Gladden longevity — Episode #50

Steve Reiter: Welcome to the Gladden Longevity Podcast with Dr. Jeffrey Gladden, MD, FACC, founder and CEO of Gladden Longevity. On this show, we want to answer three questions for you: How good can we be? How do we make 100 the new 30? And how do we live well beyond 120? We want to help you optimize your longevity, health, and human performance with impactful and actionable information. Now, here's today's episode of the Gladden Longevity Podcast.

Dr. Jeffrey Gladden: It's my pleasure today to be here with Dr. Ian White. Dr. White's a Ph.D., and he basically has worked at Dartmouth and Harvard. He's been involved with stem cells. He's done some really groundbreaking research, which I actually took the time to read your article on peripheral nerve signaling and cardiac regeneration, which was done in mice, which was quite a fascinating article, basically showing that you needed to have sympathetic nervous system innovation for the regeneration to actually take place. So, that's fascinating in and of itself.

But he's actually the CEO and CSO of Neobiosis, rather, LLC, which is really focused on regenerative medicine, and we'll talk about that. But the other interesting thing is he's a co-founder of the Space Aging Research Institute, which is another really fascinating topic. So, Dr. White, or Ian, I'll call you Ian probably throughout the course of the conversation.

Dr. Ian White: Yeah, that's fine.

Dr. Jeffrey Gladden: Yeah, it's great to have you here. Thanks for coming.

Dr. Ian White: Well, it's a real pleasure. I love being able to have these conversations about longevity and health span so, very excited. Thanks for the invitation.

Dr. Jeffrey Gladden: Absolutely. So, tell us a little bit about the primary company. I assume that Neobiosis is the primary company. Tell us a little bit about that, what you're trying to accomplish there and how you're going about it.

Dr. Ian White: So, the idea of Neobiosis is really to pursue the experiments that were done many years ago called heterochronic parabiosis. That's where we got everything from. So, you're probably familiar with those experiments.

Dr. Jeffrey Gladden: Just so the audience understands, just to interrupt for a second... We're basically taking an old mouse and a young mouse… So, that's the hetero part. It's one hetero, chrono, so to speak. So, different ages: old mouse, young mouse. And this has been done with putting two young mice together, two old mice together, and then a young mouse and an old mouse, just to set the stage for that. So, yeah, I think the audience is familiar with that. So, go ahead.

Dr. Ian White: Yeah. So, the exciting outcome of those experiments was that when you connect the blood supply, the old mouse got younger, and the young mouse got older based on specific markers of aging, which was very, very exciting. And so, the researchers at the time identified these ‘rejuvenation particles’, they called them at the time; they had no idea what they were. It turns out they were the exosomes that are in the circulation of young animals, and those particles are what cells use to communicate. And what we found at Neobiosis was that there's a natural form of heterochronic parabiosis, and that's pregnancy.

And so, you have an old individual and a young individual, and they're both sharing a blood supply. And this young individual is creating these extracellular vesicles to signal to the cells in its own body, but also the cells of the mother, because, of course, the mother's immune system has to be modulated. And the mother's body has to be prepared for the rigors of pregnancy. You've heard the adage that “pregnant women glow”, and that's because the signals they're receiving from the fetus change the physiology of the skin.

They change the physiology of the brain, and they improve eyesight and hearing. Cardiac output increases by about 50%. And so, all these signals are part of the heterochronic parabiosis that is pregnancy. And so, we were the first to publish on that, and we built Neobiosis around the idea that these young tissues are capable of altering older tissues and allowing those older tissues to regenerate like they do when they're younger. And so, we started generating products from amniotic fluids. So, birth tissue, these are from healthy live births. So, the fetus isn't injured or harmed in any way.

This is under maternal consent. And we take this product, which is usually considered medical waste, and we render it in a cGMP-compliant laboratory. And from that, we end up with purified amniotic fluid or Wharton's jelly from umbilical cords, or in some cases, the umbilical cord blood cells. And these all retain the signals that the young individual has in this heterochronic parabiosis, and what's exciting is that it's transplantable to an old individual, and what you end up seeing is that the old individual can heal again just like they did when they were much younger.

