Patrick Short  0:02  
Hi everyone, and welcome to the genetics Podcast. I'm really excited to be here today with Lawrence Reed who's the CEO of decibel therapeutics, which  is a gene therapy company focused on treating congenital monogenic hearing loss and regenerating inner ear hair cells for the treatment of hearing and balance disorders. I was really excited to speak with Lawrence for two reasons. First, Decibel's, working on a really important and very underserved set of disorders. And I think taking a really exciting approach combining single cell sequencing and gene therapy, the two of which have been obviously very big topics in the last five to 10 years. And second, Lawrence is just himself had a tremendous career prior to Decibel including time and Millennium pharma now part of to Qaeda al nyalam, warp drive bio and relatively recently, as well as an entrepreneur in residence at Third Rock ventures. So I'm going to talk to Lawrence about Decibel but also about his career more generally. So with that long intro, Lawrence, thanks so much for coming on. Excited to be here with you.

Laurence Reid  0:55  
Yeah. Good morning, Patrick. I'm looking forward to the conversation. Thanks for having me. And thanks for your interest in Decibel.

Patrick Short  1:00  
My pleasure. I'd love to actually just start by going back to when you first heard about Decibel therapeutics, what peaked your interest and got you excited about the company in the first place? Yeah,

Laurence Reid  1:10  
it's a question. I never actually had any, I suppose I was fortunate, I hadn't had much personal exposure to the challenges of hearing loss. I haven't had family or close friends who would live through some of these challenges. So it's been a it's been a new adventure for me at this stage of my career, which has been incredibly educational and inspiring as well, which should you know, more more importantly, before we get too far into this, I'm going to do a little bit of a wet blanket on you and remind your listeners that I'm the CEO of a public company, and anything I say about the future success of the company or, or any of our products, which I'd love to talk about. But they all involve significant risk. And they all have a few years to go to get to market. And so I am obligated to give you that warning up front. But otherwise, I will try and do a full picture of our company. And your question. Sorry, you asked a great question. So I heard about decibel, well known about decibel, actually since day one. So that decibel evaporate day minus 720. Decibel, got formed in late 2016. And the company was actually run by Steve Holtzman was the first CEO of Decibel. And if somebody I worked with many years ago, and I've known for a long time, so I would hear about decibel, and the excitement of trying to find novel therapies for the ear. Through Steve. I'd heard about it a little bit before that, you know, Third Rock, and maybe we'll talk about Third Rock later on. But Third Rock likes to incubate these ideas as you know, embryonic companies, and they do an incredible job of that. And so that's what had been worked on for a while before, people really got the impetus to be ready to pull the trigger and invest and really believe that molecular innovation is coming to the inner ear, which it clearly is. And then in terms of actually ending up being an employee at the end of 2019, Steve decided he was going to retire, I was actually going back through a phase of my career of working again with Third Rock and contemplating spending time there as an executive in residence, and decibel, started looking for a new CEO. So I knew about it through Steve, I knew about it through third rock, but really knew nothing about the field as soon as I learned about it, and the opportunities to make new medicines in an innovative field and the opportunities to really changed the lives of people with particularly severe forms of hearing loss or severe forms of Balance Disorder, new completely new field to me, and actually a very new field, really for the industry in terms of therapeutics. And I was incredibly excited by that. And that that remains absolutely the case two and a half years later. So love to tell me more about that.

Patrick Short  3:38  
Yeah, within this category of diseases involving the inner ear, maybe you can just introduce us how many diseases are there? What are the common ones? How many rare ones are there? And what is the Where do you all focus within that relatively broad?

