Jeff Karp, PhD - Towards Accelerated Medical Innovation

And uh it's my pleasure to introduce uh Doctor Jeff Karp um for our first grand rounds. Um, he is a professor of medicine at Brigham Women's Hospital, Harvard Medical School, principal faculty at the Harvard Stem Cell Institute, um, and, uh, he's been faculty at Harvard since 2009 after completing his PhD at the University of Toronto and postdoctoral fellowship at MIT with Doctor Robert Langer. Um, his work spans very broad areas. He'll, he'll, I'm sure talk about, um, including drug delivery, medical devices, stem cell, uh, technologies, and tissue adhesives. Several products. He's actually, the work, um, from his lab has, um, led to the formation of 6 different companies that raised over $100 million in funding, including, um, Skintifik, which is a higher, high-tech skincare, uh, company, Gecko Biomedical, Olivio Therapeutics, Frequency Therapeutics, molecular infusions, and Lansdowne Labs. Um, so, incredibly prolific, uh, uh, um, prolific, uh, researcher, translational researcher, um, and, uh, and also mentor. Um, he's, uh, mentored over 20 trainees who've gone on to secure faculty positions. Um, so, um, it's really my honor to, um, present Doctor Carp. Thank you. All right. Thank you so much for the nice introduction. Um, you know, it was always my childhood dream to be a doctor, um, but I applied and was rejected, and now I know why. I'm not a morning person. Um, so, uh, my institution requires that I disclose my conflicts of interest and as mentioned, uh, I've started a number of, of companies. I hold equity in the companies and I continue to, uh, to consult for them. So 11 late summer evening, uh, Doctor Del Ndo here, uh, contacted me and, um, described a challenge that he was facing in the operating room, namely septal defects. And he described how, um, often when he was, uh, suturing, uh, sometimes the, the tissue was just so fragile, it would tear, and that there had been, uh, devices that Had been developed for uh adults that have worked quite well, but the challenge is you can't simply downsize them because they're permanent materials, they don't degrade, and, uh, he explained how it would be unacceptable to have to come in for multiple revision procedures as the heart was growing with the child over time. And so, um, we started thinking about opportunities to develop a new tissue adhesive that potentially could work in this environment, uh, but we immediately knew that we were up against some significant challenges. Um, namely, getting a tissue adhesive to work inside a beating heart is probably the most challenging environment. In the human body, uh, given the multiple expansion contraction cycles, materials can easily, easily delaminate from surfaces, uh, under such conditions. Also, the sheer, constant shear against the surface, um, clearly it's very wet, lots of enzymes, cells, uh, very harsh conditions for, uh, for a tissue adhesive to work. Um, but we were up for the challenge, uh, and we kind of envisioned that what we might do is develop a patch that you'd put inside the beating heart, uh, would immediately attach and seal the hole, um, and then cells would migrate on top, form new tissue, the material would slowly degrade, and the patient would be left with their own tissue sealing that hole, which would then be able to hopefully grow with the patient. So we started advancing, uh, and, um, we quickly hit a wall, and it was very frustrating, um, difficult, uh, to, to know what to do. Um, but one of the things that we've been trying to do in my laboratory is to realize that in the lab, often it's difficult to come up with, um, Lots and lots of ideas. Most of the ideas that we come up with are fairly similar. And so we, we've been looking for ways to kind of go outside of the lab, um, and look at nature, uh, for inspiration. And it's really this, this idea, uh, that there's hundreds of millions of years of research and development that are happening all around us, and that evolution is truly the best problem solver. Uh, and I strongly believe that, you know, we are actually surrounded by solutions. Any creature that doesn't develop an approach to overcome its environment or whatever it's up against, um, will quickly become extinct. And so anything that's alive, um, has solved incredible number of challenges to be here today. And, um, and so what we often do is we'll look at nature, uh, to bring in new ideas that we wouldn't have otherwise thought of. And so in the case of uh the septal defects, we asked a simple question, which is which creatures exist within wet dynamic environments? And uh we kind of focused in on uh a couple of different creatures. One sandcastle worms that exist in the sea. Sometimes you'll see them sitting on a rock, and the waves are hitting them and they're not moving, uh, or if you'll see a, a snail, for example, on a leaf, and it's raining, and it's not moving, or sometimes, you know, it's walking along the ground, you see this kind of goo behind it. So these creatures have a couple of things in common, um, that became very relevant to us. One is they have viscous secretions, and so things that are viscous have natural, uh, uh, have inherent adhesive properties. So if I take, uh, honey, for example, and I put it here on the floor, and I try to remove it with a hose, it takes some time to wash away. Um, and then when we look at some of these viscous secretions, we realize they contain hydrophobic agents and things that are hydrophobic can repel water. So that gave us some, uh, some ideas, some insights that were very different from what we were thinking. Um, tissues tend to be very hydrophilic. This was telling us, well, maybe if we were to develop a hydrophobic adhesive, we'd be able to repel the blood away from the surface of the heart. If we put this tissue adhesive in. Um, and there was blood in between the, uh, material and the tissue, um, it would just attach to the, the blood cells and then it would fall off. So we needed this to intimately contact the, the tissue. Um, and then the thought was, with this viscosity, if we could make this viscous enough, then the clinician would be able to put it in place and, and then be able to kind of step back and make sure that it was in the right place before a final cure. And for the final cure, we develop a lot of light activatable materials in the lab, and so that's what we thought. There's been a lot of innovation in delivering light into, um, the body used to require massive boxes, and now you can, can do it with small, small pens. Um, so, We went ahead with this, uh, and about 2 or 3 years later, after constant iterations, we were able to overcome a lot of significant challenges, um, and actually meet all of our critical design criteria. So what I want to show you next is the most challenging experiment, or one of the most challenging experiments that we performed. And so, what you're gonna see here, um, so this is a, a rat, um, and we're using a, uh, dermal biopsy punch, uh, to make a hole in the heart, so pretty significant hole. We're gonna attempt to seal this, um, with a patch with glue, no sutures, no staples. So we have this purse