Sore knees? Can't run? Bad hip? Need replacement? Shoulder injuries? Why doesn't the body reproduce cartilage as it does when you are a teenager?
Well guess what, it does. New research from A Stanford University study shows a breakthrough in stimulating stem cells and actually regrowth of cartilage. Maybe you won't need that knee or hip operation one day in the future.
We talk to researchers Dr. Matthew Murphy currently at The University Manchester, and Charles Chan Assistant Prof. at Stanford's Palo Alto campus in California.
Sore knees? Can't run? Bad hip? Need replacement? Shoulder injuries? Why doesn't the body reproduce cartilage as it does when you are a teenager?
Well guess what, it does. New research from A Stanford University study shows a breakthrough in stimulating stem cells and actually regrowth of cartilage. Maybe you won't need that knee or hip operation one day in the future.
We talk to researchers Dr. Matthew Murphy currently at The University Manchester, and Charles Chan Assistant Prof. at Stanford's Palo Alto campus in California.
The fountain of youth, sometimes known as Aqua Devita was a legendary spring that restored youth or granted immortality from anybody that drank from its waters. Are you guys offering us a little drink?
Speaker 2:Uh, it would be a little bit of a drink for your knees, but yes, that's essentially what we're trying to do here. Specialized types of cells in the body, they are essentially to fountain of youth.
Speaker 1:Hi everyone. And welcome to this edition of backstory. I'm Dana Lewis from London. I want to share with you what could be a bit of magic. If you are a runner or just aging and you need hip surgery, shoulder problems, knees are wearing out. Let's talk about STEM cells definition. They are capable of giving rise to indefinitely, more cells of the same type translation, those magic cells in your body to make you grow things like cartilage, but that wears away. As you get older, I'm missing some cartilage in my knee. And since the COVID-19 pandemic began, I don't miss a day running, but my knees hurt and I've had two operations over the year to clean up my knee. And the cartilage is wearing thin in my knee joints. In fact, almost everyone suffers the same problem as they age. Especially if you do a lot of sports, tennis, rugby hockey, you probably suffer some knee problems. Are you ready for some earth shaking health news? What if there was a way to reverse aging and make Cartlidge regrow by stimulating STEM cells? Well, a new study out of Stanford school of medicine has succeeded in doing exactly that. I want to run a marathon. Maybe you do to listen to this backstory. It's very promising news.
Speaker 2:[inaudible]
Speaker 1:All right. I want to introduce you to the two people who put most of this research together and we'll walk through it with them. First of all, as dr. Matthew Murphy, I know hazard to be here, and then we take you all the way into another time zone. It sounds like the Twilight zone, but it's Chuck Chan is speaking to us. He is an assistant professor at Stanford, but he's in the Palo Alto, California campus. Hi Chuck. Hi.
Speaker 2:Yeah, thanks a lot for the opportunity to be here.
Speaker 1:Well, it's great to talk to both you, both the fountain of youth, sometimes known as Aqua Devita was a legendary spring that restored youth are granted immortality from anybody that drank from its water. Are you guys offering us a little drink?
Speaker 2:It would be a little bit of a drink for your knees, but yes, that's essentially what we're trying to do here, right?
Speaker 1:Yeah. This is really exciting because I don't think people realize how many people as they get older. And I'm an older runner I will confess. I know I don't look that way, but I don't think people realize, um, you know, one in 10 people by the time they're 80 has had a hip replacement one in 10,
Speaker 3:And it may be even higher than that had, has had a knee replacement. And what you've done in your research is untold is that you are finding a way to regrow cartilage. So who wants to, who wants to take the first run of this Matthew? Dr. Murphy? Do you want to explain what you've done? Sure. No problem at all. Well, my background is I did medicine at university called stubborn, and while I was over there, I really focused on hand surgery and we applied to principle known as microfracture, the joints of the base of the thumb, which was new at that time. However, microfractured to the knee, as you might know anyone, who's an avid sports person who might've had my profession surgery has been around since the 1960s we thought. And we, it has always been believed that by microfracturing you're able to somehow rejuvenate the joint by forming a scar tissue known as fibro cartilage. However, the positive effects seen by microfracture often wear away with time. So I wanted to find out, and in order to do this, we had to really go down to the very basics behind it. The purest form of signs to look at it at a cellular level. And professor Charles Chan at Stanford have found the mouse, skeletal STEM cell and subsequently the human skeletal STEM cell. So in order to see, first of all, does microfracture even activate these cells? We had to try it first on isolating these specific cells from the joints of mice and then in human tissues as well. So it was really important to see that skeletal STEM cells exist in mass and human tissue, like old arthritic knees back. We just, before we go on with that, will you take me back? And, and Chuck, if you want to do this, when you are young, you have STEM cells that grow things like cartilage between your knees. Yes, jacks, as the, as that shock absorber between the knees and then suddenly untold around 14, 15, 17, your body kind of turns it off. Is that, is that accurate?
