fellowship training in neuro pathology where was that? I was all at the university of Pennsylvania. Oh, great. Okay. And so then you finished in what year? So all of that training took me about to hit must have been a two thousand five. Okay. I think and then at that point I took a different path instead of continuing sort of in the academic research path in in which I had been working for many many years at that point. I took an entrepreneurship path and took one of the projects I have been working on even. A graduate student and started a company around it. How do you do that? Well, at the time, I actually didn't know the answer that question how I do which was probably helpful. Because it's it's a difficult thing to do particularly. So you even more than today back, then I think it was it was a bit more unusual for someone from Accademia to God. And start a company at the time. I put my father's three big things you need to have a company one. Is you need the technology. And in this case, of course, the technology, which I'd been working on was co inventor of had all been invented at the university. So belonged not me and the other vendors, but to the university how things work so you have to get that. But of course, you go to the university and say, hey, we want to license it, and they say well, great. We license acknowledges two teams. So show us the the people who's your team and you need money. So show us the money to to develop. Of course, I didn't have those other things. So then I went and said, okay. Well, maybe I could go hire some people and. Started talking to experience drug developers and see if I can put a team together. And of course, they said, well, we sounds like an interesting idea, but you don't actually have the technology, and you don't have any money. And so then I said, okay, let me try the money side. And you go out and talk to venture capitalists. So you want to invest in the psychology? And what do they say we need a team, and we need to get the pick -nology. So the the first year or so is trying to get those three things together. And how do you assemble those resources the people that technology the dollars? So you can get started. And eventually I had some traction there put together team which grew to be over one hundred people and over time worked on this. This idea that we had an academic. How I I'm I'm somewhat what muscle to flex like how do you even start to? How was this? Like you thought that you could do this. Or did you have some other people that were with you a week do this or how does that happen? It was mostly me, actually. So I I had friends. Who had different experiences some who had more on the business side than I did. And so I mainly ask them for free advice, which they gave me, and and then just started reading on the internet and making phone calls and driving around in my car to meet people and how much venture capitals, it take to get something like that started well to get started. It's it varies in my case. It was a million dollars that made me think that it was going to be real which just shows little I knew at the time right on because now, I know a million dollars isn't actually very much for this kind of endeavor. But but at the time, I I remember the day very very well where I after, you know, intense work negotiation at closed on on a million dollar financing. And I kept calling my Bank, which was just my neighborhood Bank. Because again, that's that's what I knew they were open on Sundays. And that's what I needed. And so I kept calling my Bank, and and saying his is my money there and the teller should okay. Now, see a new balance in your accountant. She's like it's one hundred ten. Oh, no. It's a million. Wow. One hundred it's like, okay now at now, I've made it, and of course, so we went on to raise nearly I must been sixty or seventy million dollars to to develop this product. So that was just just the very beginning. Right. Okay. So that was about what year two thousand and five naive accompanying. Now, you want to develop drugs what what do you do next? So when I started my company, we working we haven't said yet what we're doing which is we're working in Alzheimer's disease and our goal. There was to develop a drug that could be an imaging agent to see the plaques in the brain of Alzheimer's disease and help detect the disease diagnosed the disease. So the first thing we needed was chemistry because we had to design create a molecule, so I hired some chemists and. The first chemist I hired a said, okay. Our our first job is to build a laboratory. So we can make molecules and he and I went around and bought equipment initially. We even went to companies that were going bankrupt in selling all their use laboratory show up. There might truck in literally with a Bank check because it was sort of a cache type transaction, and we say, okay, we want that machine in that machine that one and load them up and take him back to the lab and see if we can I'm working or not. And so we we spent some time building a lab, and and then hiring more chemists and getting to work. Okay. And then how do you actually make? I mean, I'm sure there's multiple steps here. But a part of what I'm trying to how do you? Then what do you do? I mean. Now, you've got a laboratory. So you wanna make this? We call it a dry it doesn't sound like a drug drug. Yeah. Okay. But it, but it's for diagnosis. So what you now have all these people. What would you do? So we started making molecules making chemicals that have the properties that we were looking for and then testing them in different ashtrays in the laboratory and trying to get closer and closer to a molecule with the ideal properties. And. The goal of of that stage of