string suture that's here, that's just, um, making sure the animal doesn't bleed out during the procedure. We're gonna remove that. Um, and we also had to develop a second material, which was a patch, which had to be biodegradable, elastic, and then also transparent because we're shining light through it. Uh, and then there's a thin layer of glue on the underside of this. So you can see we apply the light here, just in a proof of concept experiment, uh, for 5 seconds. Um, but this is one of the first animals we operated on, um, and something went horribly wrong, which was, um, we were not very prepared. Uh, we made the patch a little bit too small, it kind of slipped away. And so, while you see it attached, there's still this massive, um, hole that's here, so we had a leak. So we're freaking out, not really sure what to do next. Um, and someone's like, well, why don't we just try the glue? So we put it on a spatula and apply, and if you can see here, it's actually a little less red, it's repelling the blood away from the, uh, surface of the heart because it's viscous, it stays in place for another pulse of light, um, and we end up with a perfect seal. And we took these animals out 6 months, and they all did fine. So we're pretty excited about that, um, but we wanted to move one step closer to our intended application, which is, would this actually work inside a beating heart. And so, for this, uh, we moved to a pig model, um, and using Doctor Del Ndo's cardio port device, we attached our adhesive here on the end, made a small incision in the myocardium, places up against the septum, uh, uh, shine the light for about 1520 seconds, remove, sutured the myocardium. Um, and there, we looked at two separate pigs. And so when we look at the echo, you can see here, here's the patch in one, and here's the patch in two. We got 82 beats per minute. Um, so it attached, um, so we're excited about that. And then, uh, we came back at the 4-hour time point and added epinephrine to increase the, uh, the heart rate just to see if it would maintain attachment under those conditions. And so here you can see 165 beats per minute, and both patches, uh, remained attached. And then we um came back at the after 24 hours, um, so it's just a short term proof of concept experiment, uh, and the patch was still there. Here you can see a suture, which was part of the deployment mechanism. Um, but we were, uh, we're quite excited about this result, just this ability to, uh, adhere a patch inside a beating heart. Um, and even though it was a short period of time, um, this gave us, uh, gave us a lot of hope. And we've been able to, uh, demonstrate not only does this material, uh, can it be useful for sealing holes inside potentially a beating heart, um, but the glue alone, we showed, uh, we could seal the carotid artery of a pig, the aorta of a pig, um, could affixed to gut tissue and attached to, um, to many other tissues in the body. And I just want to pause here for one moment. Um, and highlight two individuals, uh, Nora Lang, who is a, a cardiac surgeon in, in Doctor Del Ndo's group, um, and Maria, um, who's a material scientist in my group, a PhD student from the MIT Portugal program. Um, and the two of them were the co-leads on this project and really, um, one of the major reasons why we were able to advance as far as we, we could. I think a really good example of this, you know, multidisciplinary, um, collaboration of a material scientist and a surgeon, um, working closely together. And so, you'll notice, um, with this procedure, while it was quite promising, we had to make a hole to seal a hole. Um, and so, what we did next is we teamed up with Connor Walsh at the Wies Institute and Ellen Roach, um, who was in his lab at the time, who's now a professor at, at MIT, um, to see if we could develop a device to deploy this via interventional procedure. And so I just wanna show you, um, how we, uh, were able to develop this device. See if the sound will work here. I don't know if the sound's gonna come through. Um, So I'll just talk. So, um, The idea was to be able to deploy a catheter into the beating heart and have the patch um inside the catheter. The patch is elastic, and so it's able to unfold. We place this through the hole and then uh deploy the patch here and have a balloon on this side, and then have an opposing balloon on the other side, which will allow us to get intimate contact. Um, and then what we do is we shine a light. Um, towards the end, this has a metallic coating on it, the balloon, which then reflects the light backwards through the transparent patch to activate the glue, which is contacting the tissue, and then we leave a tiny hole, um, within the patch. uh, which Doctor Denitos said should, should likely self-heal, and then, um, the tissue can then grow, uh, on top of this. So, we were able to, uh, to demonstrate that this, uh, could work in a couple of different, um, models in Doctor Del Ndo's lab. And, uh, and I think this, uh, you know, still a long way to go on this approach, um, because trying to get something to work inside a beating heart in a child, I think is a pretty, pretty high bar, uh, and so we have kept this specific project in the laboratory and trying to push it forward, but because these materials that we developed, uh, are so promising for a lot of other applications, uh, we started a company called Gekko Biomedical in 2013. And the company's, um, first product is a tissue sealant, um, that it received a regulatory approval for in Europe, uh, just last year for vascular reconstruction. Um, the company has, uh, has gone through and, and produced a GMP scale material now, um, and now they're moving towards a commercialization in Europe and then starting, uh, US, uh, FDA trial, uh, later this year or early next year. Um. And they continue to advance this for, for multiple applications. I think one of the um most exciting applications, at least in my mind, is being able to deploy this in minimally invasive uh procedures where it's difficult to tie knots in small spaces or hard to get, you know, staplers into those environments, where this glue, we could deploy it via a catheter and it doesn't really matter whether it contacts blood or other fluids en route to its um destination, it will still, still work. And the mechanism of adhesion is not a reaction with the surface, it's actually infiltration of the glue into the tissue, um, and then when we shine the light, the light can penetrate, you know, 100 microns or so, and then cure that glue to a, to a final state. So it's really a mechanical interlocking. We think that this should make this glue, um, a fairly universal approach, uh, for, for soft tissues. And then, um, the company has uh now advanced this, uh, in multiple directions, um, and it's not just about the polymers, but it's also about the devices that are used to deploy. So here you can see spraying onto tissue, we can spray the glue, that at a blue dye. Here this is a vacuum device, um, where we can apply it underwater onto tissue and get intimate contact. And then here is, um, Uh, showing how we can deliver this during a, uh, in, in a minimally invasive manner as