Speaker 2:That's correct. So, as Matthew explained, um, normally we have these specialized types of cells in the body. They are essentially to founded youth, but for every single different types of tissues, there is a different fountain of youth it's you can think of as a fountain of youth, because this is where new tissues come from. These are the cells that forms new tissues. They have the ability to make different types of tissues, and they also have the ability to make more of themselves during development. These are the cell types that are responsible for making the majority of the tissues. That's the organism. And so there are skeletal STEM cells normally early on into joints that is in responsible for forming the cartilage. However, unlike bones, which these STEM cells also form at, which has the ability to regenerate adult cartilage has practically zero, which are ability long
Speaker 3:Tragically. So, because if you get older, you inevitably wear out that cartilage between your knees. Are you aware of that other parts of your body?
Speaker 2:Yes. Yes. And unfortunately, the more active you are in some people that it wears out even faster. So this, this is due to the facts that, um, at least we thought that there was a lot a change in STEM cell activity during aging, and we thought
Speaker 3:Translation, you just stop making STEM cells.
Speaker 2:Right. That's right. They're found out you youth has been turned off. Okay. But what we found was actually that is not entirely the case, that there were still skeletal STEM cells residing within the cartilage and underlying bone.
Speaker 3:All right. And that's, that's where we go back then, before I interrupted you, if you that's where we go back to, you were able to activate
Speaker 2:That's right. They're, they're simply quiescence, they're asleep basically. And in their response,
Speaker 3:Will you lead me through then the injury that you did to bone in mice to begin with about how you're able to activate that? So, uh, we tried to replicate or try to imitate what commonly is performed by orthopedic surgeons. So frequently, any microfracture surgery, uh, results in the formation of fiber Carters. And how does that is you have to bride off the diseased cartilage first, and you make small holes into the underlying subchondral, which means under the cartilage bone and frequently orthopedic surgeons do that using truck cars. However, there's been used studies that show what's that mean Trump cars are like pointy needles that they use to poke holes down through. And there is results leads to like a blood clot that forms within the area that you've debrided and this then forms fibro cartilage. But there's studies that showed that using a TRO car or like a pointing needle, doesn't have as good effect as if you use a micro drill, because it's actually using a micro drill and very small drill, same size of the same diameter as the needle actually allows you to maintain the architecture of the subchondral bony space. And this allows for better activation of those STEM cells. Okay. Now, after two operations on my knee and people telling me, you should just go get knee replacement because your knees are shot. Your cartilage is never going to come back. I did have STEM cell and, and they, they told me that it might help you with inflammation.
Speaker 1:Uh, but it wouldn't regrow cartilage. And then I had somebody else saying, well, yeah, it might, it might regrow cartilage. And, and they were, you know, probably judged by most professional surgeons as false promises and smoke and mirrors. So now I've been holding back on any kind of knee replacement, because I think that eventually we'll turn the corner on STEM cell and brilliant people. Like you will be able to lead us to the, to the point where we can regrow cartilage. And a lot of people are saying, that's snake oil. Now, are you telling me it's, you're telling me we've arrived at that, at that corner. We're turning that. Now,
Speaker 2:This is the first time that we've actually seen. And other investigators have reported formation of this so-called hyalin cartilage. You know, we've been talking about different types of cartilage during this interview, there was a fibro cartilage, although it sounds like it is the same type of material as normal cartilage in the joint. It's not, it's more of a scar tissue that's made of a fibrous capsule and it's better than bone rubbing against bro. You know, it, it forms a sort of a bandaid over the injured area, but it doesn't have the same mechanical properties as true cartilage, what we refer to as Highland cartilage. So what we have managed to do in this process is form true durable Highland cartilage from the skeletal STEM cells. And the way that Matthew discovered that this happens is that the scalpel STEM cells that he can awakens through this surgical procedure of microfracture normally has the option to turn not only into fibers, fibro cartilage or scar cartilage, which is not really true cartilage, but also bone as well as true Highland cartilage. This was in mice. This is in mice and also in human joint tissue that we have grown on the backs of mice. So we would take some of these tissues from a patient and then grow it in a mouse by attaching it to a blood supply. And so these would be viable human tissue growing on the back of a mouse. And that was in order for us to test whether or not this combination of factors that we use to coach these awakened STEM cells towards true cartilage, also functions in human tissues rather than only in mouse tissues.