research is to get something. Good enough that you can eventually test it in people and see if it works. So does it I in would with cells or animals where where did you start? Some of the initial screens were what we call in vitro grants or just in a test tube using different chemicals and extracts to test them. And then another stage screening was using human tissue from people who had died without timers donated their brains to research, and then we're able to see okay, if this is supposed to detect amyloid plaques in living people can at least see it on postmortem tissue from from people who had died. So that was another level of screen, and then you can go to animal models like mice said say, okay, what needs to get into the brain. So when we injected into the blood does it travel into the brain and get in there. So the those are the types of experiments that ultimately can lead up to human testing. And this came from. Your work as a graduate student. You're saying, yeah, I'd actually started this project at the tail end of my graduate training, my train his PHD in the night continued to work on it through some of my postdoctoral training. How did you even come up with the molecule to begin with? I mean where where did it come from? Yeah. So my background is I'm a neuro pathologist, and in neuro pathology one of the things that we have relied on for almost a hundred years is histo-pathological stains that are essentially dies that came from the textile industry that people discovered could stain different kinds of tissues in different ways. In one of those stains that you might remember for medical school was called Congo. Red attractive name that the textile industry gave it to make it seem more attractive Congo red binds, it turns out to amyloid plaques, and it was just sort of empirically discovered by histopathology many many years ago. And so the idea that we had was to take that die which must have. Some affinity for these plaques and start modifying it and see if we can make it thousands of times better at doing it. In fact, there was another dial also called Thia Flavin that had the same kind of property, very different chemical structures. So we're working on that as well one of the breakthroughs came when we saw that structurally we could have elements of each of the two molecules combined. Okay. And that was one of our breakers. Then led to the ultimate compounds that we developed, and you're just synthesizing compounds trying to get them to fold the way you want. I mean, all the way back to again chemistry. It's organic chemistry chemists. Adding will what happens if we add oxygen in this position or nitrogen in this position and over time. And this is still this is how we do drug discovery even lily is you start to develop a a an understanding, and we call it a structure activity relationship or S A R, which is okay. If I modify the molecule in certain parts in certain directions to the left side becomes bigger, for example. Than that seems to work better bonds better if the right side becomes smaller that works less. Well, of course, there's many many different properties that's a gross oversimplification, but the chemistry team combined with the biologists who are testing these molecules start to develop that kind of an understanding, and then they can make rational decisions about how to modify the compound. And of course, we're always trying to change optimize for many different things. At once. One is how tightly does it bind your target? But that's not enough. You also need to make sure that it gets into the target organs on this kiss. Does it get into the brain? And sometimes those things will be conflicting when you make a compound that works better binding does work as well. Getting the brain. And other thing might be metabolism. Your body has all kinds of ways of metabolising chopping up foreign molecules make sure it doesn't get chopped up too quickly or in a bad way. Optimizing for safety. It has to be something that is is safe often in drug discovery. We're looking for things that can be taken orally and those properties are often. Been very unique and different. And so the job of the medicinal chemist is to make modifications that can simultaneously optimized for all of these properties months. We have something good enough. We go onto him testing. Okay. So you've got not to the point where you feel like you've you've got something you've been testing it. You think it binds? How do you know, you're ready for human testing? Yes. So you set criteria at the beginning of any campaign say, okay, if I get a molecule that he hits these criteria certain level of Finnity, brain, entry, etc. We'll go on tested in humans, and we had one. And and on it went one wrinkle here is that the first molecule we tested didn't work in Pearl human. So it was a bit of back to the drawing board. How do you even do the human testing nominee account? Obviously, you don't put out a shingle and say we want to want to give you pillar shots. How how do you actually get that done? Yes. So so drug companies big companies and small companies, although we we sort of say we do human testing. Of course, what we really do is is collaborate generally with academic physicians as well as private physicians who see patients who do the testing on our behalf. So in this case, it was in in typically in early drug testing, it's very specialized so there are specialized physicians who can do that kind of testing, and they have all of the safety precautions and the apparatus set up to to be able to do it in our case that also required brain imaging. So a. A very complicated thing to do. So we worked with academic centers that could do that kind of brain imaging, and they found