well. So there's multiple devices that the company has developed, um, to, uh, to deliver this glue to various places in the body. Some of you, um, whoever's been to the, uh, New England Aquarium will recognize this, um, this image, um, which is right at the, uh, the penguin exhibit. And yes, I did give a talk in the presence of penguins, um, which was not something that I thought was going to be as challenging as it was, um, but it was kind of a disaster because the, the penguins, um, I think they, you know, this is their home, right? And so I was coming into their home, and they, um, were, they just got incredibly noisy and rowdy, um, when I was speaking. Um, so I was concerned that no one would hear what I was saying, um, but, uh, Doctor Bill Rosenblatt, um, Luckily heard, uh, he was at the time chief of uh dentistry at Angel Memorial, it's the animal hospital here in Boston, and he said, you know, I think this glue that you're, you've developed could potentially be useful, um, for pets and in particular in dental, you know, craniofacial medicine. So we kept in touch, and then he contacted me maybe 2 or 3 months later and said, um, you know, I have this bulldog, uh, I, it's a 10-year-old bulldog, um, it's about to die, it's not eating. I pulled a tooth from its mouth, it left a massive, uh, oral nasal fistula. Um, it's infected. He said he's done 3 separate surgical procedures to pull a flap over it, um, but because there's so many forces in the bulldog's mouth, it just tears every time. Um, so he said, is, you know, is there any way that, um, what we could do is, um, deliver the glue, the glue alone, um, multiple layers to fill this hole, so we cure it, uh, a few times and then pull, uh, the flap over top, and then the idea would be that this cured material would take on some of the mechanical load, so take it away from the flap, and then the material would serve as a scaffold for cells to, to migrate and form new tissue, um, and then the material would, would degrade. Uh, so here's what the, uh, this oral nasal fistula looks like, and you can see it's, uh, it's filled with a lot of debris and, and, um, infected. And so, I mentioned this to, uh, Doctor Yuhan Lee, um, who's an instructor in my lab. Um, and I come into the lab the next day and I see this on the lab bench, which is kind of shocking because you don't usually see a cow head, um, you know, in a, in a laboratory. Um, but Johann had a great idea, which was we had never shown that this glue could attach to the oral mucosa, um, and we just wanted to make sure, you know, trying to think like what experiments could we perform to de-risk this. Um, and so here you can see he's applied the glue. He had just gotten this cow head, I think from a butcher, hopefully it was from a butcher in town. Um. But uh you see, he applied the glue here and then he's trying to take a spatula to remove it and it stuck really well. So that was really the, the one experiment we did um before moving to uh to this animal. And so, uh, Doctor Rosenblatt's team, they, uh, debred this, um, and then cut the tissue flap here. Uh, we cured multiple layers with 3 or 4 layers of the glue, um, here, and you can see it's a little shiny, maybe a little bit difficult to see, uh, but it's there. And then there's the tissue flap over top. And so we came back at the 3-week time point, um, and, uh, took a look, and this was a moment I'll, I'll probably never forget because Doctor Rosenblatt was almost crying. Um, and I kind of realized at that moment that, you know, this was a patient that he had been treating for over 10 years. He had a relationship with the family. He had done 3 separate surgical procedures with these tissue flaps, which had failed after 2 or 3 days every time. Um, and, uh, and this had appeared to have worked, and, um, And then we went out several months and it was, was, uh, was still working really well, um, so we're pretty excited. So just to show you, um, the key data that we have for this, um, this experiment. Um, I have, uh, this picture here. So this is the, the dog before the procedure, and you can see he's extremely unhappy with his, uh, with his oral nasal fistula here. So you can see the, the unhappy look. Um, and then this is the, uh, the after, wait for it. So we have a dramatic improvement. We're going from unhappy to extremely happy, ecstatic. Um, and this dog, um, its name was Poppy because the owner liked the Boston Red Sox. Um, and I, you know, Google everything, um, that I hear pretty much. And so I looked up Poppy and I found this. And I thought, hmm, maybe, yeah, now I know why he called the dog Poppy. Uh, and then the local news got, um, you know, wind of this story, um, and they didn't want to talk to Doctor Rosenblatt or I. They just put Poppy on this, um, operating table and just, you know, 3 separate television channels showed up to, to film him. Um, so this was, this was pretty interesting experience for me and, and some of the members of my lab because, you know, we'd always envisioned, um, you know, things that we were developing would hopefully go through clinical trials to help humans, but we never really thought that there'd be an opportunity to help pets, um, and in such a short Period of time. Um, and so I did grand rounds at Angel Memorial and keep in touch with some of the clinicians there, um, and it was amazing to me how, um, sort of seamless it was to, you know, have these technologies in, in my lab and be able to, to test them, to try them. Um, on, on pets. I thought we'd be up against a lot more barriers, but it went, um, super, super fast. Um, so we continue to interact with some of the, uh, clinicians at Angel Memorial and think about how some of the other technologies we're developing might help pets in a shorter period of time. So in addition to tissue adhesives, we've also been interested in tissue regeneration. In my lab, we do a lot of work with stem cells. Um, we primarily work with mesenchymal stem cells. Um, and, uh, in general, stem cell therapy involves taking cells out of the body, manipulating them, and then putting them back in the body. Um, and, um, several years ago, we started thinking, Um, you know, is there a way to reduce the complexity because the costs escalate, the challenges, manufacturing. I mean, there's just so many challenges when you have a living therapeutic compared to a, a small molecule or a protein drug, for example. And so, we thought, you know, is it possible to develop an approach where we could take small molecules and target stem cells and progenitor cells in the body, um, so we wouldn't have to remove the cells and manipulate them, we could just target them in situ and try to control them. So as a starting point, um, we just, you know, started looking at nature and there's lots of examples of, of tissue regeneration in nature. We thought, you know, it's important for us to have a deep understanding of, of, um, the regenerative processes that exist. And so we know that sharks can regenerate their teeth throughout life. We know, um, certain lizards, you can cut off their tail or a limb and they can completely regrow over and over again. Um, so we said, well, what's the most