Dr. Jeffrey Gladden: Yeah, that's really, really fascinating. I think the audience is familiar with exosomes and, really, they’re packets of information. My analogy is it's like mail that cells send between each other. There's an envelope and a content and a signature, so to speak, and-

Dr. Ian White: And address.

Dr. Jeffrey Gladden: Right. And there are fragments of DNA, messenger RNA, some fats, and some protein in there. But basically, they are messengers that tell cells what to do, or, "Hey, this is going on in our neighborhood, it should go on in your neighborhood too," thing. Some of it’s warnings, some of it’s regenerative, et cetera. So, that's fascinating. So, have you been able to go inside the exosomes and see exactly what is being signaled? Have you been able to unravel that portion of it as well?

Dr. Ian White: Yeah. Of course, there's a lot more work still to be done, but we've been able to identify over 400 bioactive proteins that are present not only in the extracellular vesicles themselves that are secreted into the amniotic fluid because amniotic fluid itself is this remarkable material full of urea, full of hyaluronic acid, and full of these proteins that the body needs to be able to heal itself. But we've also identified cohorts of regenerative RNAs. We've found cohorts of immunomodulatory RNAs.

And so, all these RNAs are what the cell uses to make new proteins within the cell itself, and again, the message is the instruction manual, which then uses the raw materials, the building blocks that are present in the amniotic fluid and in the other extracellular vesicles.

Dr. Jeffrey Gladden: So, let's talk about RNA for a second. And I think most of the audience understands that when you have DNA, that's basically your blueprint. And then RNA is what's transcribed off of the DNA, which then goes to the ribosome, and then it becomes the blueprint at that level for the protein to be built. But there's lots of different RNA. There's messenger RNA; there's micro-RNA; there are things like that. So, what RNA are we talking about here in the amniotic fluid? Are these micro-RNAs because they seem to do a lot of signaling? What have you found there?

Dr. Ian White: They're actually both. So, there are many different types of RNA. There are probably about three or four different types of RNA that are present in exosomes. So, it really depends on the source of the exosome that you are looking at, whether it's culture-expanded MSC or whether it's from amniotic fluid, which is more heterogeneous. So, we have a lot of different types of exosomes with lots of different types of signals. So, we're seeing the message from the DNA. We're also seeing the micro-RNAs, which are the little snippets that are regulatory in many ways.

So, we're seeing the entire gamut of instructions that the organ or the cell needs in order to be able to respond and heal itself because that's the key here. We're not actually providing a drug. What we're doing is we're providing the raw materials and the instruction manual for the body to heal itself because that's why we age. That's why we go gray. That's why we wrinkle. That's why we have more difficulty healing when we're older because we lose those raw ingredients. We lose those mortar and bricks, and then we lose the instruction manual, which then we can supply with the perinatal tissues.

Dr. Jeffrey Gladden: So, messenger RNA and RNAs, in general, tend to be fairly fragile. Proteins are reasonably sturdy. RNA is actually not so sturdy, and we do some transcriptomics in our practice and some other things, and collecting the RNA and actually preserving it to get it to the lab work where it can actually be analyzed can be a challenge at times. But I think we have that figured out. Point being, though, how are you handling this product? Are you freezing it? How do you take care of the fragility that's in there?

Dr. Ian White: Yeah, that's a really great point, and I never get that question. So, that's a really good question. RNA is very labile. It breaks down very easily. RNA is all over the place. And that's very important for evolution because if it weren't and you got an aberrant signal that could be perpetuated, you could end up getting some very serious diseases. So, it's very important that the body has a way to break down RNA, which is the direct conduit to making the protein, which is the functional aspect of the cell. DNA, of course, can last for millions of years.

