Chronic Pain Chronicles with Dr Karmy
Join Dr. Grigory Karmy M.D., a distinguished chronic pain management physician with over 20 years of experience, on a captivating journey through the world of pain relief in his podcast series. Delving into the latest regenerative medical treatments like PRP, stem cell injections, and prolozone therapy, alongside educational discussions on pain transmission and various medical options, Dr. Karmy shares invaluable insights and real-life stories, empowering listeners to find relief and regain control over their chronic pain.
Chronic Pain Chronicles with Dr Karmy
Episode 11: Acorn Biolabs and the Future of Stem Cell Treatments in Canada
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Join Dr. Karmy for an interview with Acorn Biolabs CEO, Dr. Taylor, where they discuss the unique approach his company is taking to stem cell treatments.
The wide ranging discussion will also cover his vision for the future of his company and how it fits into the broader field of regenerative medicine.
Acorn Biolabs: Acorn Biolabs - Personalized Regenerative Medicine
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Ended up applying and being accepted to medical school and was ready to head off. And then at the same time was offered a contract from the Blue Jays. And so I had a bit of a difficult decision to make. I figured I could always go back and and do medical school, right? There wasn't as big of an age qualifier tied to that. But with baseball, I had a very limited window to see if I could, Take that, play professionally, but also ultimately make that jump into to play professional baseball at the major league level.
Dr Karmy:Hello, this is Dr. Karmy for Chronic Pain Chronicles, and today on the podcast we have an interview with Dr. Drew Taylor. Hi, Dr. Taylor!
Dr Drew Taylor:Pleasure to be here. Thank you so much for having me, Dr. Karmy.
Dr Karmy:Just to give a little bit of a background Dr. Taylor is CEO of Acorn Biolabs a company in the regenerative medicine field. Let me s tart with a little bit of a softball question. You have a very unusual path to becoming a CEO of a company. You started out in baseball. You played with Blue Jays. You played with Philadelphia Phillies, and you ended up in business. Now, when I was raising my kids, I was a little bit of an opposite of a hockey dad. The kids had to study. That was mandatory. And what they did with their free time, I didn't really care. They could play hockey or they could play video games. It's so good to me. So needless to say, they didn't grow up to become athletes. But is there you think, skills that carry over from sports into, when people become adults?
Dr Drew Taylor:For sure. I definitely do. And baseball was always a passion of mine, but I think through and through what I wanted to do in my career was being in health care. And specifically, I think, when I was younger, I wanted to be a physician delivering that care. Now I've gone into the business side of health care, but always was healthcare was what I was going forward with. And baseball was something that I was doing adjacent to that. And I had a great example growing up my father was both a physician and had been a professional baseball player. And you could say I was falling into following in his footsteps very much and probably thought that I'm going to do both of these things simultaneously because of his lead. So very grateful for that. In any case, I was going to head off to medical school. I went to university down in the US, University of Michigan, played baseball for their team there. Had a great run at University of Michigan. Did all of my pre med requirements there. Graduated early and started a master's degree there while I was still playing baseball in my last year. And ended up applying and being accepted to medical school and was ready to head off. And then at the same time was offered a contract from the Blue Jays. And so I had a bit of a difficult decision to make. I figured I could always go back and and do medical school, right? There wasn't as big of an age qualifier tied to that. But with baseball, I had a very limited window to see if I could, Take that, play professionally, but also ultimately make that jump into to play professional baseball at the major league level. So I signed a minor league contract with the blue jays played with them for a number of years and then the phillies even for another year, but all the that entire time I was still a full time student. So in the backdrop, I wasn't allowed to do an MD at the same time. I wouldn't talk to the Dean and unfortunately they said, look that's too much. You can't do an MD at the same time as playing baseball, but have you thought of doing a PhD? And so that was how I got pushed down the PhD pathway. There's a little bit more flexible of a program and less patient interactions that were very time dependent and scheduled working with cells in, in the dishes are much more patient than patients, so it was a little bit more flexible. And so I started a Ph. D. at the University of Toronto. I focused on biomedical engineering as my major and focused on stem cells and regenerative medicine. And so that was really a fantastic opportunity for me to continue my education while still seeing if I could, play baseball. Ultimately, it was probably a good thing I did because I didn't last forever with baseball. I ended up having a shoulder injury. That slowed down my career and my progress there battled back from it and played for a number of years in the minor leagues, but did not make that jump into the, to major league level, but was able to continue my education. And by the time I had finished playing baseball, I also had a PhD. So that was a fantastic decision. I think there's a tremendous amount of lessons and opportunities that are presented in baseball that can be translated into both healthcare and business. And I think the biggest one is in team sports. Baseball especially has a very diverse group of athletes. The makeup of a pitcher is very different than a first baseman, which is very different than a catcher or an outfielder. Some positions are best suited for speed and agility and others power. Hand eye coordination and all of these things are very important across the board, but there are particular sets of skills that really behoove players to certain positions. And it's no different in a team environment, in business, or in healthcare, in the O. R. It takes a multitude of different people with different skill sets to come together to produce that great result of either a successful company. It's a well oiled machine or a successful surgery and delivery of a service to a patient. And so for me, I think that interaction of really making sure that I knew what my job was on the field, and I tried to do that to the best of the ability, and I trusted the people behind me to also be performing at the best of their ability. And that was phenomenal. There's a lot of discipline and hard work and perseverance that go into to becoming an athlete at that level. So I think those are all great lessons. But the biggest thing that I took away, I think, is how to interact with people that you ultimately are gonna depend upon to accomplish a goal, how they should be treated, how they should be told when they've done a good job, how to deliver constructive criticism. These are all massive lessons I learned from my background in sports.