regenerative tissue in the human body? Um, and, you know, some may argue the liver cause you can, um, remove a large, um, part of the liver and it will completely regrow. Um, but we, uh, focused in on, uh, the lining of the intestine, which regenerates every 4 to 5 days throughout life. And um this is um really powered by these epithelial stem cells that exist in the base of the crypts, um, that are marked with a receptor called LGR5, um, which is uh uh interacts with the uh the WIN pathway. And so, these um stem cells are dividing throughout life, uh, you know, maybe once every 24 hours or so, and our life depends on it. They, um, uh, form all the cell types of the, uh, the epithelium. And so when we started this work, um, what we realized is that, um, there was no capability to grow these LGR 5 stem cells in, um, pure form. Um, you needed these cells to sit next to a panic cell. Um, the panic cell provides uh signals to maintain that stem cell in a stem cell state and to keep it dividing. Um, and if you take the panic cell away, then the stem cell differentiates, and that's actually how it works in this system, is that you have the panic cells that sit next here, next to the stem cells, and as they're dividing, you get more stem cells produced, which don't touch the panic cells, and then they start differentiating, uh, and they form the entire epithelium. So, the only way to culture these cells would be to have pana cells, um, um, touching the stem cells, which makes a really complicated, um, uh, cell culture model if you need, need co-cultures. And so, through understanding some of the signaling that the pana cells, um, how they interact with these LGR 5 stem cells, we started taking small molecules and asking if we could activate the same pathways. Um, and, uh, we looked at lots and lots of combinations, and eventually we found a combination that could do it. And so we were able to take, to isolate crypts that have, um, you know, small numbers of stem cells, very small numbers, maybe 1% of the total epithelium, um, the stem cell, the cells that are there are these stem cells, and then adding our small molecules, um, we were able to generate huge populations of highly enriched, um, LGR 5 stem cells. Um. And so we're pretty excited about this, and this has really unlocked a lot of um new opportunities for my laboratory, um, because the cells in the epithelium are terminally differentiated. So you have a lot of really important cell types that are there, like goblet cells that produce mucus for barrier function. Um, the panni cells which secrete antimicrobials, uh, to regulate gut microbiome, um, enteroendocrine cells which secrete incretins, um, so a lot of important cell types, and it's hard to work with these cells because they don't divide. So the only way to get them is to isolate fresh tissue and then isolate those. Cells, um, but now this capability has allowed us to generate lots and lots of stem cells, and then we worked out culture protocols for each of the major cell types of the epithelium. So now we have large populations of goblet cells and panta cells, and we've set up high throughput screens now to try to regulate that. So one project in my lab is actually we've been working with the Broad, um, and set up a 3D4 well, um, high throughput screen for panaces because, um, you know, there's great interest in regulating gut microbiome. Um, but the challenges there are, um, are many. One is, you know, how do you, how do you modulate that? You can deliver bacteria or you can kill bacteria in the gut. Um, but there's a, the new opportunity I think that might be emerging from this work is that we have a panic cell that secretes naturally antimicrobials, and so it's a natural way of regulating the gut microbiome, so it's a new axis. So, we have a, a 3D4 well plate with panaces that we're exploring as a new way of controlling the, um, the gut microbiome, um. And so, um, so we continue to kind of advance this in, in multiple directions, and this has applications for inflammatory bowel disease and some other diseases of the, the epithelium and, and, and others. Um, but we kind of step back and what we like to do in the lab, I feel like we often kind of gravitate towards incremental, um, research, um, and, uh, like to try to stop that and see if we can step back and say, OK, what's the biggest thing we can do next? What's, what's really gonna be the most impactful? And so, um, At the time, uh, a few years, uh, before, there had been, um, a paper by Albert Edggentown, um, who's at Mass Pioneer, who had found that the LGR-5, um, um, cells in the cochlea can actually are responsible for making hair cells. And so this became very interesting to us because hearing loss is a major societal problem that's actually getting worse and worse, um, and, uh, the World Health Organization. You know, says, uh, I mean, there's just a gazillion people who have, who have hearing loss. I think in the US it's, it's tens and tens of millions of people. It's estimated, you know, a billion people, um, are at risk. Um, and the problem is, is that, um, We're only born with 15,000 hair cells per ear, and they're in our, our inner ear, our cochlea, um, and these cells never regenerate throughout life. Um, so you're just, you're stuck with whatever you're born with, and, um, but we know when we look at, um, nature, so we look at birds and amphibians like frogs and toads, they actually are able to regenerate their hearing throughout life. So we know the biology is there, but in mammals, as soon as you're born, you stop the ability. To generate new hair cells. So here's what it looks like. You have in your inner ear, you have these three rows of outer hair cells, um, which are more of like an amplification system. Um, and then you have the inner hair cells here, a single row, which are more like the, um, detector of the, of the sound. And when you apply noise, um, you literally kill these cells. They, they die. And so we started um getting interested in thinking like, could the molecules that we developed to control the LGR 5 cells in the intestine be applied to the inner ear, um, and could this potentially, you know, advance as a new therapy for, for hearing loss. And so, what we did is, um, we went to the, uh, the inner ear, um, uh, Shaolet Yin, an instructor in my lab at the time, um, isolated the cochlea of mice, which is extremely challenging, you know, have some of the hardest bones in the body in the ear, um, and the cochlea of mice is extremely small. Um, so he was able to develop a protocol to isolate the cochlea. And I'll never forget, um, when he sent me the first image, I was in Montreal visiting my family. I'm Canadian, if you haven't figured that out yet. Um, but he sent me this image and, um, which is literally blown away because, um, previously, you know, it's possible to make maybe like a single hair cell in culture, just really, really low numbers. Um, but here, um, what, what, uh, Chalet had done. was take the molecules, add them to um the cells from the cochlea, we were able to proliferate the progenitors and then differentiate them into hair cells. And so, here you can see, they're called