Speaker 1:Can you give me some, some perspective on, is this just like, you know, minute amounts or do you think that you could actually stimulate enough to replace this damaged cartilage in the knee? For instance, I know there are other joints that we're talking about, but you know, I'm selfishly talking about knees too much today. There certainly is the potential to be able to use it for larger joints.
Speaker 3:However, it's very important that we take our findings with, uh, with an element of really, um, making sure that we do rigorous tests before we try anything too quickly. And so it's important that we ensure we're showing these results in smaller mammals. It's important then to take it to larger animals studies and subjects subsequently then moving towards human studies in a controlled environment where we know specifically what's happening to the cells, as you mentioned before, yes. Other groups have mentioned that they have STEM cells and STEM cells is a very cool topic. And it is, I think he used the word snake oil. I'm not sure exactly what that means. Snake oils, when those guys used to go around in the, you know, the old Western movies and they used to appear in the town square and they'd be selling some kind of snake oil and they'd say it was a curable and it would, it would solve all of your ills. Right. And it was probably just some water with some dye in it. So w and actually it's a very old term, but when I saw a doctor in England about my knee in London, he said, you know, don't believe any of the STEM cell stuff. It's just snake oil. And, you know, the balloon would poof for me because I thought, wow, if we can get to STEM cell regrowth, uh, how incredible that would be for so many people. And I think when you mentioned, are we turning the corner? I think we are because groups like professor Chan's in Stanford have the ability now to more accurately hone in on the specific cells. And therefore we can see the effects of what we do mechanically, chemically, how we alter the environment, how that would affect those STEM cells. Whereas before we had less ability through technologies that were more limited, that we couldn't identify specific cells, or at least more specific some types of cells. And so therefore they were all grouped that often a lot of it it's like, you know, finding the new worlds and labeling new countries and things. People have a habit of sometimes over promising and over labeling, but not to sound like a pessimist. It's important to take it step by step and to be cautious with our findings and not over over promise too many things. But I think as you say yourself, I think technology has allowed us to now move forward in a more controlled and more specific way that we can really accurately predict how the sales might act in a controlled environment. Chuck, what was that novel of mice and men, or, or if I recall in high school, reading mice are not men or women for that matter, do you think that you can go to larger mammals and then human testing and that this will hold up?
Speaker 2:Uh, I think that's the hope, the factors that we use in this study, that one of the things that was exciting about it was that they are already FDA approved in the U S for use in humans. So one of these factors, um, it's called BNP too, and it's also marketed as infuse. And this is a product that's normally used to fuse bones, um, during spinal fusion. So that's a chemical that's already been used in humans and it's it's properties as somewhat well known. Um, and then the other drug is a product that's similar to Avastin, and that's an anticancer drug that blocks is, um, a certain type of blood vessel forming cell signaling.
Speaker 1:What of these two drugs do that when you're, when you're doing the, the small fractures, is that when you use them
Speaker 2:That's right. So the unusual thing about the signals is that you can think of them as letters in a word they're kind of an alphabet. And if you rearrange these signals a different way for a different type of cells, it means a completely different thing for instance, than what it would mean for a cancer cell. If you combine these two factors together for their joints, um, it means two things first make more of the STEM cells. So that's what the BMP does. It's expands to STEM cells. And then second, the anti-VEGF, which normally means, um, makes, tells the tissues not to not to make blood vessels. Instead it tells these amplify skeletal STEM cells not to make bone or fibroblasts. And when these two options are shuts off, then the STEM cells turns into the default state, which is cartilage really that's right. So really don't make bone or scar tissue and you'll make cartilage.