patients injected the compound for the first time, which is kind of nerve wracking because you don't want to hurt anyone, of course. And we're very very happy that we we never did. But testing a new a new drug in a patient is always a carry some risk. And and then look at the brain scout. And see if it works on right? Okay. So you did it originally did not work. That's right. And so what do you do next? So we had a strategy to test multiple compounds nearly in parallel. So we had a number that we're going to come forward. Almost regardless of what the first one. Did we knew that we would take a few attempts to to optimize? And eventually we had a few that looked pretty good. We pick the best one and took it through longer stage testing ultimately became a drug. What do you do next? Yeah. So the next big goal is to get medicine approved by the FDA. And this global regulators around the world that are that work like the FDA doesn't the United States. And so at that point. There was lots of discussions with the FDA will will how should we demonstrate that this really works because we're trying to diagnose Alzheimer's image, something in the brain in Alzheimer's disease hasn't been seen before one thing. You can do is say, okay, I'm gonna I'm gonna image ten twenty people who have a clinical diagnosis Alzheimer's in ten or twenty people who don't in show, you there's a difference too. And of course, we did that that's early testing in. What you see is that most of the people are Alzheimer's show that they had a brain full of plaque. But some of them didn't our view was those are people that the clinician is making a mistake. They don't actually have Alzheimer's. That's why we want to develop a new test as the diagnosis isn't so good. And when we took older patients who don't have a diagnosis, Alzheimer's damage them again, you can image twenty of them a few of them. Look like, they did have and. Would say, okay, we'll those are patients who are likely to go on to get Alzheimer's disease. And maybe the physician hasn't noticed the changes in their their cognition yet. So anytime you're developing new diagnostic tests like that that's supposed to be better than anything else. That's out there. What do you compare yourself to show that you're actually right? And we call that a truth standard. What is your true standard? So lots of discussions with with the FDA on on that culminating in what's called an advisory committee where the FDA calls a panel of its top advisors, and we present our ideas. And at that meeting, we presented an idea that we would do something. No one had done before which is image people's brains and see whether they had the plaques or not and then follow the people over time until they died. These would be people who've agreed in advance to donate their brains to research, and then we would look at their brain under the microscope and see was the test. Right. So the gold standard would be the neuro pathology at autopsy that was a difficult idea on a difficult trial too. Deduct and so we went to hospices, and to researchers who are studying Alzheimer's disease in said, we're looking for people who are have perhaps cognitive decline or maybe not when you both kinds. But also have another reason why they might be near the end of life. So do they have cancer or heart disease or lung disease? And so we were able to find a people like that which was really meaningful that these individuals said, I I know I'm in the end of my life. But I want to do something to help science and helpresearch some of them had family members without numbers some had Alzheimer's selves in their family members that this is this is what my wife would want to in her in her final days to be able to give something back to research. So really touching in meaningful contribution from people who sent me at the end of the study. Photos of their loved ones in poems. They had written in articles in newspapers that they had contributed everybody. I think wants to help out on Alzheimer's disease. And so able to conduct a study and and show that it was successful. And then bring that data back to the FDA here. Look at it really works out. Well, and then ultimately got it FDA approved. And it's now available has been for for several years. Unfortunately, it's not covered by most insurance payments, which has been a deep disappointment for me, and for many people with Alzheimer's really just because it's it's expensive to do. It a test like this involves a very specialized scanner and radioactive drug and physician to read. It means it's been out of reach for most people just too bad. Yeah. So what what do you do even at this step? Yes. So we little lucky to to contract with national companies that can make the radioactive. For us the imaging agents. And so we have been able to make available for for people around the country. But again that facility needs to get paid and had the doctor who administers it in the doctor who owns the scanner or the hospital owns a scanner and the physician that reads the scan. So that's been a barrier. We worked over the years with Medicare because that's the primary there for for elderly patients worked with Medicare and were gratified to get some progress with coverage with evidence development where they paid for for people who were involved in research and. Thousands and thousands of more than ten thousand people have gotten access to it through that which which is something but still out of bounds for most people. What is their rationales or what's how do they make the decision about whether to cover it or not this is these are tough decisions? And they're they're people who whose job it is to decide whether or not certain medical technologies in procedures