hair cells because of the stereocilia that are here, which move in response to sound, and then the cell converts that signal to an electrical signal that's sent through neurons to the, to the brain. And um we teamed up with Albert Edge at this stage cause he had all the assays um for this uh type of uh um these biological experiments, and every single assay that we looked at, um, showed that these were bona fide hair cells. They had all the machinery to sense and signal, um, it was all there, all the proteins and, and, and everything. So we're pretty excited about that. And so, um, we started this company called Frequency Therapeutics, uh, a few years ago. And, um, what we envision is, so a very simple procedure to inject into the middle ear. It's done, um, you know, all over the place for, um, for middle ear infections. Um, and so what we envision is uh taking a, uh, a needle, we have a material that we suspend our molecules in, we inject it into the middle ear, it sits up against the round window membrane, which is the entrance to the cochlea. Cochlear fluid-filled, so the molecules can diffuse across, um, and then the cochlea actually is a very small volume, uh, of fluid, and so the molecules will diffuse there, um, and then ideally activate the progenitor cells, um, to divide. And so, um, one experiment that the company performed was in a, a cat model, um, with a similar, um, uh, similar anatomy to, uh, to humans, and so, what we're able to do is, uh, do an injection, um, and we're able to show that these molecules could go, um, uh, from the base all the way to the apex, and we could get, um, therapeutic levels based on our in vitro, um, culture results. And so, we envision that this in the clinic could be actually a very quick procedure. The injection doesn't take very much time. Um, so this could really just be, uh, you know, a short, a short visit, um, to get this done. Um, so the company has done a lot of experiments, um, and has actually advanced this to an animal, animal model of hearing loss, and the results look really promising. So we've pushed ahead to, um, some clinical studies. So we just, um, did a short phase one in Australia, um, and we've just begun a, a phase 12 here in the United States, um, for hearing loss. We're really excited about this. Um, no one has ever developed a, uh, um, a, a therapeutic, um, to restore hearing. Um, so there's a lot for us to learn, uh, along the way. Um, we have lots of molecule, uh, combinations of molecules and approaches, um, but, uh, we're advancing right now, uh, into the clinic, and, um, hopefully we'll, we'll see a signal. So, in addition to, uh, to bio-inspiration, I just wanted to share with you one other strategy that we've been using in the lab, um, which I like to refer to as radical simplicity, and it's really this sense that when I started my laboratory, we started, you know, developing these really complicated solutions, um, but realized very quickly that, um, that this was never going to help any patients, um, because it was just too complicated, um, and there were just too many significant, um, challenges. Um, to, to advance this and through a lot of difficult conversations that I had, I realized that if we were gonna have an opportunity to help patients, we would need to make our, our approaches very, very simple. Um, manufacturing actually kills so many different technologies because you need to do quality control at each step, and if you have too many steps, it can just be too costly and too, too challenging. So, um, I want to share with you just a, a, um, a story or two, in my laboratory for how, um, we've gotten, um, how we've kind of integrated this concept, which I like to refer to as radical simplicity. So this is my daughter, Jordan, here at the Children's Hospital getting an infusion of Entyvio for her ulcerative colitis. She was diagnosed at age 5 and she's 9 now. Um, and, um, since she was diagnosed, I actually had already started working in the area of inflammatory bowel disease in my laboratory. Um, and it was, um, actually really interesting how after her diagnosis, um, my collaborators became her doctors, um, and, uh, and, and I've also started, um, uh, a number of other projects in the lab because of my new interest in this, uh, or, or, or increasing interest in this space. And so one of the challenges in ulcerative colitis is most patients will require at some point in their treatment regimen, enema-based therapy, and enemas, um, Have, uh, a lot of challenges. One is, you know, patients have to retain them, which can be very difficult. Um, two, you can get, uh, systemic absorption and so you can get toxicity. Um, and 3, the dosing is quite frequent, you know, multiple times a day or once a day, um, and so compliance is, is quite low. So we were interested in just asking the question, could we develop a technology that may be able to address some of these challenges? And so, um, one of the insights that we gained, um, was when we started looking, um, more deeply at the, uh, the ulcers, we realized that, um, sites of inflammation tend to have a net, um, positive charge. Um, and so we started thinking because in the, in this concept of radical simplicity, you know, we could take antibodies and try and target, but then that really increases complexity and, and challenges along the way. So we're thinking, could we just use physical chemical targeting here? And so what we did is we went to the, instead of synthesizing a new material, we went to this list called the generally recognized as safe list by FDA, um, it's a long list of agents that have been in human use for a long period of time. Um, and, um, you know, they can be in foods or other, other kind of things that, uh, Um, uh, that are common. And so what we did is we looked at this list specifically for amphiphiles. So these are molecules that have a hydrophobic group and a hydrophilic group, um, also molecules that had an enzyme cleavable bond like an ester and amide, and also, um, molecules that had a negative charge, and I'll explain, um, Uh, in a moment, um, actually, I'll explain right now. So, the reason why, um, we did that is because many of you may be familiar with my cells and liposomes. It's a self-assembly process, um, where you take an amphiphile and what happens is, is you may put it into water, um, and it won't dissolve, so you, you heat it or you add a solvent and it dissolves, and then as it cools, um, These can then arrange, um, and, um, the hydrophilic groups will point outward, the hydrophobic groups will point inward, um, and this will form, um, spheres. So, what we did is we were able to coax the system. The problem with my cells and liposomes is that they, you can't really control the delivery, you know, it hit a biological surface and they open up and release their contents. So we were able to form a, a gel with these, um, With the same self-assembly approach. So essentially instead of forming spheres through just kind of modifying the system slightly, we could form a hydrogel. Um, and when you look at, um, high magnification, these are hundreds of nanometers or, or about 1 micron or so across, and then, um, these are 10s to