If anybody's familiar with Jurassic Park, they're familiar with the idea that DNA is not labile and very stable, the same with a lot of proteins. They're very stable, especially if you don't heat them. But RNA is very, very labile. And what's fascinating and why this works is because of the extracellular vesicles that these RNAs are packaged into. So, these EVs form a phospholipid bilayer, which is protective and doesn't allow the RNAs in. And so, that's what allows the signals, what we call cargo, to move around the body without being degraded.

And then, when it reaches the target cell, it's liberated through a process of Laplace's law, which allows a small vesicle to deliver cargo to a larger recipient, which is the cell, the membrane's fused, the cargo's delivered, and then the RNA is able to be translated.

Dr. Jeffrey Gladden: Beautiful. So, one of the things in using plasma and some other things, and I'm assuming biologic tissue and that thing, is there any issues with rejection or antigenic stimuli that comes from this where the immune system gets fired up because it's seeing something that's not... is it from somebody else's placenta or somebody else's amniotic fluid or something like that? Are there any concerns or conditions that you've seen related to that?

Dr. Ian White: Well, what's exciting about this field is that we do not see rejection. And in fact, there are a lot of studies that use the umbilical cord blood for bone marrow transplants. So, if you have a cancer patient that can't get a bone marrow match, often you can take one or two units, if we're talking about an adult, of cord blood, and you don't have to worry about an HLA match because they don't get rejected. So, that's really very, very exciting. And it follows for amniotic fluid and other perinatal tissues as well. They're not immune-privileged, but they are immune-evasive, which means that they don't elicit a graft versus host disease response.

They don't cause many problems in the majority of people. Of course, there are always outliers, but we just generally do not see that, especially when we consider the number of people that are being treated around the world with these tissues.

Dr. Jeffrey Gladden: Just out of my own curiosity, walk me through how this actually works. So, a woman is delivering, let's say you collect the amniotic fluid, then it goes someplace, then it's stored someplace, then it's sent someplace else to be used, or just walk me through how that works.

Dr. Ian White: So, we work with FDA registered, ATB accredited, so that's the American Association of Tissue Banking, accredited cord blood banks in the United States, and they have the ability to go into hospitals and work with physicians during scheduled C-sections. These are only C-sections that we utilize. And then, at the time of birth, they've had consent from the mother to collect the tissue. And so, rather than it going into the trash, which usually happens after birth, they're able to collect this tissue. They process it in the sterile environment of the surgical suite, and they send it to our laboratory overnight. So, it's shipped on ice overnight, never frozen, only on ice to keep it cool.

We receive it within 24 hours at our cGMP-compliant ISO 7 clean rooms, and we process it there and then. And it's processed immediately and then frozen. And once it's frozen, we're able to store it while it's in quarantine. And then, once it comes out of quarantine, we're able to use it in the clinical trials and clinical studies.

Dr. Jeffrey Gladden: Okay. So, how long is it in quarantine for? 30 days?

Dr. Ian White: Fourteen days. So, the standard, we use an independent, CLIA-certified laboratory for all our testing. And so, they do a 14-day sterility test. We take a random sampling of our lots. 10% of the vials that we manufacture go for endotoxin and sterility testing. Then once it clears that 14-day culture and there's nothing growing, we're able to then release it from quarantine.

Dr. Jeffrey Gladden: We get that it's a clean product, we get that it's non-antigenic, that it doesn't really typically, at least, elicit any immune response in either direction. And so, now, how is this being used? Is it being used to treat people that have disorders of some sort, or is it used for longevity medicine to help reverse aging and things like that? I will bring up one point, which is that pregnant women do have that glow. But it's interesting when you look at the epigenetics of pregnancy; pregnant women age to some extent during the pregnancy, and then they regain that in the subsequent year. Epigenetic studies have been looked at that.

So, apparently, the exosomes are not enough to fully compensate for, let's say, the stresses and strains of pregnancy per se. But how are these being used? What are the indications for their use?