are paid for by insurance. Or not in this case. I think the the basis of their decision was we don't really know that whether diagnosing Alzheimer's disease earlier, more accurately will result in changes in care and changes in outcomes for patients. So that's interesting. So tomorrow, we came up with a drug that they said, well, if you get this early it would prevent Alzheimer's, then all of a sudden, I might be a very different. Calculus course. Yes. Yes. And that was that's sort of always been the the end goal. Here is. While it's very important to detect Alzheimer's Israelis possible. This is what one of the things that neurologists been oughta time doing because they can offer counseling to patients, and they can offer different therapies to patients. None of them are cure, but can have important impacts on people in when it's not Alzheimer's, that's important to know too. But ultimately our goal is is to say how can we help develop a drug that can really meaningfully stop or stop or meaningfully slow down the progression of the disease would still sound like the drug that we've been talking about this conversation is super important for research because how else would you pick up the patients who are potentially at high yesterday. And well, it's been deeply disappointing that it has been available to patients for me. It's been extremely gratifying that just about every modern Alzheimer's clinical research trial uses this to find the right business to treat or one of the related technology in their to others came out after are, so okay. So you've done that you're next. Yes. So that that pathway led me in two thousand and ten. I sold my company to ally lily of Melita in Alzheimer's disease research who who shared our vision for what we could do in Alzheimer's disease and saw the value of this for patients, but also for research, and I became part of of this company and then over the years from from the until today, I've had different roles inside company learning and leading different parts of our research organization in then for few years leading the drug development organization research is how we discover drugs development is how we test them in in patients, and now I have the privilege of of leading research and development being the head of our indeed lily, so I brought my head around the story of how you got to your drug or the one we've been talking about where we know that the stains were can we manipulate this Dana make work. But how is that? Is that the story for most drugs is that I mean, how do how do you come up with the drug the so? Yeah, that's right. There's a couple of different. As to to find new medicines. But you often have to think about what's a reasonable starting point in. And sometimes it's something that's out there in the literature. That's not very good. But gives you an initial handle on where to start another way. We can do it which is a lot more sophisticated than anything. I had available back. Then is we can actually determine the structure of the target. So if you have a particular protein in mostly we're we're trying to drug proteins. So that we can talk about other ideas in a minute. You can do what's called crystallize it which then allows you to determine the structure, and so you're seeing the structure of the molecule almost at an atomic level. So you can really understand the shape of it. And the drug is supposed to fit into a particular groove on the molecule, and you can actually see the groove and then using sophisticated computer software and simulation as well as know-how medicinal chemistry. Can say, okay, I can design a molecule with this particular, shape and pattern of charge that could fit into that grew very tightly in. So we call that structural enabled a drug discovery where we actually know the structure that we're working on. We're not it's not just trial and error. Right arc. And that represents a great deal of what we do. Now that I understand that. Why does it fail? Like why? Why can't you just nail it? Yes. So there's a couple reasons why actually, unfortunately, there's many many reasons, right? Dr joy discovery. It's been said that developing a drug is not rocket science. It's actually much much harder in most of our our attempts to fly a fail Hambo flu. We learn from each one. So. If we have a target that we want to make a drug to actually most of the time not always given enough time and money, and we'll have large teams of chemists working on things for many years. We can find a molecule that can impact it. That's because we choose our targets carefully. And there are some targets that we just know our undrivable, we don't know how to make a molecule, and so we just avoid those. But the ones we go after we generally have an idea of how we're going to be able to make a molecule and given enough time we can make a molecule that that can hit it. But it turns out that many these won't be safe and will fail because of safety that even in preclinical models will see well. Yes, it inhibits protein exit you're going for. But also why z which are dangerous or sometimes we'll get all the way to human testing. And we'll discover that there's some safety abnormality which we hopefully in unusually thankfully detect. Early that a particular enzyme in the patient might go up that is an indicator that if we kept at this could cause long term harm we stopped in. And sometimes it just turns out that our understanding the biology that we know that hitting protein x might be a good idea to stop a disease, but we were wrong about that. And actually, it's really an important target for normal bodily function or it's not an important target for the disease. And so the biology lets us down a lot and those sort of