Laurence Reid  3:52  
Yeah. It's a great question. So let me sort of start at the highest level. And, and also just, you know, put our finger on a paradox right out of the gate. So the paradox is that, you know, hearing loss is a massive, global unmet need. And there are literally hundreds of millions of people around the world who are afflicted by some form of hearing loss. And there's a huge range of causes and aetiology. And I'll give you a sort of a landscape of that. And there are no therapies for hearing loss. And obviously, that's our excitement is to get into the field and try and bring new pharmaceutical innovation to the field. There are a number of assistive devices, hearing aids, of course, most commonly, and we can talk about hearing aids and then and then sort of the next level of technology beyond that is really a device called a cochlear implant, which is used in people with very severe forms of hearing loss, which in simplistic terms is a microphone that gets tapped literally directly into your central nervous system by a device that's embedded in your inner ear and both increasingly are in a remarkable pieces. have hardware cochlear implant been around sort of 20 or 30 years, you know, and the back is that, you know, they're not disease modifying, and so they are not able to provide, you know, 24/7 hearing. But almost more importantly, they can't provide the quality of hearing that you and I were lucky enough to be born with it. And where that matters most is in is in a in a complex environment. So the easiest examples, and I'll go back and talk about the whole landscape, the uses examples, actually, if you think about a child in a classroom, or an older person, in a multi person, social context, those are environments where the sound is complex, there are multiple people contributing and one's ability with limited hearing to really digest all that information and participate in that social process and benefit from the cognitive impact. And the cognitive development or the cognitive maintenance impacts of that is really, it's really undermined if you don't have a, you know, full set of physiological hearing capabilities. So I think that's, that's the important bit, but let me go back to your landscape question, which is a really good one. So amongst that massive landscape, little bit of biology, and then we can talk more about about biology later on sound is transduced, into your ear by what are called hair cells. And these are cells that are able to detect a mechanical signal, which is a sound wave, and transduce that into your brain as the concept of what of what we think of a sound and those hair cells, everybody loses them approximately linearly over the course of your life. So we all get to a stage, late middle age going on until later in life, where you start to hit thresholds where our hearing with respect to the cochlea, or our balance with respect to the vestibule, start to lose the acuity that they have early in life. So we're all gonna start to hit those thresholds. Right. And, and that, in simple terms, is the common aetiology of why the numbers are so massive. And then on top of that, there are various insults that can make that a much more acute or severe problem earlier in life. And the best examples of that are going up one example really is noise. And that people who are subjected either to severe acute noise, veterans, people in the military being the most obvious example, or just acute noise, high and high noise levels over a prolonged period of time, construction workers is another very, you know, fairly common source that could also drive the destruction of your of your hair cells or the impairment of their function. So that contributes, that drive you sort of down that degradation process more quickly. So suddenly, more regular middle aged are starting to be to be affected that or young men coming out of the military who have been exposed to, you know, a particular type of event that can be highly, highly damaging, you know, hearing loss, and it challenges, big problems to the veteran community. And then other examples of certain kinds of pharmaceuticals are also very good aminoglycoside antibiotics, certain types of chemotherapy, or one of which were involved in working on actually, in other words, on the ototoxicity, could also kill ourselves and have a very acute impact on your hearing capability. And then back to you know, much earlier in life and where we're spending a lot of our time now, there are many genetic forms of hearing loss. And as a slice of the multi 100 million person pie. Genetics is a small piece, but many genetic forms are severe, we work on a certain condition with with very profound hearing loss, you know, a congenital basis, and which is, which is incredibly important from a child's development. So there's an overall backdrop of loss of hair cells. And then there are either acute, or prolonged or genetic impacts that that can override or exacerbate or accelerate that in terms of different stages of life and more acute outcomes that are that a branch.

Patrick Short  9:09  
That's perfect. And it seems like you all have both a genetic focus, but but you also have a real understanding of the biology of the inner ear, right? And that's why you can address each of those different categories rather than just one specific genetic form, for example, right. Tell me a little bit about that, that platform and understanding of the inner ear biology.

Laurence Reid  9:28  
Thank you. That's a that's a great leading question. So it decibel what we think we've really brought together I would say is, is three components, two of which are technological, and one of which is really human in terms of building the platform that we're using to to develop novel therapies that focus on the hair cells in your inner ear. So the three components that come together are really our modern single cell genomics based platform and the bioinformatics analyses that go with that in terms of really a complete molecular characterization of each of the critical cell types of the interior. Secondly, out of that a technological ability to turn that into a pipeline of what we refer to as precision gene therapies. And by that we mean the ability for a fraud gene therapies to include molecular controls, such that we impose self selective expression on the trans genes in our, in our gene therapies, which we think is incredibly important in terms of delivering a gene as closely as possible to the physiological environment, either in which nature intended it to work, or if it's a regenerative medicine, we want to drive that effect in a very self selective manner. And we drill down a little bit on that. And then the third piece, which is broad, but is really critical, and was certainly a major factor for me. And getting excited about decibel is really a set of of expertise in corporate biology of the area broadly defined. So my colleagues have, I would say, exquisite understanding of the cell and molecular biology of the cells of the interior, we also have fantastic experience in thinking about the patient populations whose conditions are driven by pathology in the inner ear. And then the third piece of that actually, skills that have been acquired over the last few years are really how do we access the area? And how do we deliver safely and effectively medicines, whether small molecules or gene therapies to the area, there are huge advantages to the to working in the area that I think are under recognised and why I think Gene therapy is going to be such a powerful modality has the potential to be such a powerful modality for the inner ear, but you need to access it, it's this tiny little cavity and it's enclosed in bone. And so that's a chat, you've got to get that I think the gene therapy, if you know how to get it, there can be an incredible technology for conditions of the inner ear.