Dr Karmy:Are you saying that former athletes might make better CEOs?
Dr Drew Taylor:I don't think you have to, have been an athlete to make a fantastic CEO. And I don't know if they're better. I think it all depends on how that individual used their time in sports. And I think that there's also all sorts of other opportunities to have similar experiences for individuals to bring that into their job as a CEO or in business. But I think the pathway through sports provides one of those opportunities to learn some very essential skills for being a successful leader.
Dr Karmy:So I'm interested in regenerative medicine. I am running a Health Canada approved stem cell trial. Stem cells are basically the cells that can make anything in your body from heart muscle to brain to cartilage and worn out joints. And there's a number of businesses in the sector. Some businesses focus on a specific therapy. So they will take these stem cells and they will sometimes alter them or even genetically change them, expand them and trying to find the right therapeutic approach. And then there's another set of businesses which is a little bit more like Rails. They're more focused on perhaps providing the tools for those therapies for when they do develop, that patients would be able to take advantage of them more easily. The grandfather of some of all sorts of approaches where umbilical cord banks that I think started up back in maybe 15 years ago, maybe longer where, after your baby is delivered, you can store the cells in the umbilical cord, which I presume are very immature cells. And then if some days you need them for whatever purpose, most common purpose that actually stem cells are used for currently is for treatments of leukemia, where they'll destroy all the cells in the immune system, including the leukemia cells with chemotherapy, but then the patient would of course die if they have no immune system. So then they would transplant immune system typically from another person via stem cells, which would then populate your bone marrow. So that was one of the earlier approaches to this. And then I guess traditionally in orthopedics there was stem cells are used still in somewhat experimental capacity. Typically they obtained either from fat or they obtained from bone marrow. That particular type of cells are mesenchymal stem cells and then they injected into joints. In fact, I am aware of a couple of companies that allow you to store your stem cells that's obtained from fat. But in case of Acorn Biomed, they decided to use a different source of cells.. So can you maybe touch a little bit how you got there?
Dr Drew Taylor:Yeah, absolutely. So you touched on a lot of approaches really, that I think have been incremental steps forward in trying to solve some of the problems that we have. Ultimately as a grand challenge, what we are trying to do is make sure that a patient has their own cells available to them into the future that are of high quality. And ultimately, we know that over time, our own cells are unfortunately depreciating with age. And so getting to an opportunity to have younger cells available, stored and banked in the past so that you can leverage them in the future is an ideal scenario. Now, our first effort from that you pointed out was umbilical cord cells, and the original focus on umbilical cord cells actually was harvesting hematopoietic stem cells, so blood lineage. And unfortunately, that has a limited capacity for regenerative focus. It has been traditionally extremely difficult to multiply those cells, so they don't culture well in the lab. And they are very difficult to combine with some of the new, newer approaches iPSC reprogramming. And so you end up having a limited use case for them. They're fantastic when we look at leukemia and treating blood conditions. But that is the focus of where they have demonstrated utility. So since then, we have really expanded the opportunities to try to look at other cell types, even in into adulthood, that provide patients a better source of cells for themselves at a potentially harvestable at a younger age. And mesenchymal stem cells certainly emerged as a cell type that has a multitude of uses, can be expanded readily in culture so you can make more of them on demand. And on top of that, they can be stored long term very well and used in some of the new technologies like reprogramming and creating iPSCs. So they checked a bunch of boxes that the hematopoietic cells did not. And we can access, and we have known that we can access these cells, of course they're in small populations within these groups, but you can find these cells in your bone marrow, you can find these cells in your fat. And ultimately, you can also find them in your hair follicles, in the bulb at the base of your hair follicles. And that really is a lot of the work that we have focused on at Acorn. And so there's been objectives over the past, 10 years of looking at, banking your bone marrow. Of course, that's a very invasive procedure, right? You're drilling into the iliac crest and harvesting stromal cells right from the bone marrow. It doesn't tickle. In fact, we get a lot of complaints from pain. There is a morbidity to it. You definitely feel the effects of it for a few months afterwards, and it is something that is not exactly people are going to be lining up for and paying as a service in advance. All of that being said, it does provide a valuable cell type for patients into the future. The next wave was looking at fat and ultimately you can harvest fat through liposuction. So it is something that is a little bit less invasive, right? Although it still requires an invasive harvesting of that by liposuction surgery. Now the other thing that should be known about those cells is the mesenchymal stem cells in fat is a very low proportion of those cells. And so ultimately to get at the right cells for storing them, if you want to exclusively look at those cells, you have to separate those cells out of the rest of the adipocytes or these fat cells. And that's actually really important because when we store