the the two basic paradigm is sometimes you've got a great drug that perfectly in cleanly hits the target you want. But the biology was wrong that that target is in great to hit. And sometimes you have a great target. But you can't make a drug that cleanly hits it because the chemistry is too too challenging it's not not cleanly drug -able. Of course, the the beautiful targets are the ones that have both really great biology that we totally, you know, at least we think we totally understand that hitting this'll will have a beneficial effect in. In. They're clearly drug -able. We know how to make a drug inset. Those are the golden targets. They go fast. Anytime someone has an idea you can imagine most of the pharma companies will jump on that in the first one or two will have a medicine the rest of us will will step back because we don't need six drugs against a given target. So what are you trying to do with most of the targets who tried to block them? You're trying to make him. Go fast. You're trying to break him. What are you trying to do mostly were good at turning things off? So it's a target. We look for targets that are overactive. So that we can turn them down the other thing that that we sometimes can do is his supplement the activity of target. But that's as you can imagine a little harder to make something work better than Nature Genetics. It it's often easier to make it work less. We we're often in the inhibitor game. But sometimes we can do activators. You know, I talked a lot about chemistry in in in small molecules, we call them because they're relatively small compared to proteins which are big molecules. But. We can also sometimes more and more use what we call biologics, which are now they're not made by chemists, but they're made by cells, and we can engineer cells to be our laboratory to make new medicines and often those will be proteins themselves or a specific temperature called an antibody, which is what your body uses to fight off infection. We can actually create antibodies that can turn off in in some cases, turn on signaling pathways in yourself. And then that becomes the medicine is is antibody itself. This is almost all over Wilma. How do you? How do you figure out? What thing to do for what disease or what is it just all throwing the kitchen, sink it everything? Or is it more thoughtful it has to be more thoughtful because it takes so long and it's so expensive. We who he has a company spend between five and six billion dollars a year in research and development to discover new drugs where is that money spent his that on like Queant labs people it's mostly on. The clinical testing costs a lot to run these trials which involve thousands and thousands of people volunteering to participate in research all over the world. But for that investment, we and other companies that are size. We hope if we're wildly successful. Our goal is to deliver to new medicines. Every or so six billion five or six billion dollars in two medicines out. So that's that's what it costs. Of course. It's it's also time delimited. So we it the money might be spent many many years before you have the medicines. So you also have to think about the idea that a dollar ten years ago is much more valuable than a dollar today. So that's that's the business. We're so we have to make careful decisions because failures in drug development, particularly in late drug development are extremely expensive. Which means we have less money for the next project. So we we spend a lot of money and time. Trying to understand biology of disease. So one way of doing that. It's genetics and understanding. Okay. People with a change in certain gene, might be more predisposed to to certain disease. That's an important clue. Yep. We'll also do things like systems biology, which will be study specimens from patients with the disease. So maybe we're studying at patient with Krones or also have colitis inflammatory bowel disease and take a little biopsy from their intestine in look at all of the things that are dysregulates. Okay. All of these things. It's like traffic is flowing in different direction in this city. And how can we reverse the flow of traffic? So instead of understanding disease is a single abnormality. It's a system pattern of things look for the the nodes that can reverse from from diseased to healthy tissue. So that's another way that we approach thing. And then we're careful observers of clinical data as we test our molecules in in patients, we always learn and see what's impacted and and how he co an a new direction. From there. How do you decide whether biologic is the answer versus small molecule versus something else? So biologics mostly antibodies. These are really big the great opportunity is that because we can kind of use a biologic process to make them the specificity is exquisitely high. So what that means is that if you have a a protein target, and we develop an antibody to it the antibody most likely will buy jest that protein target and nothing else. It's very very clean. The downside is because these are big they don't get inside of cells. So they can only hit targets that are on the outside. So we say see something on the cell surface. That's a very good target for antibody. But most of the action most of the proteins in yourself on the inside and for those we can't use biologic. So we focus on small molecules. So even when we go to small because I mean, given that there are so many cells and then so many molecules in so many says. How's it possible that we'd give a drug it can affect enough molecules all over the body that it works? Yeah. That's it is somewhat magical to think about this. Right. And one of the ways that this happens is is it's driven by very