Patrick Short  11:47  
This was this was actually exactly one of the questions I wanted to ask. And it will betray my lack of understanding the anatomy of the ear. Because I've had past guests in the podcast working many of them in gene therapies and brain Yeah, other hard to reach organs. And the challenge there is always always twofold. You've got to make the medicine that works. But you've got to deliver it isn't often that the delivery is the big challenge. My naive assumption was that delivery to the ear would be more straightforward. But like I said, it betrays my lack of understanding that your anatomy, maybe you can explain Yeah, explain a little bit more about how that works and how you would get a gene therapy to the inner ear. Yeah,

Laurence Reid  12:22  
I'd love to. So we really are very excited, as I said about the potential of the inner ear for gene therapy. And I think it's a really exciting alignment of a technology and an organ, and a significant set of unmet needs of the type that only comes along, you know, from time to time, and maybe at the end, we'll talk more about where some of these technologies go. So the area has, it has analogies to AI, which of course has been one of the forums in which there have been some successes with gene therapy in recent years. The inner ear is a tiny, enclosed compartment. And the bad news is it's enclosed in bone. And so you have to get there. The good news when you get there is it's 100 microliters in volume plus or minus and the treating cell populations are literally 1000s of cells as opposed orders of magnitude more so that so the advantages of that which which are which are very real, A, the man of dose and the amount of drug that you're deploying is really tiny, between about three to four orders of magnitude less drug that people are talking about for systemic gene therapy trying to, you know, address the liver or the muscle. So that's fantastic. From a manufacturing perspective, both the simplicity of manufacturing cost of manufacturing. Secondly, the fact that the compartment is enclosed means that very little not zero, but very little of the drug is ever is ever distributed into the systemic circulation. And so we believe that that there's a decent chance but over time, that's going to give us tolerability advantages, combination of the magnitude of the dose and then its enclosed nature relative to systemic exposure is going to give us advantages in terms of you know, ultimate tolerability by by the systems outside the year. And then the third is you really get really get to the livery. And so, the when you access the inner area, that the beauty of it is you can then deliver the the gene therapy directly into the sub organ is that you know, that one is trying to that contain 1001 is trying to address so it's it has a real advantage of local delivery, we access it actually, we've spent a lot of time working and thinking on this we access a decibel our strategy is to access the area by a surgical incision. That is the same basic incision that is used by the NT surgeons when they embed a cochlear implant in the area. And what we like about that is it's a surgery that's done on a daily basis throughout the development And it involves an incision through the mastoid bone, which is right behind the flap of your ear. And we can go through that with existing technologies with catheters and a 510 K approved technologies to deliver the drug effectively directly into the cell into the or the sub organ and hit the cell types that we're looking to hit. And then the final advantage is that the cells that we're trying to hit the hair cells or the sport cells, these are post mitotic cells, they're not dividing, which gives us ultimately hope that we're able to have the kind of durable effect that one wants from gene therapies. So it's a complex set of drivers and variables that are going into how do we get this exquisite technology from a molecular biology perspective into the right place. And, you know, we think the year is a very, you know, very exciting opportunity for gene therapy, we really see the year now as one of the Vanguard's of the gene therapy field. So of course, that we've still got a way to go in terms of proving that the various pieces that I just articulated, that we can join them up in clinical studies, which we'll get to in the next few years. I'm incredibly excited to do that.

Patrick Short  16:09  
Yeah, you anticipate my next question is, well, what does it looks like from here, obviously, this disclaimers, and it's speaking broadly, but what is the path to ultimately getting this to patients and start to help these young children and, and other people that could really benefit from this from here.