Speaker 1:So do you think you could make enough in humans to replace
Speaker 2:In the case of the mice, when we deliver these factors in using this material, we were able to resurface most of the entire joints. Well, so if we were able to scale this approach, um, appropriately, then there's that possibility. But as Matthew pointed to out right now, one thing that we're concerned about is potentially surgeons trying to use these drugs on their own, which are already out in the markets, um, and getting undesirable results. Because what we have observed is that the concentration and the timing of these factors are very important. There's another aspect to this that we're still working on, which is the shape of the new cartilage that's formed. So it's gotta be the right shape. That's right. And so what we're afraid of is that if you were just to inject these two factors, um, without the proper material, to give them the right shape, you will have cartilage that doesn't really conform to the appropriate contours. That's right. That's right. So you would, it just wouldn't be the right shape. So
Speaker 3:That's something that we have to work on next in larger animals, larger animals. And then Matthew, when do you think, how soon could this go to human testing then? Well, I know that certainly the factors that are very close to they are FDA approved as professor China's already mentioned. Um, and so I think, I think once we have confirmed it in larger animals, and we can see that it's robust carpets that's formed in as larger animals, then we'll be able to move forward in a controlled way. I would say that currently, I mean, you've mentioned knee arthritis, but there's also other forms of osteoarthritis that affect other joints. And at the moment I'm currently an academic clinical fellow at the university of Manchester, and I've rotated through a hand rotation with professor Lee's and mr. Misha. And they have often looked at patients that suffer from quite severe arthritis of the base of thumb. And this is a particularly debilitating disease at the moment. The current treatment is to simply take out the affected bone. So they don't even replace it with anything like you would in a knee joint, you have your knee replacement in the base of thumb. They simply take out the bone. So it's pretty crude operation. So it would be great to see how these factors might work in a bone that we would otherwise be removing, because if there's a negative result, the end result would be that we would remove the bone anyway. So there's no real loss. Um, and so this allows us more potential, more potential flexibility in transferring or translating this basic science finding into more clinically relevant findings, both. I mean, I think, yeah, absolutely. And, and obviously it's got to go forward in a reasonable way. Right. But I think STEM cell is probably one in and, uh, uh, platelet, um, PRP is probably, I mean, these are some of the biggest rackets. Uh, that's my word, but I know they take thousands of people. I was a clinic in London, which I won't mention said, give me 50,000 pounds, you'll your eyesight will improve. Your skin will look 10 years younger. Uh, your liver and kidney functions will be different. Your knee will regrow cartilage. And I said, seriously, this is a few years ago. And I said, will you show me, show me the MRIs, show me some proof of other patients has gone through that. And they said, well, because of patient confidentiality, we can't do it. And then eventually I think the government of Canada stopped some of the STEM cell injections that were going on because people have been promised the moon and STEM cell, obviously it's while it's promising it didn't produce. Right. So this is one of those cases that you worried that doctors know are going to pick up on some of this and just go and start trying to experiment with patients or this because there's drugs involved. Maybe it's going to have to be a little more regulated. Well, 100% have to be more regulated and there will always be those so-called with snake oil that will be trying to sell you everything and more, but if it sounds too good to be true, it normally is too good to be true. Um, and certainly coming at it from a more vigorous, basic science approach, it takes a lot more time and a lot more thoughts before anyone with a conscious conscience could really reliably tell you that it works well. Um, and so it will take a few more years to come through. Um, I mean, people might try and use those compounds, but to do so would be quite dangerous because even though we seen a positive effect in smaller animals, I would be cautious having seen the great effect that it has. I would still be cautious moving forward, but humans, I know one of you do an analogy to a Jiffy lube model of cartilage replenishment. Where was that? You Chuck? I don't know where,
Speaker 2:So does all of this work was done in a collaboration with a mentor of my, um, Mike Longacre? Yes. As Stanford university, he's the director of the, uh, regenerative medicine program there.
Speaker 3:The, the parallel with Jiffy lube is you wouldn't necessarily go and do this treatment once, but you may do it sort of a regular cartilage replant.
Speaker 2:That's right. So if we see that these two factors, um, could stimulate cartilage regeneration, perhaps, um, we can also try delivering it, um, in the proper format, in their proper combinations periodically before the cartilage has completely eroded away. And maybe we need to see cause that's right.
Speaker 3:Some cartilage there, or because if you can stimulate STEM cell production, does it, do you need old cartilage to bond to, or does it matter how far along the deterioration of cartilage is already?