Dr. Ian White: What's exciting is that they can be used for many, many different things because anything that the body needs that it's lost because of age can theoretically be regained by using these young tissues. So, as we age, we lose the ability to heal wounds on our skin. So, we're able to utilize these products for wound healing to accelerate healing like you would heal when you were maybe five or six years old, and you scraped your knee. That healing just is very rapid and very complete. Whereas now, in our 40s, 50s, 60s perhaps, it takes a lot more time, and it's a lot more complicated.

But by providing these raw materials, by providing these instruction manuals, we're able to accelerate that healing process just like the old tissue. But also, it's been used in cosmetics because, of course, these extracellular vesicles contain a lot of signals for young collagen, which we lose as we get older. And when you inject it or put it around the skin of the face, it's able to be absorbed by the fibroblasts that make collagen, and you're able to make young collagen again. So, it is really the entire gamut.

Sports celebrities use these products to get back onto the field a lot faster after an injury, especially with a concussion. We're seeing a lot of concussion uses in the NFL and other organizations where a player will have inflammation of the brain, and these products can immediately reduce the inflammation. But what's exciting for me right now is we are looking at space as well because, of course, we age faster in space, which is very interesting to use as a tool for studying aging, but also, we lose the ability to heal as well in space.

Dr. Jeffrey Gladden: Let me interrupt you for just a second because space is a fascinating topic I want to get to, but I want to talk to you for a minute about the use in people in general here on earth, so to speak. There's things that we do currently that can accelerate healing. There are different peptides that we can use and different regimens of peptides and combinations of peptides. There are different stem cells that can be used, everything from MSCs to even very small embryonic-like stem cells to other things. And so, I guess the question I'm asking for the sake of the audience is, where does this fit into that?

And many times, what we've found is that it's stacking some of these things together where we even get a more optimal benefit for an individual. So, how do you see this with your stem cell background? And obviously, you understand the peptide world, I'm sure, as well. So, how do you see this fitting in? Is this a standalone, or it's used in combination with other things? How do you see that playing out?

Dr. Ian White: The biological system of the human body is very complex. And so, there's never going to be a silver bullet that's going to cure everything. And so, these products, what they do is they provide, again, the instruction manuals and the raw materials to allow the body to heal itself. But in combination with peptides and other cellular products, you're really giving the body a lot more of the resources it needs. So, just to clarify, MSCs are not stem cells, but they do produce exosomes that have signals that can modulate inflammation and promote healing.

So, when physicians are interested in using products like this, it's often a good idea to make sure the patient is doing everything they can to reduce sugar because sugar is one of the worst things you can do for aging. So, cutting out sugar is essential if you're considering regenerative medicine. But also the combination of peptides in an IV therapy to prepare the body for receiving regenerative medicine because all this is cumulative. It all works together in synergy with the body. So, that's how I imagine this evolving.

Dr. Jeffrey Gladden: Okay, that's perfect. Yeah, because we tend to think that way as well. We see this as a symphony, quite honestly, that's being played here.

Dr. Ian White: Yes. I use this analogy all the time. It's the analogy I use, symphony.

Dr. Jeffrey Gladden: Exactly. It's really a symphony. Okay, well, that's helpful to understand how that fits in. So, if we want to start using this in our clinic, we can talk to you or talk to somebody at Neobiosis and then start to bring the product in and put it in conjunction with other procedures and things that we happen to be doing. Is that understanding that correctly?

Dr. Ian White: We've recently submitted an IND to the FDA for a clinical trial using purified amniotic fluid to treat the post-COVID syndrome. So, we are working with physicians to get future INDs and IRB-approved protocols through the regulatory process. So, that's where I'm at right now.

Dr. Jeffrey Gladden: I have a couple of IRB-approved protocols, so maybe I'll talk to you about offline, or maybe what we'll do is we'll hold that for some bonus material on this podcast. We'll talk through some of the trials and what people can do to access that. So, let's move to outer space. So, space does age us, and we're exposed to more radiation and more damage. Lack of gravity is not a good thing for the body, quite honestly. It takes its toll. And so, talk us through a little bit about your understanding of what happens to us in space and then what your strategy is for compensating for that.