hundreds of, of microns. Long. And the amazing thing here is that it just will have a consistency of butter or margarine, let's say at room temperature, but the amazing thing is that what you're looking at here is a single molecule that's just stacked over and over again. There's no recipients, there's no polymers, um, it's just a single molecule. It's a very simple system. There's no covalent chemistry. It's all non-covalent. And so during this assembly process, um, we can incorporate all kinds of drugs, hydrophilic, hydrophobic, um, and recently we figured out how to get biologics, um, including antibodies into these gels. And then in the presence of enzymes, so at the site, sites of ulcers, um, there's increased concentration of enzymes like esterases and MMPs. This will cleave this enzyme, um, cleavable bond, like an ester bond, for example, and then release the, uh, the drug that's loaded into the gel. And so I don't have time to go through all the, the details, um, but we've been working on this for some time. We've been able to show, um, that this can selectively attach to ulcers in gut tissue in animal models as well as from, um, patients who have ulcerative colitis, selective adhesion to the ulcers versus the healthy tissue, um, and why that's important is because, Um, we can reduce systemic absorption of the drug, which we were able to, to show, um, because the gel sticks to the, the ulcers and stays there, um, we get more continual release of the, the drug exactly where it's needed, and we were able to reduce the dosing regimen of the, uh, enemas in the animal model that we use, so from every day to every other day. And if you dose just the drug alone, every other day, it doesn't, it doesn't work. So, um, so we needed the, the gel there to maintain the, uh, exposure. Um, and, uh, and then we've also been able to take this, um, this, um, these gels and administer them in a model of, uh, eosinic. EOE, um, I'm not gonna be able to say that this morning. Um, apologize for that. Um, but, uh, we've been able to administer this in a model of EOE which is, is frequently associated with inflammatory bowel disease. Um, it's becoming more prevalent and it's really challenging because, you know, when you drink something. It just goes through your esophagus so quickly, it's hard for something to attach. So by using this gel, we're able to show that we can get greater exposure of the drug that we load into the gel, um, into the inflamed tissue of the, uh, of the esophagus. And so we're continuing to, uh, to advance that. So this platform, we've also been able to show that it can be useful um in many other settings, um, one is in the context of inflammatory arthritis, where you have flares followed by periods of remission. And so in a paper we recently published, we showed that there's potential here that you could have a, this gel, this really simple, um, uh, enzyme responsive or biologically responsive, we like to call it inflammation responsive, um, drug delivery platform, injected into the joint and then it will, Ideally only release drug in the presence of a flare, and when you have a period of remission, it will slow down or stop releasing the drug to preserve it for the next, the next flare. So that's one of the challenges of having continual release when you have this kind of pulsatile, um, uh, um, you know, disease mechanism that's happening is really you only want to release the drug when there's a flare and not during a period of remission. So we showed that there was potential to do that here. Um, and then we also, um, teamed up with a group in, in Switzerland. Um, to do a, uh, limb transplant model, where what you're looking at here is actually a very difficult surgical procedure to do, um, where they took a hind limb from a black rat and transplanted it onto a white rat. Um, this will get rejected within a matter of 15 or 20 days or so if you don't do anything. Um, and so what we're able to do, there's this, um, This, uh, this sense in the transplant, uh, community that, that you may actually not need significant levels of your immune suppressant systemically and, and just having it there locally, um, may be, may be enough. And so we injected, um, tacrolimus into this transplanted limb immediately after the procedure, just a single time point injection, um, throughout the, uh, the transplant. Um, and we were able to keep this alive for 100 to 150 days. Um, and then what we did is we dosed every 90 days and we were able to keep the limb, uh, alive and, and functional for, for about 270 days. Um, and then we've also been moving to a pig model and showed that this, um, This also uh worked in the pig model, so there's always a low level of inflammation that's there, um, in, in, in the body, you always have enzymes that are everywhere, so we have slow release, and when we inject this gel, we get very slow release, um, and we were able to detect drug being released for over 100 days. In this, uh, in the system. So we started this, this company called Olivio Therapeutics, uh, a few years ago, that's now in the process of moving this, uh, this technology to the, uh, the clinic and formed that in uh collaboration with uh Pure Tech Health in town. Um, So, one of the, just a, a, a couple, couple of quick things um to uh to finish off here, um, one is a uh a, a paper actually we just recently published within the last uh several weeks, which is um a collaboration, really exciting collaboration that I've had with uh Doctor Ali Tavacoli at the Brigham, who's a bariatric surgeon, and, um, he approached, uh, Fred Shone several years ago with this, um, Idea of trying to mimic the beneficial effects of gastric bypass procedure, um, so patients who get gastric bypass procedures who have type 2 diabetes, uh, 50% of them go in their type 2 goes into remission, um, and most of the others, um, do, do, um, do fairly well. And so there's this, um, belief, well, the mechanism is not fully understood, there's this belief that if you isolate, um, the proximal gut, um, that, um, And, and delay, uh, or, or reduce nutrient exposure in this, this part of the gut, um, that, uh, this is really what's, what's, um, mitigating these beneficial effects. Um, and, um, and I know there's a lot of hand waving there, um, but there's, uh, a lot of work being done to try to understand this mechanism, but that was enough of a concept for us to start to develop an approach to potentially see if we could mimic some of these. Beneficial effects. And so the thought that um Doctor Tavakoli had or the idea was, you know, could we develop a pill that a patient would take potentially before a meal that would transiently coat the upper GI tract, um, would not be absorbed, would reduce nutrient exposure in just that area, um, and, um. And then would just pass through the GI tract, um, and so this could be a much less invasive approach to gastric bypass procedure, which is permanent irreversible. Um, many patients don't qualify for it. I think you need a BMI of something like 40 or 45. Um, and for those patients who do qualify, very few actually get it, um, because, uh, for a variety of reasons. So, um, uh, Doctor, uh, Shone, uh, who's