high affinity. So we kinda talk about although this analogy doesn't work perfectly. We talk about a lock in a key that that this is a key that fits a particular lock. But now, you have to imagine a room full of doors, right, and the and one locked that sort of floating around, and it's literally just floating around being bounced around by Iran enforces that eventually fits into lock and turns it so when it fits better stick there and stick really tightly. So that it doesn't have to find it again. Because most of the time it's not gonna find. It's it's lock now. I mean when you get down to fill level, amazes me any drug works at all. Like, I mean, just how does it get to all the sediment all the molecules even people have to take the take the medicine for to work and often? That's why you have to take every day with to keep the blood levels such. Certain concentration of this small. So it can find all of its its targets. The problem isn't often that the target is too rare. It's actually the other way round if the target is too frequent if there's lots and lots of that keyhole with that particular lock then you're going to need a lot more keys, and then you start overwhelming the system with that Zoe. I think about that as well. So your job today is I would say, I mean, you tell me if I'm wrong. I'd imagine much more overseeing a lot of research going on. So what do you do now at lily? We work across a couple different therapeutic areas. Of course, diabetes is our our longest standing and largest therapeutic area. Diabetes includes the complications of diabetes, heart disease, and kidney disease, and liver disease, called Nash in altogether. Of course, that's still the biggest killer in society, heart disease, and and then complications of diabetes important 'cause of Avila's. So that's one area on college. All the different cancers is another area that we work in immunology, which is disease is where your own immune system attacks, your body for various reasons and causes disease like psoriasis rheumatoid arthritis inflammatory bowel disease that I mentioned before these are all examples of immune diseases, and then in our science we continue to work under general diseases like Alzheimer's disease, Parkinson's disease as well as the area of pain. In fact, pain is the number one reason people go see the doctor something doesn't feel right? And it hurts and so we work in headache like migraine recently launched a drug for migraine as well as chronic pain, like back pain and osteoarthritis pain. It's an area that pharma didn't pay much attention to a for many years, and then recently has become much much more important organized by diseases organised by symptom is organized by the types of drugs. Get developed. Here's where the biologic so organized, you can imagine a matrix or grid and across the top you could write the different disease areas, and then those could be the columns, and then the rose could be that therapeutic modality. And so we'll have scientists who are focused on a particular technology and other scientists who are focused on a particular pathway of biology or particular disease, and so perhaps the person working on psoriasis who's really interested in the biologists rice in particular one pathway will then find a person who's really good at making biologics because they'll think oh, we need a biologic for this target. And then that starts to form a team around a particular target. So you need all kinds of expertise, and I greatly simplified it to say, they it's just those those two, but people I mean, you might have the examiner would like how many people are are working in labs. Yeah. Well, we have over six thousand people working in research and development at at Lillian on all my different teams. And of course on any individual project is much smaller. But I guess I'm trying to think like how much how many people in labs trying to develop each we talked about. There's Kim the two us. I think it was Doug drug development. And then drug discovery discovery. Okay. So how many how get to buy? Yes. I don't I don't think I have the exact numbers for discovery and development, but it's probably around four fifths of our resources are in drug development. So few said okay in a given year if we spend about five billion dollars three and a half to four of it is is going to be on on drug development and one or one to two will be on on drugs. Isn't that blows me way? Because it feels like we should be able to do that more efficiently. Lake. There's just gonna be a better way to do the testing because it would seem that the the hard part. Maybe I'm just naive. Again, would be the come up with the actual drug, and then there should be some kind of machine not I mean less physical machine, but some kind of organizational machine to to do the test. I agree with you drug drug development seems more straightforward. And yet it's such a major investment in in time in money. We can certainly get better than there's lots of ideas and lots of investment to try and make things better. But right now clinical trial starts with going out and finding hundreds of investigators who are interested in particular research project, explaining the protocol to them in getting all the ethical could sense to to start the research. And then they go out start looking for patients and they start with zero. And then they asked him onto you want to participate this trial on and so forth. So we spend a half the time in drug development, something like that just looking for patients to participate in research. So that's a major focus. How can we start a clinical trial with a list of people who already to consent wanna participate because they're known? They're out there. If you start