Laurence Reid  16:25  
So so we're decibel is today is we're hoping to fight off first ind or CTA in Europe for a gene therapy for a rare, profound congenital hearing loss, monogenic hearing loss this year, this calendar year. And so over the last couple of years, we've been involved in regulatory interactions, learning about how FDA and the Europe the various European authorities think about gene therapy applied to a new organ that was one gene therapy trial in the year a few years ago, led by the team at Novartis and which wasn't successful was very educational in terms of understanding particularly delivery routes to the IR. Biologically, the target that they chose to go after. Now doesn't look like perhaps the most informed initial choice, but that's with some hindsight, several years later, but it was still, you know, very valuable for the field, although it was not a, you know, a medically valid product in the foreseeable future. And the next generation that is coming through Decibel, and you know, and others, including our friends that are cu us, is that there are going to be gene therapies that are really focused on monogenic forms of congenital hearing loss, where one is really using gene therapy to complement a gene that is that is defective because of mutations that you inherited from your parents. And so it's the most simple form of gene therapy, I think, in the sense of, you've got these genetic mutations, you put back a wild type gene to actually it's as simple as it gets. There are there are many complications and risks that we will all be working through in terms of looking to try and overcome those risks that haven't work in human being

Patrick Short  18:05  
how many roughly rare, monogenic diseases are there that that affect the inner ear that we know of? Is it single digits 10s Hundreds,

Laurence Reid  18:15  
it's a lot. So the estimate is that there are about 100 different forms, genetic forms, excuse me, or simple genetic form monogenic forms of hearing loss, some of them are syndromic, for example, Asha syndrome, some of these conditions have impact on hearing, and balance, and then often have an optical component as well. And then there are others that appear to be pure forms of genetic hearing loss. And yet, within there's about 100 or so some of them are exceptionally rare. And we work on three that we've talked about publicly that aduna mutations in genes called Oda Ferlin, GGB, two and stereo selon, GDB, two and stereo cylinder, two of the more common forms of genetic hearing loss over the phone is rare genetic form of what's known as an auditory neuropathy, where you lose signalling to the brain because of a calcium sensor, you know, in the hair cells. And, and so there, there are different types of genetics and those genes then have odour fallen seems to have a somewhat homogeneous impact on children who are born lacking that gene GTB, two as a more complex distribution of genotype phenotype relationships, and stereo Asselin. And various in quite large patient population but a more moderate form of hearing loss, which raises interesting questions about gene therapy as as a product for those children. So there's a landscape there are different areas where where the first we think the first product candidates are going to get developed. And, you know, in terms of picking amongst them, the way we think about it, obviously, when it's trying to, you know, influence and try and change lives for as as many people as possible, but also there are of that 90 to 100. There are some were children who are born with a profound lack of hearing the impact is probably going on, you know, in utero and But he hasn't developed properly. And in terms of postnatal gene therapy, it may be that those are not accessible to us, you know, immediate future. So we try and focus on ones where there's a decent patient, a decent sized patient population that we can imagine, you know, running a trial and having a, you know, ultimately a viable product that with a significant number of lives to be influenced, but also that our understanding of the biology of the area, despite the genetic appears to be functional, such that if one then returns the gene that is mutant from parents, that you actually think you've got a, you know, reasonable probability of success that the child is going to emerge with, with a more normal form of a form of hearing. And so there, you have to think very carefully about targets from that perspective, Vodafone, and where we and others who've chosen to start seems to really tick that criteria. And it would appear from both human studies and animal studies of genetic models that the ear is functionally intact, except it lacks this one specific gene that functions in the hair cells of the inner ear. And we and others have done extensive rodent models studies where we could rescue the phenotype in a pretty convincing way in an animal model, and actually achieve that quite a long time after the birth of the animal, which gives us hope that therefore we're going to do that, perhaps over a range of ages of children. So it's a lot of variability and a lot of thought that goes into Okay, where are we going to start from a clinical and drug development perspective?

Patrick Short  21:35  
Yeah, I think that's such an important point, I first ran into this concept of a kind of therapeutic window, I did my PhD in rare, rare genetic disease that cause intellectual disabilities. And it's one of the central questions in that field as well, if you have a child who's three years old, four years old, and were you able to, to deliver a gene therapy or other kind of therapy is it actually still possible to make some, you know, some corrections or improvements. And I think the same work is going on there right now. And in some diseases, that seems to be actually the therapeutic window is quite large, where you could treat relatively several years after birth. But in other cases, it seems that for whatever reason, the damage may may be done an irreversible or seemingly irreversible. So it's interesting to see the similar parallel, where some of them may be just seemed like you say, simple replacements. And when you get the gene back, things slip back on. But in other cases, there may be structural damage, or something else that happens.