cells long term, we rely on technologies that inhibit ice crystal formation, At these ultra low temperatures in like liquid nitrogen negative 196 degrees celsius, right? Well adipocytes is a very unique cell in our bodies that is fat soluble, right? So these are different cells than other cells and so we have these MSCs that are embedded that don't have those same properties. And so you end up having a lot of cell lysis. You end up having a lot of difficulty in making sure that the MSC, the MSCs within are supported in those mediums, those liquid mediums that support freezing at those ultra low temperatures, because you've got this vast proportion of fat cells around it. So processing is an important step and that can be costly. And so ultimately we've got all of these hurdles in delivering this to patients, physicians understand the value of having these cells into the future, and we've seen where regenerative medicine is going really the next frontier in health care. But there are difficulties in making sure that we're providing this to patients, and it can be cost, it can be pain it can be just the surgical hurdle of that it can be the fact that the cells only have limited use use cases, that the cells are fragile and not stored very well. So the hair follicle for us, was an opportunity to really try to get across and over some of those hills and some of those problems, right? It's a fairly non invasive cell source through plucking follicles. You can just from, if you ever plucked an eyebrow or an errant hair, right? This is a way to get access to high quality cells, MSCs. It's almost painless, right? Like a plexus follicles is not something that I would write home about. The cells are of extremely high quality. They're actually quite robust. They're packaged together already around in a matrix together in this bulb. And so they have very good shipment properties if done in the right conditions and storage properties if stored at the right conditions in liquid nitrogen and a supportive media. And so we've crossed a lot of those barriers. The other two big things that we've demonstrated is that those cells can be outgrown readily, so we can create more of them on demand. And they also are able to be used in some of the new technologies or newer technologies like reprogramming. So we can create iPSCs, induced pluripotent stem cells, from those cells on demand. Which is really the plug in to some of the long term strategies that are being investigated right now to tackle some of the world's worst diseases. Like Parkinson's and macular degeneration and some of these studies that are going on currently, you have to get the cells and sources cells to iPSCs first.
Dr Karmy:So basically you are getting cells from the hair follicles which is much less invasive procedure than some of the other alternatives. You are saying that you have a much more pure combination or much more purist stem cells which are not intermingled with other cells, which makes it easier to ship.
Dr Drew Taylor:Well, just to make sure I'm accurate, there are other cell types that are present in the hair follicle, right? You've got keratinocytes, you've got fibroblasts, there's actually two different types of stem cells. You've got the MSCs, but you've got these dermal papilla cells that are specific to your hair follicle. But alll of those cells are actually valuable. So we like to have those cells, along with it. I would say that the adipocytes that come along with fat MSCs don't have that same utility. In fact those cells are more filler. They could be used as filler, for instance, right? And that is a strategy. But the cells that we get from the hair follicle have other utilities. beyond that. So I think that the multitude of cells that we can access in the hair follicle all have purpose and even though they're not, all pure MSCs, there is a population of MSCs that you can specifically outgrow in the, in, in targeted conditions. So you put it in the right media, liquid media, and the MSCs will preferentially culture out and you can harvest them specifically. So you can purify those cells.
Dr Karmy:Okay. It's a simple question, how long can they be stored for without damage?
Dr Drew Taylor:So that's a great question because this is one of the limitations that has come up previously, right? Our. Our conditions around storing cells have definitely improved technology wise, right? The first cryogenic efforts was in the 60s, and so we've come a long way since then. That being said adipocytes posed a specific problem, and one of the biggest issues with adipocytes was you couldn't store them long term. They have lower survivorship, and so you end up getting it. attrition over, the next three years essentially, right? You get, get this reduction in their viability. When we look at ourselves, we have cultured these cells out in our studies from samples that have been banked years prior. And we take a sample out every year to continue to test that. So obviously our company has only been around since 2017, but we've got data going back to demonstrate that there is no drop off in viability of these cells over time. Also, the cell types that we're targeting and those, that robustness have been targeted previously in frozen. Other cell types like fibroblasts, keratinocytes, They've been actually reconstituted from samples that have been stored long before acorn existed all the way back to the 60s and shown that they are viable. We've shown that you can do this with cells in fertility, eggs and sperm, you can keep them banked for decades. And right now, there are cell types that are able to be frozen, that we believe will have an indefinite future as long as they're maintained in the right conditions, without fluctuations in temperature. And you could have them stored for a thousand years if you wanted.
Dr Karmy:There's another question maybe a clarification more than anything. How many stem cells, when you harvest stem cells, how many stem cells do you actually get and can they be used as is or do they need to be expanded in the future before they will be used?