Speaker 2:I think it might match her to have to ensure that the new cartilage does bond with the old cartilage and gestures from the mechanical perspective of getting the joint to function properly and getting to new cartilage to stay in place. However, we have seen that these factors can also restore cartilage, even though all the cartilage has gone by directly growing new cartilage. On top of the subchondral bones,
Speaker 3:You guys got to get going, I'm not getting any younger and we need to get this done. So when, when do I sign up? I mean, what is the next big, what is the next big animal you go to before, before you come to me,
Speaker 2:There are some certain types of animals like sheep, for instance, and dogs that normally develops osteoarthritis. And so what we would like to do is to perform a large animal study in various joints. We know we would try the joints at the toes, for instance, and also the knees to try a certain combinations of these factors to see if we can optimize the type of cartilage that's formed. That's probably going to take us around like one or two years.
Speaker 3:Incredible. And so, and just to clarify, I understand, soon as you get an injury, you have, you, you have inflammation, you have arthritis, but you may still have cartilage, but so does this help with arthritis?
Speaker 2:It helps with DF, right? As it certainly helps with the pain. So I think Matthew can talk a little bit about how we showed that in mice.
Speaker 3:So yeah, so the, to get mice, to observe mice and see how they are, how they are responding to the treatment, you can actually this technology that allows you to look at how the mouse walks and that we described that as the gate of the mouse. And so you can see if they have a limp and you can see it, their stride and where they're placing their weight on each of the feet. So it's an, it's a Suprep technology. However, again, looking at smaller animals, they're very different to larger animals. So smaller animals are knowing to be able to mask they're paying quite well in a survival mechanism. And that prevents them. It's the fight or flight response that prevents them from being eaten by predators. So, um, so again, smaller animals are very different to larger animals and we'll have to reassess that on the larger animals themselves. So I dunno if you have a golden Labrador, they'll probably be able to walk sooner, hopefully something lucky dogs, but this treatment might, we might see a good response with those. And then we can grow it on with the, um, the human, the human trials. So with me, it may reduce pain. It may reduce levels of arthritis. It's not going to reverse severely arthritic joints that are completely locked.
Speaker 2:That's one thing that we're hoping that it actually might be able to do. We want to resurface the whole joints. And that actually depends on the utility of a procedure that is commonly used for treating joint injuries and that's called arthroscopy. And so the surgeons and these are performed many times a year in the U S is fairly routine. There is their surgeon makes an incision on the knee and sticks of fiber optic cable within the knee. Now you can do this for the joints, right? But you can't do this for a lot of other tissues for instance, the brain. So this is a well established technique. And so what we're thinking is that we will create an, a new type of scaffold that would allow you to deliver this material during an arthroscopic procedure. So you would go in into the bride. Most of them are missing pieces of cartilage or their free floating bones. And then you install this new material and it will regrow some of the new cartilage thereby, um, at least perhaps even replacing the need for a joint replacement processes to be installed, replacing the knee, or,
Speaker 1:Or short-circuiting the need to replace it. That's right. Bypassing the need for a joint replacement. That's why it's so promising. That's why it's so promising. Chuck Chan, the assistant professor at Stanford and dr. Matthew Murphy, an amazing medical evolution. And a lot of what we have is, is pretty crude in terms of dealing with joint problems. And this, this is the future, and we're all, we're all hoping you guys do well because then we're all going to be the best. We're all going to be the benefactors of that. So thank you so much. Thank you very much for this opportunity. And we'd like to also think our supporters at the national Institute of aging, the arthritis, national research foundation, and American Federation for aging research for supporting this work. Also the California Institute for regenerative medicine, because there are, there are tens of millions of dollars that are going into this area of research, right? So many people are affected by arthritis and bed joints and yes, yes. So we're really, really grateful for the taxpayer support of this research of, um, of basic science. Matthew. Thank you. Thank you very much. And I'd like to take this opportunity as well, to thanks you for your time, but also to thank my two mentors, professor Chan and professor Longacre, as well as my co worker Lauren co-PI. He did a lot of this fantastic work as well. Exciting stuff. It is. It's been tastic. Thank you very much for your time. And that's this addition to backstory on it. STEM cells and the regrowth of cartilage. We are years away from this new medicine, but maybe, maybe only a few years. I want to run that marathon still. And I'll keep you up to date on backstory as this progressive it's fantastic medical science. I'm Dana Lewis, the host of backstory. If you would like to become a sponsor of backstory, get in touch and please subscribe and share our podcast. I'm off for a run. I'll talk to you again soon.