Laurence Reid  22:33  
That's exactly right. The other thing that is just the back sort of the bigger picture of the lives of these human beings, and that, to me, was just so compelling as I started to learn about the field. So you know, a child born with biallelic, mutations and out of Ferlin, is born profoundly deaf. And from a medical perspective, we view that as what's what's referred to as a neurodevelopmental emergency. And the way to think about that is that a child, a lot of our linguistic skills and basics of our language. And if you think about them, language, and early in life is what drives all of your social interactions with your parents, with your classmates, with your teachers, it's an incredibly important input into your cognitive development early in life. And those linguistic skills are being acquired during the first sort of two to three years of life. And often you made this point, often, we do a great job very early. So in lots of the developed world, a kid is taken from the delivery room and has a very simple hearing test performed on their ears within 48 hours of being born. So we do we do really well early. And then after that, it gets much more challenging our ability to follow up and pass aetiology if there's a problem is very ragged, very heterogeneous, different parts of the world, different parts of even within the US or different parts of Europe, different cities in the US a more or less good doing that. And, you know, and that's the emergency, right? You, you've got this sort of three year window, with a cochlear implant, they put a cochlear implant increasingly into a child's ear during that first year of life. It used to be sort of more like one to two years, but people are doing that earlier and earlier. And it'll eventually be the same if the gene therapy start to work, same kind of thing that you'd really like to get into that that year and restore the signalling really as early in life as as possible. And really try and contribute to those early formative years. You think about babies acquiring those social interactions and those early linguistic skills if you're, if one remembers once kids learning starting to learn language, a year a year plus, right, it's just an incredibly important part of our human development. And I think if we if we were that development doesn't happen in its most full form, the implications of that command run for many years whether they are literally today Hearing and development, intellectual and cognitive development, but also some of the emotional implications of that come back for a very significant period of time beyond that,

Patrick Short  25:08  
what is the diagnostic pathway look like for some of these patients genetic testing accessible? Or it depends on on where I'm curious how

Laurence Reid  25:18  
it's very mixed, it depends a lot on where. So in an ideal world, if you've got a child who was diagnosed with a profound form of hearing loss, or a less than average form of hearing loss, you know, the follow up in terms of beginning to dissect what the problem is, you know, we have the technologies to sort of begin to break it apart just based on physiological readouts. And then, you know, from our perspective, increasingly, we want those children to be, you know, to reflect on a genetic diagnostic part, and access to genetic to drill, genetic testing for differentiation of different, you know, molecular etiologies of hearing loss. As I said, it's pretty ragged. So I'm talking to you from Massachusetts, there are a couple of incredible hearing based oriented institutions, and our ability locally to get to the most sophisticated form of diagnosis, including genetic is pretty good. But that process, across even the USA, very heterogeneous, and incredibly frustrated, you talk to parents of families with work through this, that our ability to progress a child through, okay, you know, even picking it up, it is not picked up at birth, picking it up early in life, our sensitivity to detecting that your child might not have a full, you know, set of hearing skills is pretty crude. It's often, you know, Nanny at a birthday party notices that the balloon got popped by and your kid's head and you know, he or she just ignored it, right? It's sort of it's that kind of stochastic observation that people pick up. Okay, this isn't, this isn't quite on a on a on a usual trajectory here. And then the ability to march that child through what happens and the sophistication of is there anything that can be done about it? And how do we dig into that is poor and heterogeneous? And it's very frustrating for parents who are very, I think, emotionally challenging the parents to usher their children through that a they're worried about, okay, what are the implications of this for my child's longer term, you know, trajectories? And then B, what, if anything, can I do about it, and it's say, it's, we need to do better than now, because there's a paradox, often with genetics, right? The therapy drives the diagnosis, and the other two things go hand in hand. So part of what we're trying to do at a decibel, and other places, is drive education campaigns for people EMTs and audiologists, where people are thinking about genetics as an overt cause. And then we're investing in technologies, we have a collaboration that enables free care, free access, excuse me, to genetic testing for a very 200 or so genes that are believed to be candidates for for hearing loss. So root trying to drive education and the beginnings of you know, of a more robust process to get these kids sort of go through that type of access to real genetic diagnosis that hopefully will, you know, at least allow some of them to go on and get a genetic based therapy.