Dr. Ian White: So, it's really quite an unexplored area with, pardon the pun, but space is unexplored, but also our physiology in relation to space is largely unexplored as well. But what we do know is that the immune system becomes dysregulated in space. And so, we lose the ability to fight infections, and we lose the ability to heal the skin as well. So, minor injuries that would otherwise heal very easily on earth can become life-threatening in space. And so, what we're hoping to do are develop therapies using perinatal tissues that teach the body how to heal like it did when it was younger, to try to counteract as a countermeasure to what's happening in space.

And we still don't fully understand what's causing it. We know there's radiation, and as you mentioned, that just by being away from earth, just the being in microgravity has a significant effect as well. But there are other things at play that we just haven't even considered at this point. It's impossible to treat something without actually knowing the cause, except we do know that the body can heal itself. It has all the resources, and then when you supplement with this young tissue, you're able to give, again, the instruction manuals, the raw materials that the body needs to go through the process that it would normally go through.

Dr. Jeffrey Gladden: So, how are you testing this out? Is this on the International Space Station, or you're working with Elon Musk on something? How are you actually checking out how this is going to work?

Dr. Ian White: So, we're collaborating with companies that are already considering space travel. So, there's a very fascinating organization called Twin Orbit. And the idea there is that they are recruiting twins and triplets as controls to send some to space and to keep some on earth and treat them differently with various countermeasures to see what effects they have on the epigenetics, the glycan age on a lot of these patients as well because it's not just the epigenetics that changes. It's the oxidation level, and it's the glycan level.

And if the audience isn't familiar with what happens with glycation, that's essentially when we consume sugars, we cross-link our proteins, especially our collagens that are in our joints and around our joints. That's why we get stiffer. And it's often irreversible. It's very hard to get rid of. And so, aging is a process of glycation, which cross-link proteins, oxidation of proteins, and also methylation of DNA. And so, we're going to be measuring all those things, hopefully in conjunction with this group and others with controls of twins in space and twins on earth.

And, in fact, with triplets, it's going to be very exciting. We would have two triplets in space, one receiving a treatment, one not receiving a treatment, and then the third triplet on earth. So, I think we're going to generate some very robust and exciting data.

Dr. Jeffrey Gladden: Yeah. I wonder how many people are signing up for that. It sounds like quite the adventure, right? Quite the family adventure.

Dr. Ian White: Yeah. Well, now that space travel is becoming more affordable, we can have short-term excursions to space at very low costs relative to the initial costs. And so, these experiments have now become possible. Before we had to work with mice and redox and other species, and it doesn't really translate to what happens with humans. And so, we really need to get humans up there.

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So, when we're talking about getting humans up there, are we talking about Richard Branson arching into space and coming back down? Is that enough, or do people need to be on the International Space Station for a week or a month?

Dr. Ian White: Yeah, we do experience accelerated aging in space, but it's not that fast. So, we would need to have extended stays in space. We're probably looking at several months to a year, but probably something in the range of six to eight months.

Dr. Jeffrey Gladden: Got it. Okay. Yeah, fascinating. I know atherosclerosis gets accelerated up there too, and I suspect that senescence is accelerated up there on some level because senescence really seems to be a driver for a lot of issues. The glycan age and glycation cross-linking are very, very important in aging. There's actually a test out there called GlycanAge, which actually isn't looking at cross-linking. It's actually looking at endogenous sugars or sugars that the body manufactures itself. It's not like table sugar, but different other ones like mannitol and mannose and things like this that actually get attached to IgG molecules in particular configurations.

And there are configurations that are consistent with more inflammation in the body or more tendency for inflammation in the body, which again, correlates to an aging process or less inflammation in the body. And so, when you're talking about measuring glycation, are you also measuring that, or are you measuring only the cross-linking of proteins, or both? What are you doing?