the, uh, vice chair of pathology at the Brigham, I have known him for a number of years, so, uh, he connected us, and so, uh, Doctor Tavicoli and I started working together, um, and, uh, and we developed a potential, um, solution that we've been advancing. And so just to show you, just very quickly what this looks like, um, so we've developed a material that has a paste-like consistency. And so here you can see it's on the spatula in a wet form. Um, this is just some gut tissue, and you can see as we just move it across the tissue, it appears to form, uh, a coating very easily. We envision, you know, putting this in a pill and having it open, um, in the duodenum, um, and, um. This material here, when you put this underwater, you can see this nice white coating. So this made really a, uh, a uniform coating on the tissue. Um, and, uh, sometimes, People in lab get a little creative with the videos, um, but here you can see that this paste actually can remain attached, and so we did, did, uh, a lot of experiments in animals and we showed that indeed this was non-absorbed, it was transient, and that we could reduce nutrient absorption by about 45 to 50%, um, with this, uh, with this approach. Um, we've also been able to show that this potentially could be useful for drug delivery applications, um, and, uh, and so what we've done is we've put biologics into this material because it's a paste consistency, it's not a gel or, um, it can protect, um, biologics, and then when we put, uh, model biologic in. We come back after 24 hours, because this pace moves really slowly through the GI tract, um, we can detect that, um, the biologic is still there. Um, so this may be an interesting approach to improve the exposure of drugs to the, uh, to the GI tract, so to alter the local, local PK. And so we're in the process now of trying to design a clinical study um to see if we can reduce nutrient absorption in patients and then ideally um show that we can have beneficial effects for um a type 2 diabetic um patients. And finally, I just wanted to share with you something that is unpublished, um, and so this is a, uh, a project that actually we've been working on for quite some time, um, and it's in the area of, uh, developing new needles and, and, and trocars, um, to, to try to address some of the unmet needs. And I think, um, you know, one of the, when you, when you start looking at needles, you realize that there really has been minimal innovation in the clinic, um, over the past, um, century or so. Um, but these technologies are not without their, um, challenges, and so there's many situations where a needle may go too far, um, you know, for various reasons, you know, maybe placing epidural anesthesia or a lines or, you know, whatever it is, um, and so recognizing that in certain patient populations or certain centers, it's, um, it may be challenging to get a needle or a trocar to stop where it's needed, we were interested in developing a really simple solution. Um, to, uh, have a needle that could target various sites in the body. And so let me show you just one example. We've developed several needles, and this is just our most recent one. and so the idea was to create a needle that would automatically stop when it reached an area of lower resistance or a tissue cavity. And so for this, what we did is take a standard syringe, and we have this um plunger that's here. We've added a second plunger here and the needle, uh, we attached it to the second plunger. So, uh, and we have our drug within a fluid that's here. Now, if you, and then the end of the syringe is just sitting on the tissue. Now, if you start to push on the, the plunger here, what happens is, is because this uh tip of the needle is in a, a tissue, um, it, the fluid flow is blocked, and so this volume of fluid will start to advance, um, and the needle will advance as well. So, this is, again, the end of the syringe is sitting against the tissue. We push on the plunger, um, and this needle then starts to move. Um, and then when we hit an area which is a tissue cavity or an area of lower resistance, what ends up happening is, is that now there's no resistance at the tip of the needle, um, and so the drug can be, um, delivered. And so we wanted to demonstrate whether, you know, see whether this could work in a very challenging setting, and so we were interested to test this, um, in the eye. So you, in the eye, you have the sclelera and the choroid. The choroid pushes up against the scalera, um, because of the intraocular pressure, but the two tissues are not actually attached. So you have a potential space that will track all the way back around the eye, um, and there's huge unmet needs to develop better, develop better strategies to deliver drugs to the back of the eye. Um, and so what we did is, um, we took this needle, we put it into the, um, scalera, and we were able to show that it could automatically stop in between the stelera and the choroid, and then we could inject drugs that would go, um, all the way to the, the back of the eyes. So you see here this um radio contrast agent has Gone all around the eye, um, and then we're also able to deliver cells. So we took cells here, um, delivered cells, and then we actually took another needle in another part of the eye and we're able to remove the cells, so they traveled all the way around the back of the eye here, um, and we showed that these cells were still, still. Viable. So this may be an interesting opportunity to target drugs to the back of the eye, um, to target the choroids, there's a number of diseases that affect the choroid, um, and we also have some evidence that drugs in the suprachoroidal space are able to diffuse, um, to the, uh, to the retina. So we're now in the process of trying to figure out the best, um, uh, um, therapeutic agents to partner with this technology and, and, and try and advance it forward. So, in summary, um, describe for you a number of technologies that we're developing in the lab and some of the tools that we've been using, um, to maximize the potential that we can bring some of these technologies to patients. I talked about, um, bio inspiration. This is not biomimicry, we're not trying to copy nature in every detail. It's more of taking a basic idea in nature and then improving on it with our own purposes, really starting with the problem and then looking to nature, um, and then radical simplicity, which is really, um, At the very beginning of projects and throughout, thinking of ways of how we might simplify our solution at every possible step, recognizing that um any degree of complexity is going to reduce our potential to uh to help, help patients and we'll make things more, more challenging, and I've realized that there's many opportunities to simplify. Sometimes you need complex solutions, but often there are a lot of opportunities to simplify, um, along the way in a, in a project. So at this time, I want to acknowledge, uh, um, the, uh, really wonderful people in my laboratory, um, and, uh, many collaborators. I'd like to thank my, um, uh, funders, uh, for the lab, which there are, are many, um, we're very grateful, um, and I'm happy to address