Patrick Short  28:09  
Do you need to think about your trial programme from a global basis from the outset? How rare are the diseases you're working in? You mentioned the EU, you've also got the US? Or how broad do you have to look in order to make this work?

Laurence Reid  28:25  
It's a great question. And in one sense, these these hearing conditions are like every other rare disease, and there's a sort of, there's an immediate problem of okay, how do I structure a scientific clinical trial with great scientific basis and get to some children and begin to validate that you actually got a scientific path? And then longer term? How do you get to children all over the world and try and give them access to the capability as if and as you start to see positive results, we have a fantastic collaboration with a team in Madrid, but the Romani Kahal Institute, and the team there has built what we think is the largest database of people to do throughout Spain and Portugal who have hearing loss attributable to mutations in order Ferlin. And they have been doing various natural history studies, some of which we've, we've helped collaborate with and work with them on and both retrospective and prospective gets to questions like what's the potential for intervention at different ages to be successful? Without using that as a it's been an intellectual basis for how do we think about the patient population? Firstly, from a proof of concept perspective, right? How do we find a cohort of very young children with the right type of molecular diagnosis and the best characteristics to begin to validate the hypothesis? And so as I say, for scientific reasons, there have been these efforts in certain European countries. So we, my colleagues have invested a lot of time and effort and relationship building in those and then of course, the US, you know, our trial, you know, when it gets going public information. We've talked about finding an IND and or a CTA. Ideally, it'll be a transatlantic trial with with access to patients in the US, and in perhaps one or two European countries. And so as you as you understand the challenge in the short term is find a cohort of patients that are well characterise good diagnosis where we can prove principle, and then you really start thinking about, Okay, what's the broader international problem, global problem, and we know we have information that suggests that these these genetic bases, I mean, any any genetic cause of disease, one sees heterogeneity in different race groups across across the globe, but a lot of these hearing loss conditions appear to be brown, and people have completely different backgrounds and racism. So ultimately, you know, we're excited about trying to develop products on a broader basis. But the first focus is trials, you know, relatively small numbers of children that can really validate the hypothesis and really begin to say, yeah, we can have an impact or not, I mean, do that. In you know, in the right conditions.

Patrick Short  31:02  
I did want to come back to third rock ventures, you're wearing your your third rock ventures fleece, it sounds like decibel was incubated in Third Rock. And I just curious what makes that organisation so special and so great at launching so many incredible biotech successes, it you know, I could stand here and name them. But there, there are too many other websites name, but I'm curious from your perspective on what is it that, that they that makes them so special that they do so? Well?

Laurence Reid  31:29  
It's a great question. And they have a lot of biotechs talk about teams. And and the third rock team itself was an incredible set of combinations of investors and executives who came together to found Third Rock back in, I think it was 2007, if I remember correctly, and the blue who I've had the privilege to know, for sort of 20 or 30 years, many of you are involved in building Millennium pharmaceuticals. So I think it's, it starts with the thing, this is all public information, it starts with an outstanding team, right? The people who came together to start Third Rock, they believe that people who've been involved in building great companies that had skills that they were going to be able to reproduce, you know, to help, you know, start and nurture new companies. And you know, they have to, and then on top of that you need to overlay an investing savvy for which often is a question of, you know, is it the right time for this technology, and you know, what's a sensible investment strategy in terms of how much capital how quickly, for example, so started with a team of just people fans of the firm that they all manage all of who had operating experience and had a track record of building great companies themselves. Secondly, they have a, they have a model that is very patient. And so they their ideas are very much generated inside and with their cadres of advisors, and they take a problem, like hearing loss is it time for innovation in that field that can support the birth and growth of a new company, and they are willing to kick those ideas around for a year or two, if that's what it takes, I really believe that they've pressure tested the ideas, they've gotten to assemble a team and that they that it really is the time to make that first material investment of money together with great people into starting a company and they're willing to kick back ideas, they're willing to beat on ideas for four months, and then reject them or send them sort of back to the drawing board. That's all long, long, long before I was involved or even heard about it. I had a couple of friends who worked on it. And there were technologies that were maybe coming from sources or Big Pharma, and they worked on it for a while before they decided to pull the trigger on it. And you know, and here we are six years later, and some of the ideas they had, you know, have continued and some of them, you know, the dust along the way, this is not a perfect process, which is why I think their attitude is like, Okay, how do we really understand the problem and really bring people together and really define what we think the early plan should look like, before we invest that I think that other investment firms may pull the trigger on writing a check sooner. But that means that the company is then doing a lot of this sort of continuing to explore where the best opportunities are inside the company. It's just a it's a it's a different way of thinking about remodel the formative, the formative years,

Patrick Short  34:16  
you've spent your most your career it seems like working rare disease, precision medicine, one or the other, or both. I'm curious to close out here. How much of things changed over the course your career? And how optimistic are you now about the future, given all the changes that have happened compared to maybe when you when you started or when you were at Millennium as an example?