Dr Drew Taylor:Great question. So what we look at ultimately is the use of these cells ,in a number of different ways into the future. We believe the first wave of use cases in these in cells for patients deriving benefit from them will actually be a cellular applications that are created from their own cells. And that absolutely requires the cells to be cultured out. So we take that small number that we have in the hair follicle, we culture that out, and we grow millions. And in that case, what you're actually doing is you're harvesting all of the media that the cells are releasing contents into called the secretome, what they're secreting into that media. And that includes proteins, growth factors, matrix molecules, and even a very hot topic today, exosomes, right? These little mini packages of content that include proteins and mRNA and even DNA. And so we can harvest those things over that culture time and essentially create a highly concentrated secretome is that patient's own biologic materials is bioidentical to that patient has been produced by their own cells. We can even lyophilize that or freeze dry it so that essentially it's now shelf stable, deliver that back to physicians. And those physicians can then reconstitute that powder of a patient's own growth factors and exosomes into either hyaluronic acid or even saline and can be used in applications for that patient and the first wave of them that we're looking at right now are topical. So it's really in dermatology, plastic surgery, wound healing, areas of topical application. And that is really the first wave. I think the second wave will enter into looking at actually more invasive applications. So injecting these for orthopedics and sports injury. Um, and then I think we'll end up moving into a period of regenerative medicine where we're increasing the complexity instead of the secretome, we're actually growing out live cells, harvesting those live cells and using those live cells in the application. And that would be the next era that I think we'll be entering in. So right now it's leveraging those cells to create acellular applications. Cellular applications will be next. And I think is a third stage that we'll see in the future is when we manipulate the cells that we're growing out and put them back in. And that's a very big distinction between just unmanipulated cells or minimally manipulated cells, technically, and manipulated cell lines where we're using CRISPR. We're using reprogramming to change the genetic makeup of those cells and essentially edit out disease before putting them back in so that we actually create a population of cells that are still our own but have a Detrimental trait removed from them as an example.
Dr Karmy:Obviously MSCs have been, as you said, used very extensively in various regenerative medicine startups, various regenerative medicine studies. I guess one of the things in the back of my mind has always been that yes, you can take these cells and you can make them into cartilage cells and you can make them into, I think, muscle cells and any, and a number of other cells, but it's not necessarily clear to me that's how they actually function in our bodies. From what I understand, they circulate throughout the blood. They will go into different areas. They have all sorts of effects on the immune system. I guess my question is, are MSCs identical to other stem cells that exist, say, in muscle, or in brain, or in the heart, or are they different?
Dr Drew Taylor:Mhm. I think there is evidence to suggest that there are differences. MSCs from bone, from fat, and from the hair follicle. We can all agree that these cells are multipotent. People have taken all those three different cell types and turned them into bone, fat, and cartilage, showing that tri lineage capability. But if you look at the secretome, what these cells are releasing, there are nuances and differences between that. And the MSCs that are harvested from the hair follicle have particular proteins that they're releasing that are more specific to their niche, right where they live to support wound healing their skin support the hair follicle and the dermal papilla cells that exist there. There are factors that are very unique, uniquely released to that area. And so while these cells have similar capabilities, they also have different strengths and weaknesses. within that. And I think that that's an important distinction as well. The hair follicle is a diverse population of cells. And that's one of the reasons why we like it because those MSCs have to support a multitude of other cell types. They're not just embedded in adipocytes. They're not just embedded in those bone marrow stromal cells. They've got keratinocytes, they've got fibroblasts, they've got dermal papilla cells, these HFSCs. They have these other cell types that are dependent upon them for support. And we see that. You pointed it out. These cells move. And I think that one of the amazing things about MSCs is that they have essentially a homing mechanism, right? Obviously based on molecular cues that are released, but at the time of injury, when you cut your skin, the MSCs from the hair follicle will actually migrate out of the hair follicle towards the wound to support that wound healing. And in the same way, if you take the MSCs out of a hair follicle, those secreted factors that stimulate the dermal papilla cells when they're removed, you stop the growth of keratin and there's no hair actually that's coming out of that hair follicle anymore. So we know that what these factors are that they're releasing are imperative to the success and the performance of the cells around them. At Acorn, we've been actually doing some work with the university of Calgary in a mouse model of cartilage repair and we're taking this secretome, right? We're also taking live cells that are grown out the MSCs from the hair follicle and we're putting those live cells into the mouse knee essentially at the same site where there is cartilage damage. And then we're tracking that repair. What we found is ultimately with you, if you have your negative control, right? So just saline, for instance, you are not seeing the repair of that tissue. When you inject the live cells, you are seeing repair and filling in of that gap in the cartilage. But the cells that we're injecting are stained. They have a marker on them so that we can see them under the microscope and they appear different in color. They're not actually the cells that are filling in the gap. But what they are doing is they're stimulating that mouse's ability because of these secreted factors and the support that they're delivering into that site of injury, they're supporting the native mouse cells to repair that injury faster and better. And so while the cells aren't actually found to be still present in that site of injury, there's a distinct difference in repair when they're present and injected and when they're not there. And so these are some of the clues that we've been given as to how these cells are actually working in our body when we're thinking about delivering them therapeutically for patients that have cartilage damage, for instance, they're really about stimulating our own native responses in their current status. And that's through the secretion of soluble factors that we've tracked and looked at that are released into the media as they grow or as they perform or as they're put into a person or an animal.