an Alzheimer's trial. Of course, there's so many people who have symptoms of Alzheimer's would love to respect in research. Why do we start? Why can't we start with a list of those people clearly lily does amount of partnering with academic institution. I mean all across the table lilies. In indianapolis. We're sitting here in Indianapolis. I work at Indianapolis. I use school of medicine. It's an Indianapolis. So this is I mean, I see connections all the time. Do most of those happen on the discovery phase or most of those connections on the development phasers of both. It's both. I don't think we we could proceed in in drug development without collaborations with academic institutions at all because that's where many patients are seen in academic hospitals. And. Academic institutions have a long history of of doing clinical research on the discovery side. There's certain things that academic is to Sion's are more focused on certain things that pharmaceutical companies are more focused on. So for example, the idea of how do we identify a new target and understand its biology a lot of that happens in academia, some of it happens in pharma, the question of how to make a drug that hits that target and changes its activity that mostly happens in pharma, sometimes a little bit in in academia. So we have collaborations with academic institutions around the world, including a few here in Indiana. But it's the partnership. I think that that creates great ideas. So besides small we mentioned small molecules, we mentioned biologics. Is there anything else that's new and big the trick sided about. Yes, there there is there are new modalities of making drugs. Most of the drugs nearly all the medicines. That are valid. They say are either small molecule or biologic. Genuine antibody protein or peptide? But now for the first time, we have a new ways of of making medicines that actually involve using DNA and Arnie, particularly which are the genetic material that ourselves us, and we're particularly interested now in our in a based therapeutics and probably most people know that DNA is the genetic code, and it sits in the nucleus of the cell and termines the the fate of the cell, but all of the action happens in the site applause plaza in the main body of of the cell. That's where the the proteins are made and function. So how does the the cell get the signal out of the nucleus and tell the cell what to do it uses a short piece of nucleic acid called Aren a a particular kind of Arne called messenger Arna because a carries? The message from the from the nuclear DNA to this applies in and now we we've learned how to turn. Off and in some cases, turn on particular messages. And then change what the cell is doing so turn on and turn off gene transcription in an ultimately or translation in some cases in an alternate -ly impact the cell. So that's exciting in opens up whole new classes of things that might formerly had been undrivable. Right. That we can now impact humane example, like what what something that would be been drug -able than I think might have some promise. Yes. So. There's different. Challenges to this technology. So of course, there there's vantage I just talked about which is now you can turn on on off any particular genes. One of the challenges is directing it to the right tissue. So a lot of times these for various reasons get directed to organs like the liver, and so you can turn on and off genes in the liver, but many diseases are outside. So we're we're trying to work on getting it outside of the liver. But initially you've seen we've seen a lot of progress on some some of the rare genetic diseases where you know, it's a particular gene, that's gone awry, and might only be one in one hundred thousand or one in a million people who have this gene that's gone awry, but they've got a mutation. And now you can specifically turn it on her or turn it off. We're trying to apply that same idea to to larger diseases because we're we're focused on on helping as many people as possible. But diseases like a cardiovascular disease in particular disease, deliver called Nash are important targets that that we're working on with this technology. We're also interested though in in how to get this into the brain. And there there are diseases like Alzheimer's Parkinson's where we know that their particular genes that get turned on that are mutated that can cause the disease in in some small groups patients in greater population. Those same gene seemed to be important disease. If we could just turn them off. And so that's what we're trying to do in in diseases like Alzheimer's Parkinson's. And and these are things that we otherwise wouldn't be able to get to the biologic or small molecules. So that's why we're using our technologies. So a lot of promise it's still very early. There's there's just a handful of examples of our drugs now that have been approved by the FDA and other related technologies, actually modifying the DNA, and that's called gene therapy. And you can put a new. Gene in or you can perhaps all of this hasn't yet been there are no drugs like this yet. But you could perhaps modify a gene change a gene in a person from from a bad one to two good one if you know the mutation. So that's an exciting new area of research is well, well, this has been fascinating independence to do. I have about a million more questions. And there's a lot more. I could ask. So unfortunately, seems to happen. Almost every episode. I'd love to have you back at the time the future, we could talk more about this because there's just tons of other questions about hotels, but thank you so much for being on the show. It's been it's been absolutely fascinating. Thank you are. It's been fun.