Laurence Reid  34:38  
Yeah, that's a great example. So I'm incredibly optimistic. I just think that our ability to use genomics and genetics just continues to move at amazing pace. I mean, obviously, editing is the theme do I say the theme as usual? That's not fair on the editing people who've been at this now for a little while, are clearly going to influence massively that the future of medicine No, you're Talking to me from Cambridge, England. I was a genetic student many years ago. So I've always been fascinated both with genetics as the basis of human disease. And and then what could that teach us about how to develop, you know, really innovative therapies millennium was formed along with other genomics companies in the 90s. And it was my first foray into biotech. And it was just intellectually, it was incredibly exciting to me, the notion that genetics could form the basis of a company to understand mechanism to drive therapeutics. And I think it's objective to say that there are a lot of ideas that were thrown around at Millennium in terms of genetics, driving therapies, and genetics, driving, dying, better diagnosis, that they were just ideas that were just ahead of that time. But at that point, that's pretentious, I think it's fair. And we always understood that a target like PCs, K nine could be an absolute Holy Grail, right, that you would find a gene that a loss of function gave a good benefit to, in terms of that lipid phenotype. And, you know, we would have killed to find a gene like that, and Millennium in the early 90s. And I think in terms of just the pieces that had to come together, we will wait too early. Right, it took us a while to figure that out, I would say in terms of you know, there was no genome sequenced at that stage, we didn't have the kind of databases of snips that were available, the work that had to go into phenotyping patient populations, we understood all that. And it just wasn't there. And so, you know, Millennium, eventually got to a really interesting outcome. And I think really drove a lot of this thinking, but, but it was kind of ahead of its time, which was incredibly was incredibly environment to be part of, but I look back on some of those ideas. Now, at occasion, I meet people who are building companies driven by genetics as a way to find targets, I'm like, can't we talked about that back in 1998. And I probably look like an old an old cynic. Right. But it's true. And try to think about your focus populations to really understand disease genes, and then molecular markers for better diagnostics. That's, that's taken a while, but it remains, we've just talked about it and hearing loss, it remains, I think, a massive basis of the future of the pharmaceutical industry. And, you know, I'm in the middle of gene therapy sector right now, it's been a rough year or two for the gene therapy sector. And for reasons that are that are real, and that are that can be intimidating. If one is in the wrong frame of mind, I have huge confidence that that we will keep bringing new technologies to bear on better ways to deliver genes more selectively to the right set of tissues and or edit genes. I just think there's an incredible cadre of technologies people momentum. And so I have huge optimism, which is just to expose a personal belief statement. But I think that the progress we've been making, you know, is is remarkable, but it's and then in the short term, it's easy to be sort of depressed by the challenges of the latest gene therapy trial trying to hit the liver and some of the problems that come in terms of sustainability or side effects. You know, these these, these new Rome's, they're not built in a day took the monoclonal guys, you know, from the idea of tagged antibodies back in, you know, the late 1970s, to where it became a routine part of care, these things or pharmaceutical development, these things take decades to develop sometimes. And so you have to be really, really targeted, which is actually brings me back to the calories I'm excited about Decibel is I think this local delivery opportunity is very interesting. So but yeah, I'm an optimist at heart, even at my slightly later stage of my career, and these technologies are going to continue to change medicine over the next 20 to 30 years in really profound ways.

Patrick Short  38:30  
That's great. I think that's a perfect note to end on. I just think it's tremendous that you're using your time and talents to work on such an important area of medicine, like you said, there's no therapy, that's that truly addresses the root cause there are interventions that can help but I just think it's a really important mission. So thanks for your time today and for all the amazing work that you and the team are doing. Thanks, Patrick. Appreciate the opportunity to be here any time and thanks everyone for listening. As always, please share the podcast with a friend if you liked it. And also you can leave a review on your favourite podcast player to help other people find us. Thanks for your time and we'll see you next time.