Dr Karmy:So just to clarify, you're saying that chondrocyte stem cells are different from mesenchymal stem cells?
Dr Drew Taylor:No I think that there's a lineage of them, right? So if we think about cells in the human body, in my, the best way I can describe it is you can put all the cells in the human body on a mountain. At the top of the mountain, we have our embryonic stem cell, sperm meets egg. That cell can become any cell type in the body. Or, you can say it another way, you can roll down any side of the mountain. So it can decide to become whatever different cell type. At the bottom ring of that mountain, you've got every single cell type in the human body. As that embryonic stem cell decides to roll down a certain face of the mountain, it loses the capability of going to that other side. And mesenchymal stem cells is one face of that mountain. Cartilage, bone, fat. It's made a decision to go to an MSC. That MSC then can go, make a decision to continue to roll down to a cartilage progenitor cell, which then will make cartilage tissue or, a osteocyte, right? It, it makes decisions of which area to continue to roll down, and as it continues to differentiate, as we call it, or roll down that mountain it limits its possibilities of other faces or other sides of the mountain and going into those cells.
Dr Karmy:Basically cartilage progenitor cells at the bottom of the mountain.
Dr Drew Taylor:They're close to the bottom of the mountain. They're not all the way at the bottom, but they're very close. And and this is, there's a little further up right and can become others. So those MSCs I think are stimulating. Now, we've shown in culture and many other groups that you can take MSCs and you can create cartilage tissue on demand, right? I think the challenge with looking at how those cells can specifically fill in that wound, right? If we wanted to actually use those cells to create a patch or solution to fill in that cartilage, you're now looking at complementing regenerative medicine strategies in, in cellular capabilities with tissue engineering. Those cells now have to be surrounded by a matrix, right? Which is what cartilage is, a specific matrix that keeps them there localized. And performs a function in itself, right? That cushion on the end of our articular joints, that cartilage surface, right? It's very low percentage of cells and a very high percentage of matrix produced by those cells. And so that takes time to create. It happens in development, right? And ultimately by the time that we're in adulthood, you've got this sporadic amount of cells in this big, extracellular matrix. And when you have an injury because in cartilage there's no vascular supply, there's no nervous innervation, healing is limited. And so that's why, for us, it's, I think it's one of the major areas where we can provide improvement for patients experience leveraging regenerative medicine. Osteoarthritis cartilage damage and trauma in joints are all prime areas where we can fundamentally change the human experience by delivering regenerative medicine solutions in that space.
Dr Karmy:So it sounds like, the current solutions, they mostly stimulate your own stem cells and wash away and the future hopefully will be some kind of solution that they don't wash away. There's basically two approaches in regenerative medicine. One is autologous stem cells, which is what essentially, you're in that sector where you take your own stem cells and you use them for various therapeutic purposes. And the other one, which actually there's a lot of companies that are developing it, is allogenic stem cells. They still come from a human, but a different human, or maybe a bunch of different humans. Can you talk, discuss, talk a little bit about pros and cons of autologous versus allogenic?
Dr Drew Taylor:Yes. allogenic, meaning it's from a donor, right? You're taking cells from a different person and putting them into a patient. Definitely has a lot of attention and focus around it because the advantages with it are mostly cost and in production, right? If you can source cells from one source and process those cells and create what would be thought of as an off the shelf solution that is capable to be applied to many. That is a good pipeline of production to utility and it's trying to mirror what we do with pharmacology. So you've got one drug that can be used by almost everybody. It's difficult in regenerative medicine to be perfect that way. So the limitation is that there's much evidence to suggest that it's not going to be that easy, right? When you're taking a cell from someone else, there are complications that exist far beyond when you're just looking at using a drug, right? A chemical compound. And really that comes into our genetic makeup. We have, our impulse in receiving foreign cells will be to kill off those cells, right? Their foreign or immune system will attack them. So we have to add in layers to mask our own immune system to accept those cells. And currently right now, we, outside of some of the cell based medicine and things that, that I think the future will hold, we are leveraging allogenic sources in transplants, right? So if we have a patient that comes in and needs a new kidney, we can source a kidney from a patient. We look to make sure that it's as close of a match as possible, right? So these markers that we look at called HLA, and then we end up putting that organ in but regardless of whether we have a perfect match or not we are always suppressing the immune system of that patient so they don't reject that organ even if there's minutiae differences The patient can attack those foreign cells and so we inhibit the immune system. With an organ it also is less complex sometimes because you're plugging in usually just a small number of arteries, veins, right? You want to give it blood supply, right? In the case of the kidney, obviously, you have to have one more port for the urine to leave. But it's a limited number of plugs, essentially. or contact points with the host patient and the donor patient. When you start to think about skin, where it's infinite contact points or stem cell injections, where you're taking foreign cells that are just going to rush and flood that patient and go into their circulatory system, you're now creating infinite touch points, which means a much higher risk or propensity for an immune response. And so these are the considerations and limitations, I think, of allogenic cells. While they are beneficial in the sense of you can have a streamlined production, which is cost effective, they cause a lot of complications because They are not personalized, and I think one of the greatest possibilities in regenerative medicine is to deliver personalized health care. So we're almost neglecting one of the greatest hopes or promises from this space, and that's why I think bioidentical, you know, using a patient's own materials, is going to hold some of the greatest steps forward and advancements in regenerative medicine.