Dr. Ian White: Both. Because they're all indicators of age. And so, with what you described, it's a situation of the chicken and the egg. Is the inflammation due to the cross-linking or the addition of sugars onto the immunoglobulins, or is it a consequence of the aging process? So, all of these things are going to be critical as metrics for measuring changes in aging based on various interventions.

Dr. Jeffrey Gladden: So, let me ask you this, with the placental products, the fetal products, the exosomes that come from that, have you been able to measure different metrics of aging? In my world, we think of it as we're all a mosaic of ages. We have a brain age, a heart age, a glycan age, a telomeric age, and an epigenetic age. We have lots and lots and lots of ages. Have you been able to use these products and actually see which metrics of aging are impacted, so to speak?

Dr. Ian White: Yeah. So, we've been lucky with the resources that we've had so far where we've been able to look at telomeres, and we have seen very significant changes in telomere length. We're working with a company called True Age, which looks at epigenetic changes, but that's where we're starting the foundation, the Space Aging Research Foundation, to bring in donations so that we can actually do these experiments because they're very costly and very time-consuming, and we just need the resources.

Dr. Jeffrey Gladden: Got it. Yeah, very familiar with True Age. We utilize them in our practice as well. So, you're probably working with Ryan over there.

Dr. Ian White: Yeah, Ryan, yeah.

Dr. Jeffrey Gladden: Yeah, for sure. Okay, great. Yeah, we've done some things with him as well. Yeah, that's fascinating. So, you're going to be looking at methylation age. And then, what is your capacity? I'm getting the idea that everything that you're doing is coming in under an IRB-approved trial at this point in time. Is that correct? Is that how you're operating?

Dr. Ian White: Yeah, we have one submitted to the FDA currently, and we're working on our second IND currently.

Dr. Jeffrey Gladden: Okay, got it. Okay.

Dr. Ian White: We do donate tissues for special uses. There was a very significant burn case recently from a firework accident that was featured on the news, and the patient almost lost their leg, and we donated amniotic fluid to be applied topically, which accelerated her healing process. So, rather than the two to three months that was expected by her physicians, it only took six days. And so, we've written that up, and we've submitted that for publication.

Dr. Jeffrey Gladden: Yeah, that's amazing. Now, was that a standalone therapy, or were they using other regenerative- Standalone?

Dr. Ian White: That was a standalone. They originally had her on opioids for the pain because her pain was 10 out of 10, and then 30 minutes after application, her pain level went down from 10 out of 10 to 2 out of 10. So, she was in pain for two days, 10 out of 10. They couldn't change her bandages. They took her bandages off, debrided, and sprayed the product on. Thirty minutes later, the pain was down to 2 out of 10, and then by six days, the injuries were almost completely resolved.

Dr. Jeffrey Gladden: Oh, that's fantastic. There are so many applications for that, right? Between firefighters, victims of fire, armed forces, and even Jay Leno, right?

Dr. Ian White: Yeah, I heard that recently as well. And we're thinking even diabetic wounds, healing muscles, and we think that it might be able to help there. So, we're just hoping for the resources to do that research and the collaborators to come with us and do that.

Dr. Jeffrey Gladden: Great. So, let's talk a little bit about the nervous system and all this because the study that you did looking at, these were fetal mice hearts that you were inducing a lesion in at the apex of the ventricles, and then basically showing that normally the fetus could heal that without any issue with really, I guess, no residual scar. But if you took away the sympathetic nervous system, that wouldn't work. So, has that given you insight into how to augment healing for humans? Also, is there something that you're doing to manipulate the nervous system in all of this? Where do your thoughts go on that?

Dr. Ian White: Yeah, so regeneration in all forms comes down to enervation, comes down to nerves. And other scientists at various institutions have demonstrated that in many different species, starting with the axolotl where you can remove the limb, and it will regrow, but if you denervate the limb, it doesn't regrow. And that was the inspiration for some of my work. Enzo Perillo published in 2011 in science that the neonatal, so this is even more remarkable than the fetus. And so, it's not a fetus. It's actually been born, and it's a neonate. He was able to demonstrate that if you take the neonate and you resect a portion of the left ventricle that it regrows, and there's no scarring.