any questions that you may have. Thank you so much. Doctor Parker somehow without a microphone today, but I'd like to start by making. Coming this morning, even if it's an unseemly time for. Yeah, I think it's very inspirational. To, uh, I have one question. Obviously the, the gels that you're using for the cardiac, for the, the laser gels for the. GI tract or something that's entirely new, not a substance that exists on the FDA's approved drugs. Well, thank you. Approved drug list. Yeah. Um, what, what sort of hoops and burning rings of fire have you had to jump through for the FDA to get their approval for, for human study on those agents? Yeah, so, um, I think even, even beyond like something that I've realized, you know, as being a, um, an academic, um, is just how challenging it is to bring technologies, um, forward, and, um, you know, we had demonstrated that, for example, for the tissue glue, one of the first projects I spoke about, we had demonstrated it to work in small animals and large animals, and when we started the company, There was a sense in the team that this would, you know, we'd be able to move very quickly to a clinical study, but what happened was, we immediately encountered manufacturing challenges with that material because there's a reactive material. Um, and it actually took 2 to 3 years to figure out how to manufacture, um, this material so that it could be shelf stable for a year, um, and maintain its level of adhesion. So it was a major challenge and required multiple, um, bringing in multiple consultants to help us think through that, um, eventually we're able to, to overcome that challenge. So one, I'd say one of the biggest challenges or the biggest challenge for us was really the manufacturing challenge. Um, once we're able to overcome that, um, The, uh, and this was something again, I didn't really have a sense of in, in academia, but, um, you know, when we started the company, there was a big sense of like, how can we get this into the clinic and get it approved as quickly as possible, even if it's not an application that has like a massive market, just getting it on the market would be, you know, a big early win for the, for the company. And so they approached, um, their approach was to, there was a material called, um, Omnic by J and J, which is a cyanoacrylate, um, based material that's placed over suture lines and vascular surgery. I'm not sure it's actually still available, I think it was taken off the market recently, um, but because that had already been, there was already a pathway to move that forward to the clinic, uh, the company decided, um, that that should be the first application to get this into the clinic quickly. And so, um, essentially this just required a small trial of 25 or 30 patients, um, and the endpoint was showing, uh, anastomosis in these, these patients. So we were able to show that we could get immediate, um, you know, stoppage of the blood, um, leaking from these, um, uh, you know, from the, from the blood vessels, and, um, so I'd say the major challenge was really more on the manufacturing. Um, and then thinking through, you know, what would be the best first application to move this forward. Once that was identified, um, it was actually pretty quick, um, you know, I thought it would take a lot longer, but it was pretty quick to, to bring this, um, forward through a clinical study in Europe. Um, now the company's in the process of moving this to a, a study in the, um, in the US right now and hopefully we'll start, you know, later this year or next year. Additional questions for Doctor Carp Doctor Fauza. Jeff, it's uh refreshing to see a lab with such a diversity of interests, which is unfortunately not very common, but I think it's a very smart and sensible approach to research. I have a selfish question which is not directly related to your talk, but it, it is related to work that I know you've done. Do you know of any local company with uh GMP uh capabilities for cell manufacturing, cell expansion that is welcoming, uh, to collaborations with academia? So, um, the only center that I know of in town is the one that Jerry Ritz runs, um, at Dana-Farber, which is a GMP facility that he's established as part of like an NIH grant, um, to do exactly that. Um, and I've met with him and his team a couple of times just to better understand the process. Um, and they're able to put together, um, you know, the SOPs and the package, and I think Um, uh, you know, it's also, I think, much less expensive to work with his, um, group to make these, you know, small batches to advance to, uh, you know, small clinical studies. So it might be good to talk with, with him, um, and see if he, if he can do it there or whether there's other places in town. Yes, uh, I agree. I'm aware of that group, but are you aware of any company that would be willing to collaborate with academia? Um, to do the GMP? I'm not sure, but I can look into it and I'll, I'll, yeah, if I find out I'll, I'll definitely send you a note. Yeah. Additional questions for Doctor Carp. Doctor Jackson. Uh, that was a fantastic talk, and, uh, I'm not just saying that cause I'm a fellow Canadian, but, uh, that was, uh, unbelievably good. Uh, you know, in surgery, we, uh, spend a lot of our time, uh, closing holes, and, uh, one very simple problem that we have is sometimes we put in, uh, tubes into the GI tract for transient feeding. Then we remove them and the hole doesn't close. Would your, uh, glues be useful for something like that, so we could place it endoscopically, just seal it from the inside, rather than having to perform another operation. I think so, yeah, no, I, I, I think that they're um Based on the results that we have, um, and, uh, you know, the NO1 with little poppy, um, I think that, uh, that could be a really great application for these materials. Whether you would need a, a patch with the glue or the glue alone probably depends on, you know, where the hole is and how big it is, but I think these materials, um, that we've developed and some of the data that we've been able to generate shows promise for addressing, um, exactly what you mentioned. So, yeah, I'd be very interested to talk with you more about that. Doctor Carp, thank you very much for being with us this morning. All right, thank you, everybody. I Thank you. Oh yeah, thanks again for the invite. Yeah, uh, I'm actually my interest personal in device development information. Oh cool, from my red. Come over sometime. That's what I would, I would definitely send an email. Yeah, yeah, yeah, shoot me. I have 100 things I want left, so it's really great, especially in the world of what we do. Yeah, come over, we'll grab lunch and brainstorm, and yeah, yeah, yeah, yeah, yeah, we'll see if there's some opportunities. OK, perfect. Yeah, see. Oh, was I not supposed to close it? Oh yeah, right, out of that. Oh right, just because if my noon meeting comes up and you sign us out, I'm gonna freak out. OK, I'll let you, uh, oh yeah, you're actually all signed out. Perfect. Just wanna make sure. OK, excellent, thanks a lot. I appreciate it. Yeah, thanks for your help. Sorry Yes, thanks so much you're an inspiration.