Dr Karmy:So are you implying that in order to use allogenic mesenchymal stem cells, one would have to also administer immunosuppressants, which of course have a whole slew of side effects and complications, and there's a possibility of rejection?
Dr Drew Taylor:So I think that without them, there is the possibility of rejection. And so what we find with MSCs and it depends on where they're sourced from as well is that in my experience and in talking with some of the physicians that we work with that, that have experienced in this space, there's a very wide range of experiences the patients have had. And so ultimately, I'd be really interested to hear what your experience is, because I know that you're one of the only two sites in all of Canada that are in this investigational study delivering some of this, the next use cases of these cells which is like fascinating. You're on the leading edge. So I think that this is a space where we're learning a lot. from it. I've certainly seen patients because there's not that many clinics that are offering what you are, right? Most patients in Canada, if they want to have MSCs applied, they have to go outside of North America usually. And so I've seen a lot of patients that have left for travel, medical tourism where they go down and they receive Stem cell applications. Now again, were they MSC's? Were they harvested from that patient? Were they donor cells? There's so many different questions because it's outside of, the FDA or Health Canada. We don't have any clarity. But I have seen many patients come back from these trips in much poorer health conditions than they went down in. And that scares me. As a health care provider, that scares me immensely because these patients are like going down there because they're suffering from pain or they are trying to correct performance athletically and they're coming back with zero difference at best. Or in a lot of cases out a lot of money because it's expensive. And in some cases unfortunately, they've actually required surgery to repair damage that's been done because they rejected the cells that were given to them. MSCs do have certain capacities of being what we would refer to as immunoprivileged, right? But they certainly have HLA, right? They certainly have proteins that can be identified as foreign on their surface. And the best case scenario, right? is that they release some growth factors and some elements that are not Person specific, so they won't be targeted by the immune system, but the cells themselves will all be killed off, right? They will be targeted by the immune system eventually and get gotten rid of and the hope is that in a quick period of time while that's happening. Those MSC's are releasing these proteins these factors that we want. But here's my question right in this scheme and one of the things that we ultimately want to work on and investigate. If you just take those secretions that we're targeting from these cells anyway, and we deliver those without the cells, can we get the same effect? Keep the immune system slightly less inflamed because they don't have to kill off the cells, right? Or they don't have negative responses to those foreign segments, foreign proteins on the surface. And we end up being able to have the same effect delivered or an equivalent effect without the negative side effects of having an inflammatory response that goes above what we want in that space. So I think that there's some interesting work that we're going to get into in this next phase to see if that's the difference. Now, again, if we go back to what we're talking about in tissue engineering, and we are actually, we want those cells to stay, to reside, to build matrix, to provide a function long term, that's a very different question, right? We want those cells to stay. In my opinion, I think some of the biggest leaps forward will be using our patients own cells in the near future here, because we have that biggest complication removed. The issue of rejection.
Dr Karmy:So it sounds like what you're saying is that allogenic opportunity is mostly with things that these cells release. I don't know if exosomes have an immune response to them or not, but certainly various proteins that they secrete is the biggest opportunity there. Not actually using these stem cells to build something because of the immune response.
Dr Drew Taylor:You said something very interesting that I, if it's okay to just talk to a minute because I think that it's very poignant, right? Exosomes and the question on whether they have that can incite an immunogenic response. Exosomes is a very new area. Yeah, it's a very new area of focus. And ultimately, exosomes bud off of cells. So they take the phospholipid bilayer of a cell with them and use that as the envelope. And our cells around our body have HLA. They have these things. And so there have been proteomics studies that have identified that HLA, of course, comes off sometimes. Right. If not all the time with the fossil lipid bilayer and exists on the surface of exosomes. So yes, theoretically, you can have a immunogenic response from exosomes because you have the HLA, right? Now, the question then is how does that affect the performance of those practically? And it's limited studies because this is a new field, but there's about six studies that have looked at this so far. And one of my favorite ones actually is not in the lab or with small animals. It did it in monkeys, rhesus monkeys. And they looked at wound healing models and they took MSCs from , an allogenic, so a donor monkey as well as exosomes from a donor monkey. And then they took the actual MSCs as well as the autologous exosomes from the same monkey. And when a monkey received their own cells or their own exosomes, it performed better, faster wound healing than when it was from a donor. So all things equal, if you have the opportunity of receiving your own material, It looks like our bodies react better to it and you get faster healing and better healing because of that, at least in this wound healing model. And so I think we'll see more and more of these prove that out more and more study because this is a new space. But what it did tell me is that exosomes, one, can incite an immune response theoretically, but more importantly, when we look at in practice, what is more beneficial? Having an autologous source either the cells or the exosome secratome performed better on the individual so certainly thats something we should take note of.