But what's fascinating is that it loses that ability basically after the second day of birth. So, within that first week, it progressively loses the ability. And then, once it's an adult, just like us, we have basically no ability to regenerate our heart. We regenerate maybe 1% per year for our life as a turnover, but we've lossed the ability to regenerate our heart. And the reason for that is quite clear. We have about 180 millimeters of mercury pressure in our left ventricle.

And if we have an injury in that tissue, maybe as a myocardial infarction or some other injury, and all of those cells go into cell replication to fix that injury, they would disconnect, and you would rupture, and you would die. So, the body has evolved the mechanism for not healing the heart, unlike other tissues that do heal the scar and prevent that rupture. So, we've followed on from Enzo's work and combined it with the work on the newt.

And what we discovered was, and in fact, we published at the same time as another group at Harvard who were looking at the parasympathetic system; unbeknownst to us, our articles came out at the same time. We were featured on the cover of Circulation Research that any nerve, any of this, the peripheral nerves of the heart, so the sympathetic or the parasympathetic if you take either one of those away, the heart loses the ability to regenerate. So, in those first two days, we resect the heart, we put the heart back in the animal, recover the animal, and it recovers.

If we denervate the sympathetic nerves of the heart, it loses that ability. So, what we're learning from that is that there's a communication between the nerves and the blood vessels. It's a very intimate relationship, and if you disrupt those signals, you lose the ability to heal. And so, that's why in our follow-up paper that was published just last year, we looked at the exosomes that are communicated, used to communicate between the nerves and the blood vessels, and tried to pick out some key proteins, key effectors in those exosomes.

And we then took the heart out of the mouse; we put it in a Petri dish. We supplied those specific growth factors, and we were able to induce long-term regeneration. I'm talking weeks and months of regeneration in the Petri dish, keeping the heart beating, which is usually very hard to do, and then induce actual regeneration in the heart that was featured on the cover of Stem Cells and Regenerative Medicine last year.

Dr. Jeffrey Gladden: Fascinating. Yeah, that's really fascinating. So, really, it's a protein fraction. This was a protein fraction or a number of proteins. This wasn't micro-RNAs; this wasn't anything else. It was just proteins per se.

Dr. Ian White: In this case, it was just a selection, a combination of proteins.

Dr. Jeffrey Gladden: What I'm thinking about is that in humans, let's say a human has had a heart attack and they have scar tissue. One of the issues that come up, and my background's cardiology, I think, as you probably have learned, but one of the issues is that when the heart becomes scarred, it can set up arrhythmias, right? You can get aberrant circuits, electrical circuits that can become life-threatening. And one of the things that you worry about this in the heart; you also worry about it in the brain. Let's say there's brain damage done, and because of short-circuiting up there, you now have seizure activity.

If you come in with regenerative technologies, part of the issue has been you can stimulate new cells, potentially, but sometimes that can lead to a higher incidence of arrhythmias that could ultimately be a problem or a higher incidence of seizures in the brain in that context of damage and repair. Have you done any studies in either of those areas or do you have any insights around that?

Or do you think that the fetal exosomes have a way to not only induce tissues to heal but have the ability to actually resorb scar or actually exchange good for bad, so to speak, or anything like that?

Dr. Ian White: I have a lot to say about that. First of all, we do make an aesthetic version of our products, which is commercially available. And so, aesthetic physicians are using it for scar reduction. We've seen dramatic effects on keloids, and we've seen dramatic effects on long-term scars from accidents and from surgeries. And so, we do believe that there is an ability to reabsorb some of these scars. But what's really interesting is you mentioned arrhythmias and issues with denervation. When you have a heart transplant, of course, you've completely denervated the heart.

Dr. Jeffrey Gladden: Correct.

Dr. Ian White: And there can be a lot of long-term effects, especially when we're talking about cardiac failure, long-term after a transplant. Before I left Academia, and I left Academia now I think, four or five years ago, and it was really because of a lack of grants. It was very, very hard to get this work funded. And so, I moved into the private sector to generate revenue so that I could do these experiments. But the last experiment that I did before I left Academia, which we hoped to move back into with the Space Aging Research Institute, is that I took these hearts out of the mice, which now, of course, were denervated.

And the idea of the work that I just described, it was we were providing certain proteins that I thought could supplement the signals that the heart was receiving from the nerve to keep the regeneration going. But what I really want to do is see if I can regrow nerves because I know how critical nerves are, and it's better for the body to do it all themselves.

And so, I created the system, which was quite wonderful to see, but I had these little rings, and I put them in a Petri dish, I put the heart inside, and I had scraped lines in the Petri dish, tracks, tiny, tiny. You can't even see them, but with a microscope, you can see them with a very special tool.

Dr. Jeffrey Gladden: Why did you do that?

Dr. Ian White: Yeah, because I wanted to see whether I could re-enervate the heart with DRG-derived nerve, so dorsal root ganglia nerves from dissected perinatal mice. So, I would take the spine out, I would dissect out those nerve bundles, and I would seed them into the plate, and then I would put the growth factors in the middle, and it would be like a chemoattractant. So, it attracts the nerves. Once they get in there, they didn't know what to do because there was a signal everywhere. But when they found the tracks, they got into the tracks. And what's fascinating is they rolled over the top of the hearts, essentially re-enervating the heart.

I was unable to do any functional tests. Are they actually signaling with the myocardium? But I could see because I was able to stain the nerves in a different color than the hearts. I could see the colored nerves tracking over the hearts for the first time, which was very, very exciting.

Dr. Jeffrey Gladden: Fascinating. Yeah. That's fascinating. So, that brings up a couple of questions. One is: what about peripheral neuropathy? There's so much peripheral neuropathy out there, and then you've got things like macular degeneration and hearing loss and things like this. Do these have any impact on those conditions?

Dr. Ian White: Well, as a consequence of COVID, I had bilateral tinnitus. It's not hearing loss, but it is a medical condition. That's a major issue for a lot of people. And I had it for several months, and eventually, I went to a physician, and I did get an infusion of purified amniotic fluid, which over time, maybe two weeks, cleared the tinnitus. I also had a shoulder injury, and I received an injection, which cleared up the shoulder injury as well. So, as far as peripheral neuropathy, I'm a firm believer that if we can find a protocol where we can introduce the product as a trophic agent into the periphery, that we could attract new nerve growth into that tissue.

Dr. Jeffrey Gladden: So, what would that look like? Would that be subcutaneous injections or intramuscular injections, or is it IV therapy?

Dr. Ian White: I would imagine intramuscular.

Dr. Jeffrey Gladden: Intramuscular.

Dr. Ian White: Yeah. I think maybe, coming from both sides, we're developing a product for gastrointestinal issues, so Crohn's disease. And so, the idea is that we come at both angles. We come from an intraperitoneal angle that would be an injection, but also a rectal direction as well with a suppository so that we can affect the intestine from both sides. I would imagine something similar. You go with an IV injection so that it's throughout the periphery, so it's able to get through into the nerve through the blood vessels and the capillaries, but also as a direct injection around the muscular tissue.

Dr. Jeffrey Gladden: So, another thing that comes to mind is things like spinal cord injuries. There are lots of animal models for spinal cord injuries, of course. And have you done any work with the exosomes in those models to see if you can regenerate the spinal cord and things like that?

Dr. Ian White: We have not had the luxury of doing any of those studies, but I know there are some very talented physicians out there, like Doug Spiel, who has a lot of experience injecting exosomes and seeing remarkable recoveries, considering we're talking about paraplegics. Some of the gains they're experiencing are just miraculous, but we have not ventured into that space yet.