Dr Karmy:So , there is some, in the back of my mind, there was It's a bit of a question, can exosomes cause an immune reaction? And it sounds like perhaps. So what is the evidence that stem cells in young people are better than stem cells in older people? And also, as somewhat related questions, most of the time when you take stem cells, as you alluded to, you have to expand them. So do the stem cells age while they expand?
Dr Drew Taylor:Yes it's the perfect question. Obviously, age is a major contributing factor to the performance of any of our cells, which include our stem cells. As we get older, our cells do not perform as well. Our stem cells do have the ability to maintain performance for longer, right? Like their job is essentially to try and stay as this everlasting pool or resource of cells that can continue to butt off and be utilized in all the different areas of our body, right? Fill in those responsibilities. So the cells, the stem cells are engineered to try and maintain their youthfulness as much as possible. But age catches up to every cell. So having a younger cell ostensibly is always better. That being said, I think the bigger question is, does it outweigh the costs of having a foreign cell? So if you are going to have an immune response against those cells because they're foreign or those exosomes, cause they're foreign, and again, we're still learning more there. I don't think that it is better. There's a lot of talk about trying to get to age zero, right? Can we get exosomes or can we get, stem cells from The umbilical cord and other areas that are like age zero. And I think that there's like in theory that is a great idea but the issue is in what essentially talked about is that you have to expand these cells to get utility out of them, especially if you're doing this allogenically, where you're taking a source and you're hoping to treat many people. And every time you ask those cells to divide in that culture system, you are aging them. And so I have seen groups that are taking age zero, young cells and they're passaging them four, eight, 12 times, right? Passaging essentially signifies when you take a culture of expansion. So you're growing those cells, you're multiplying those cells. Passaging is that period where you then collect those cells. Okay. and reseed them or replate them onto the, more plates to grow that number again. So if you grow that first plate, then you take those cells and maybe put it across four plates and continue to grow. So you're constantly increasing the number. And so every time you passage those cells, you're collecting them and reseeding them in low density to get them to grow again and culture. And those, the acts of passaging is like the fast forward button on aging for those cells. So they're culturing them and asking them to divide again and again, and essentially artificial inducing age in these cells and fast forwarding that acceleration of that process. And at the end of the day changing not only in some cases, the age of those cells, but the very way that they perform, because once they're outside of the body, the longer they're grown, the more they sometimes what we call either differentiate or de-differentiate, right? So they, they migrate away from their core responsibilities. So these are definitive issues. And for us, what we try to do in this first wave of study, which we have just launched with our first partners, mostly is, as we were talking about offline, in dermatology, plastic surgery and aesthetics, right? For skincare. We've started that study where you can go to a number of sites and actually get your own exosome product, your own growth factor product applied back to you. We do not passage those cells. We grow those cells. After harvesting, and that initial growth without having to passage them is what we collect. And so we, we do no artificial aging of these cells. So I think that's a very important distinction, where your cells that you've harvested, maybe even stored previously, have the ability to be younger than these age zero cells that are just cultured again and again to service a great number of people.
Dr Karmy:I'd love to talk about IPCs. I'd love to talk about what cells you've differentiated things into in your lab so far. Of the hair stem cells. Because I am assuming, obviously, the options are much wider for iPSCs, but there's a little bit more unknown. The more you manipulate the cells the more unknowns start to arise. But let me go for the jugular, in a perfect world at least when we're talking about treating osteoarthritis, and I'd love to talk about your views on pathophysiology of osteoarthritis, which is also one of those topics. But then anyway, in perfect world, the problem that we face with a lot of things that we do now, is that is percentages. You see a patient, you inject a platelet rich plasma, or even bone marrow concentrate into them. What percent of people have improvement in pain? Eh, maybe 60 percent if you're lucky. What percent of people have cartilage regeneration? We're not sure, but hopefully some do. So in some ways, it's almost like a probability game. You do a treatment, and you hope that it works, but you don't really know for sure that it'll work until you do it, right? In perfect world since, osteoarthritis, at least in part, is a cartilage disorder. What you would do is you would take stem cells, you would actually cause them to differentiate into cartilage cells, instead of hoping that they do it once you inject them into the joint, you differentiate them into cartilage cells, you, as you said, create a matrix that holds them in place so they don't float away, you glue that matrix containing those cartilage cells to the surfaces of the joint where you have a hundred percent guarantee that you have fixed the joint in the same way that you repair a car. If you replace a flat tire you know a hundred percent that flat tire is fixed you don't say there's a sixty percent chance that you know, the tire is good, right? What are the obstacles to getting there?
Dr Drew Taylor:In cartilage specifically? So, I think one of the biggest obstacles is our ability to grow cartilage. Specifically, right? Not inject exosomes or growth factor to try to help the body do it itself, but our ability to produce cartilage outside of the human body is limited. And we can create cartilage, but hyaline cartilage, the type of cartilage that exists on the end of our joints is very specialized. And it has, you mentioned using glue to affix a cartilage surface onto the joint. One of the most amazing things about cartilage is the bone to cartilage integration that exists as a gradient. And that truly is where it has, I think, a lot of the magic is made in making sure that it acts as a cushion for that bone is the cartilage and the bone interface. And that in itself, and the integration of those two surfaces is what makes cartilage perform so well on our joints. Otherwise, when you have a glue and other efforts that have been made, you can slough off that cartilage piece and you're back to square zero. So that integration step is immensely important. I was very lucky enough to spend some time with Dr. Rita Kandel at Mount Sinai Hospital, where I was working under her in my PhD, looking at efforts around creating hyaline cartilage in vitro. And there was some fantastic students there that were also focusing on that zone of integration. Everybody had a different role putting this piece together. But I think that integration zone is one of the biggest things. The other big limitation that we have with cartilage is that we talked about passaging and expanding cells. When you grow cartilage cells in culture, they change very fast. One passage and they have changed the way that they perform. And the biggest thing that you see is cartilage cells produce high amounts of type 2 collagen. So, one of the only places in the human body that we get these high concentrations of type 2 collagen. As soon as you start culturing them, they stop producing high volumes of type 2, they drop. And type 1 collagen, which is more of the collagen in our tendons and ligaments and things, that starts to go up. And so you end up getting what we call fiber cartilage. It doesn't have the same performance level for impact on a joint surface. Right? Fiber cartilage can't do the same thing as what hyaline native cartilage can.
Dr Karmy:It's less flexible, less elastic?
Dr Drew Taylor:Yeah, and it doesn't have the same rigidity as well. So it has some of these elements where it's I would say the rigidity is less, right? You have, if you feel them even, right? It's less rigid but if you look at the mechanical properties of it, the impact properties, they drop significantly.
Dr Karmy:Not as much cushioning effect.
Dr Drew Taylor:Not as much cushioning, but they have more stretch and things that are needed for like tendons and ligaments and things like that. But because they're just piled upon each other as opposed to elongated in a structure like a tendon or a ligament, that's not useful in that space, right? So I think that's probably one of the biggest things that is, is needed in cartilage tissue engineering. Specifically, to be able to go in and spot focus, treat segments of even entire condyles or entire articular surfaces of OA or trauma that happens. I think that we're a ways away from being able to do that perfectly. But, there is some work that is getting extremely close and I was very excited that I was able to be a part of some of that progress when I was working with Dr. Kandel. But it is, it's a grand challenge and some of the biggest issues with cartilage is you don't have a blood supply. There's no nervous innervation. Cartilage is essentially diffused from blood into the matrix to reach the chondrocytes. So we're talking about a lot of a long pathway for those nutrients to have to flow to get to those cells. During development, you make the cartilage and it's supposed to be there for life. You've got some remodeling of these embedded chondrocytes within that matrix, but it's supposed to really be there for you. The big job is done during development. How do we hijack that system and recreate that same developmental regeneration of cartilage? Later in life when we need it, and I think it's going to be a combination of leveraging stem cells as well as chondrocytes themselves.
Dr Karmy:So sounds like the challenges are the right type of cartilage and attaching them to the bone correctly.
Dr Drew Taylor:I agree. Yes. Yeah.
Dr Karmy:So that was wonderful. You seem very well informed, not just in your own little area, which is storage of stem cells, but where the field is and where it's going into the future. I'd love to have you come back again sometime because there's about five or six questions I never got to ask, but thank you very much for coming on the podcast.
Dr Drew Taylor:Thank you, Dr. Karmy. I really appreciate the opportunity to chat with you and thank you so much for your very insightful questions. I would love to come on again and dive into the next area, but we certainly don't want to just focus on banking, right? As a group, ACORN is focused just as much on making sure that patients have their own cells as leveraging those cells and being involved in the opportunities for patients to receive benefit from those bank cells in actual applications. It's a huge focus of what we do every day. Thanks so much. This was a fascinating interview. It seems like we're still far away from creating organs out of stem cells, and I'm including cartilage as an organ here, although it may not exactly be meet the definition at this point. The most promising approach is simply stimulating the cells that are already in the cartilage to divide and grow and make more cartilage with various growth factors and anti inflammatory factors. Dr. Taylor called this, secratome. In other words, everything that stem cells make. The second takeaway, is fundamentally a fork in the road for stem cell treatments. There is allogenic, stem cells, which are made from a donor or another human, which has advantages of consistency, reproducibility, and economies of scale. In other words, they're cheaper to produce but have a problem with potential for immune rejection. On the other side, there is autologous approach to stem cell therapies, where stem cells are actually taken from the same person in whom it will be used for therapeutic purposes. The advantage there is lack of immune rejection. Which approach will win in the long run? It is hard to say. The challenge for stem cell companies is to reduce or eliminate immune rejection. Perhaps they can use CRISPR to remove HOA markers, which immune system uses to detect foreign cells and attack them. Well, the challenge for autologous stem cell therapies is to make the results more consistent and perhaps less expensive. Thank you.
